Gene:
CYP2A6
cytochrome P450, family 2, subfamily A, polypeptide 6

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This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Related Drugs?

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page on the appropriate tab.

Links in the "Drugs" column lead to PharmGKB Drug Pages.

Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available CA VA *1A N/A N/A N/A
No VIP available No VIP available VA *2 N/A N/A N/A
No VIP available No VIP available VA *4A N/A N/A N/A
No VIP available No VIP available VA *4B N/A N/A N/A
No VIP available No VIP available VA *4C N/A N/A N/A
No VIP available No VIP available VA *4E N/A N/A N/A
No VIP available No VIP available VA *7 N/A N/A N/A
No VIP available No VIP available VA *9 N/A N/A N/A
No VIP available No VIP available VA *9A N/A N/A N/A
No VIP available No VIP available VA *10 N/A N/A N/A
No VIP available No VIP available VA *11 N/A N/A N/A
No VIP available No VIP available VA *12A N/A N/A N/A
No VIP available CA VA *15 N/A N/A N/A
No VIP available No VIP available VA *16 N/A N/A N/A
No VIP available No VIP available VA *17 N/A N/A N/A
No VIP available No VIP available VA *18A N/A N/A N/A
No VIP available No VIP available VA *19 N/A N/A N/A
No VIP available No VIP available VA *1B1 N/A N/A N/A
No VIP available No VIP available VA *1X2A N/A N/A N/A
No VIP available No VIP available VA *1X2B N/A N/A N/A
No VIP available No VIP available VA *20 N/A N/A N/A
No VIP available CA VA *21 N/A N/A N/A
No VIP available CA VA *22 N/A N/A N/A
No VIP available No VIP available VA *23 N/A N/A N/A
No VIP available No VIP available VA *24A N/A N/A N/A
No VIP available No VIP available VA *26 N/A N/A N/A
No VIP available No VIP available VA *27 N/A N/A N/A
No VIP available No VIP available VA *28A N/A N/A N/A
No VIP available No VIP available VA *35A N/A N/A N/A
No VIP available No Clinical Annotations available VA
CYP2A6 poor metabolizer genotype N/A N/A N/A
No VIP available No Clinical Annotations available VA
rs111033610 13621159A>G, 41352941A>G, 670T>C, 8412T>C, Ser224Pro
A > G
Missense
Ser224Pro
No VIP available No Clinical Annotations available VA
rs12460590 12011T>G, 1283T>G, 13649865A>C, 1436T>G, 41381647A>C, Val428Gly, Val479Gly
A > C
Missense
Val479Gly
No VIP available No Clinical Annotations available VA
rs140471703 13621035C>T, 41352817C>T, 794G>A, 8536G>A, Arg265Gln
C > T
Missense
Arg265Gln
No VIP available No Clinical Annotations available VA
rs143690364 13624082C>T, 202G>A, 41355864C>T, 5489G>A, Val68Met
C > T
Missense
Val68Met
rs1801272 13622751A>T, 41354533A>T, 479T>A, 6820T>A, CYP2A6:50707A>T, Leu160His
A > T
Missense
Leu160His
rs28399433 -48T>G, 13624597A>C, 41356379A>C, 4974T>G, CYP2A6:52553A>G
A > C
5' Flanking
No VIP available No Clinical Annotations available VA
rs28399434 13624537C>T, 13G>A, 41356319C>T, 5034G>A, Gly5Arg
C > T
Missense
Gly5Arg
No VIP available No Clinical Annotations available VA
rs28399435 13624464C>T, 41356246C>T, 5107G>A, 86G>A, Ser29Asn
C > T
Missense
Ser29Asn
VIP No Clinical Annotations available No Variant Annotations available
rs28399444 13622408delT, 13622408delTinsTT, 41354190delT, 41354190delTinsTT, 588delA, 588delAinsAA, 7163delA, 7163delAinsAA, CYP2A6:50364-50365delTT, Lys196=fs, Lys196delinsLysArgfs
A > -
A > TT
Frameshift
Glu197Ser
Glu197Arg
rs28399454 10086G>A, 1093G>A, 13619485C>T, 41351267C>T, CYP2A6:47441C>T, Val365Met
C > T
Missense
Val365Met
rs28399468 11621G>T, 13617950C>A, 1454G>T, 41349732C>A, Arg485Leu, CYP2A6:45906C>A
C > A
Missense
Arg485Leu
No VIP available No Clinical Annotations available VA
rs376817657
C > T
Missense
Glu390Lys
No VIP available No Clinical Annotations available VA
rs4986891 13622847C>A, 13622847C>T, 383G>A, 383G>T, 41354629C>A, 41354629C>T, 6724G>A, 6724G>T, Arg128Gln, Arg128Leu
C > T
C > A
Missense
Arg128Gln
Arg128Leu
rs5031016 11579T>C, 13617992A>G, 1412T>C, 41349774A>G, CYP2A6:45948A>G, Ile471Thr
A > G
Not Available
Ile471Thr
No VIP available No Clinical Annotations available VA
rs5031017 11603G>T, 13617968C>A, 1436G>T, 41349750C>A, Gly479Val
C > A
Not Available
Gly479Val
No VIP available No Clinical Annotations available VA
rs56256500 13622389G>A, 13622389G>T, 41354171G>A, 41354171G>T, 607C>A, 607C>T, 7182C>A, 7182C>T, Arg203Cys, Arg203Ser, CYP2A6*23, CYP2A6:2161C>T, CYP2A6:R203C
G > T
G > A
Missense
Arg203Cys
Arg203Ser
No VIP available No Clinical Annotations available VA
rs60711313
A > G
Not Available
No VIP available No Clinical Annotations available VA
rs8192720 13624528G>A, 22C>T, 41356310G>A, 5043C>T, Leu8=
G > A
Synonymous
Leu8Leu
No VIP available No Clinical Annotations available VA
rs8192725 13622930A>G, 344-44T>C, 41354712A>G, 6641T>C
A > G
Intronic
rs8192726 13622714C>A, 41354496C>A, 493+23G>T, 6857G>T
C > A
Intronic
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138

Overview

Alternate Names:  None
Alternate Symbols:  CPA6; CYP2A
PharmGKB Accession Id: PA121

Details

Cytogenetic Location: chr19 : q13.2 - q13.2
GP mRNA Boundary: chr19 : 41349443 - 41356352
GP Gene Boundary: chr19 : 41346443 - 41366352
Strand: minus
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for potential regulatory regions.

CYP2A6 expression and function
Human cytochrome P450 (CYP-450), family 2, subfamily A, polypeptide 6 (CYP2A6) is a monooxygenase enzyme that metabolizes xenobiotic compounds and activates toxins [Articles:19702528, 12171978, 11692077].

CYP2A6 represents approximately 4% of the total CYP-450 enzyme protein content of adult liver microsomes [Article:8035341]. CYP2A6 is also expressed in the lung, trachea, nasal mucosa, and sex organs such as breast [Articles:12171978, 16988941]. CYP2A6 enzyme activity is determined by measuring coumarin 7-hydroxylation [Articles:2334398, 2322567, 10923861, 11038160]. CYP2A6 expression, enzyme function and induction vary considerably between individuals [Articles:2322567, 2334398, 8035341, 12171978, 10923861, 11038160, 9353388, 12919726], and an individual's CYP2A6 enzyme expression and activity may depend on a combination of environmental factors (such as xenobiotic compounds) and genetic factors (including polymorphic variants) [Articles:19702528, 18666753]. Modeling human CYP2A6 activity in rodents has limited utility due to species-specific CYP2A6 ortholog expression patterns and activity profiles - for example, in rats little or no coumarin is 7-hydroxylated, and a CYP2B enzyme metabolizes nicotine to cotinine [Articles:15364544, 11336973, 11911841, 11053537, 12162851, 1680658]. The crystal structure of human CYP2A6 bound to coumarin was originally described in 2005, revealing a smaller active site than other CYP2 enzymes C8 and C9, composed of a hydrophobic cavity ideal for the oxidation of small planar compounds such as coumarin [Article:16086027]. Several structures with the enzyme in complex with different substrates and/or mechanism based inhibitors have been described since (the Protein Data Bank; [Article:19702528]).

The CYP2A6 gene
CYP2A6 was the first gene of the human CYP2A cytochrome subfamily to be cloned and mapped, and was previously known as CYP2A3 (a name now used for the rat ortholog) [Articles:3856261, 3000277, 7678494, 2726448, 2748347, 11692077]. The CYP2A6 gene sits within a cluster of CYP2 genes on chromosome 19 q13.2, thought to have arisen through duplication events, and shares extensive homology with subfamily members CYP2A7 and CYP2A13 [Articles:11692077, 12171978, 19702528]. The gene is composed of 9 exons spanning around 6kb, encoding a protein of 494 amino acids around 49 kDa in size [Articles:2334398, 19702528].

Genetic variation of CYP2A6
The CYP2A6 gene is highly polymorphic, with over 35 different CYP2A6 alleles described thus far, with additional subgroups (see the Human Cytpchrome P450 Allele Nomeclature Committee website) [Article:11692077]. Star (*) nomenclature is used to describe different CYP2A6 alleles, with the "wildtype" reference allele defined as *1 [Article:2322567]. Genetic variants in the CYP2A6 locus include alleles with single nucleotide polymorphisms (SNPs) (for example *2, *9), whole and partial gene deletions (alleles *4A-H), a gene hybrid with CYP2A7 (for example *12) and gene conversions (for example *1B) http://www.cypalleles.ki.se/cyp2a6.htm. The complex genetic architecture of CYP2A6 coupled with its significant homology with other CYP2A genes makes genotyping challenging, particularly when using SNP based arrays [Articles:11692077, 11805739]. Since single amplifications often cannot discriminate between the different CYP2A genes, special amplification and sequencing techniques have been developed for CYP2A6 genotyping, revealing errors in allele characterization in older studies [Articles:10544257, 10999944, 11207029, 11692077, 11805739].

CYP2A6 genotypes are often classified into predicted phenotype groups, describing the effect on enzyme activity, for example 'poor' metabolizer (no active CYP2A6 alleles, homozygous for inactive alleles), 'slow' (one inactive or two decreased activity alleles), 'intermediate' metabolizer (heterozygous with one decreased activity allele and one active allele), 'normal'/ 'extensive' (2 active alleles), or 'ultrarapid'/ 'fast' (>2 active alleles) [Articles:11805739, 21149643, 17112802, 17035386, 15475735]. Studies may also compare reduced (one or more inactive or decreased activity allele) to normal (two active alleles) metabolizers [Articles:20336063, 21747048]. These categories often overlap or differ between studies. In addition, the same polymorphism can have a different effect on the metabolism of different substrates. For example, CYP2A6*18 activity against nicotine is similar to wildtype enzyme, but is reduced for coumarin and tegafur metabolism, in vitro [Article:15900015], and conversely *17 activity against coumarin is similar to wildtype but significantly reduced for nicotine metabolism [Article:18216723]. People with CYP2A6*12 are slow metabolizers of letrozole, but intermediate metabolizers of nicotine [Article:21975350]. Therefore the effect of CYP2A6 polymorphisms on metabolism should be investigated and interpreted in the context of individual substrates [Article:11805739].

Genetic variants in the CYP2A6 gene can result in reduced expression by affecting transcriptional or translational processes [Article:19702528]. For example, a SNP within the TATA box of the CYP2A6 promoter (allele *9) reduces gene transcription [Article:11394901]. The CYP2A6*1B allele differs from *1A by a CYP2A7 gene conversion in the 3' untranslated region (UTR), and correlates with increased CYP2A6 protein expression and activity, likely through increased mRNA stability [Article:16378601]. Individuals homozygous for the *4 gene deletion allele lack detectable CYP2A6 mRNA expression and enzyme activity [Articles:12844137, 11779172].

Wide variation in the frequency of CYP2A6 alleles across ancestral groups is observed. For example, the frequency of CYP2A6*4 alleles ranges from 0-4% in White, 0-2% in Black, 5-15% in Chinese and 17-24% in Japanese populations [Articles:16402128, 15475735, 17130279, 16452582, 10544257, 16952495, 17220563, 15660270, 16891249, 16272956, 11779172, 21205058]. The frequency of the CYP2A6*9 allele ranges from around 5-8% in White, 6-9% in Black, up to 16% in Chinese and 19-21% in Japanese populations [Articles:16402128, 15475735, 17130279, 16452582, 16952495, 17220563, 15660270, 21205058, 11394901, 21521021]. Other alleles are found predominantly in one ethnic group, for example CYP2A6*17 (defined by the variant rs28399454, V365M) is found at a frequency of around 10% in Black individuals, but not identified in White, Korean or Japanese individuals, whereas *7 is found in Asian subjects at a frequency of around 10%, but not White or Black individuals [Articles:16952495, 15592323].

CYP2A6 as an important pharmacogene
Around 3% of the drugs metabolized by CYP-450 enzymes involve CYP2A6 (reviewed in [Article:19702528]). In the sections below, we describe known pharmacogenetic associations between CYP2A6 variants and drugs, further detailed in Table 1 and 2. When examining these associations, it should be taken into account that environmental factors, such as compounds found in food, cigarettes, hormones or therapeutic drugs, can affect CYP2A6 expression, which can therefore influence drug pharmacokinetics and responses [Articles:18666753, 19702528]. Xenobiotics in our diet, such as the flavonoid biochanin A (found in plants), can upregulate CYP2A6 expression in vitro [Article:17340576]. The hormone estrodiol induces CYP2A6 expression via direct binding of the transcription factor ERalpha to a promoter element upstream of the CYP2A6 gene in vitro [Article:17646279], and may explain why CYP2A6 activity is higher in women than men, and higher in women taking oral contraceptives compared to those not taking them [Article:16678549]. The anti-inflammatory drug dexamethasone, via the Glucorticoid Receptor, induces CYP2A6 transcription in human hepatocytes in vitro, by augmentating Hepatocyte Nuclear Factor 4, alpha [Article:17978169], likely explaining the enhanced CYP2A6 activity seen with dexamethasone treatment [Article:10923861]. The anticonvulsant phenobarbital also enhances CYP2A6 enzyme activity in vitro [Articles:10923861, 11038160]. Inhibitors of CYP2A6 enzyme activity include the antibacterial and antifungal agents isoniazid and ketoconazole [Articles:19702528, 18666753, 9143352], and traditional Chinese medicine [Article:20723593]. Identifying environmental and therapeutic compounds that regulate CYP2A6 activity, as well as genetic polymorphisms, may be important for optimal therapeutic efficacy and avoiding adverse drug reactions [Article:19702528].

Another factor is CYP2A6 genotyping. Most drug-response studies group CYP2A6 genotypes into predicted enzyme activity phenotype groups and assess associations compared to *1 homozygotes, because there are many variant alleles found at low frequencies. Some studies use the * allele name without screening for all variants in the allele as defined by the CYP-450 allele nomenclature committee. Therefore individuals may have variants not screened for, or not have all variants conferring an allele. As described previously, the complexity of CYP2A6 in terms of polymorphisms and homology to other genes means that genotyping errors can occur; as knowledge about the gene and its variants increases, genotyping assays should improve, as was seen with CYP2D6. We therefore provide genotyping details in Table 2.

CYP2A6 polymorphisms, nicotine metabolism and cigarette smoking behavior
The vast majority of published work describing the phenotypic effects of CYP2A6 polymorphisms on enzyme activity has been carried out using nicotine as a substrate (Table 1). These studies have revealed important mechanistic consequences of CYP2A6 alleles on nicotine metabolic inactivation and related smoking behaviors, and by characterizing the relationship between CYP2A6) genotypes and enzyme phenotypes provide a starting point for how these polymorphisms may contribute to the observed inter-individual variability in the PK of other CYP2A6 substrates.

Nicotine is extensively metabolized and has a short plasma half-life of around 2 hours [Article:15734728]. Approximately 80% of nicotine is inactivated in vivo into cotinine in a two-step process (see the PharmGKB Nicotine Pathway, Pharmacokinetics) [Articles:22103613, 19184645, 15734728]. CYP2A6 has a predominant role in the oxidation of nicotine to form a nicotine iminium ion, which is subsequently converted to cotinine (COT) by aldehyde oxidase (AOX) [Articles:10350185, 8937855, 19184645, 15734728]. The majority of COT is metabolized to trans-3'-hydroxy-cotinine (3HC) in a reaction exclusively mediated by CYP2A6 [Articles:8937855, 16359169, 8627511]. The ratio of 3HC/COT is often used as a phenotypic marker of CYP2A6 metabolic activity among smokers due to the long half-life of COT and the in vivo formation dependent kinetics of 3HC [Articles:15229465, 19184645, 15734728].

Nicotine metabolism is subject to large inter-individual variation [Articles:11180041, 8937855], and seven CYP2A6 polymorphisms explain most of the inter-individual variation in nicotine to COT metabolism, in European-Americans [Article:21597399]. Nicotine dependence and cigarette smoking behaviors are closely related to the pharmacokinetics of nicotine, for example cigarette craving negatively correlates with blood levels of nicotine [Article:10899369]. Polymorphisms in CYP2A6 which effect nicotine metabolism have therefore been associated with smoking behaviors (see Table 1) [Articles:10999944, 15564629, 16272956], and are an important consideration in the efficacy of nicotine replacement based smoking cessation treatments [Articles:19184652, 19793020, 19251795]. For example, slow metabolizers (as determined by CYP2A6*2, *4, *9 and *12 alleles), are less likely to be smokers, smoke fewer cigarettes per day, take smaller puff volumes, have lower levels of dependence, are more able to quit, and benefit more from regular and extended nicotine patch replacement therapy compared to normal metabolizers [Articles:15475735, 21212060, 20336063, 16765148, 16402128, 15735609, 14981342, 10999944]. Evidence suggests that CYP2A6 polymorphisms that confer decreased CYP2A6 enzyme activity result in reduced or deficient nicotine metabolism [Articles:10999944, 11180041, 15592323], and this is thought to lead to lower cigarette consumption [Article:17130279]. On the other hand, alleles conferring increased enzyme activity (e.g. duplication or *1B) result in enhanced rates of nicotine metabolism and thus are associated with increased cigarette consumption and depth of inhalation [Articles:10999944, 11180041, 15940289, 11805739, 17130279]. Inhibition of CYP2A6 has therefore been investigated as a smoking cessation treatment [Article:11805739]. In Chronic Obstructive Pulmonary Disease (COPD) patients, CYP2A6 is associated with number of cigarettes smoked per day (cpd) and age of initiation of smoking [Article:21685187]. As smoking cessation is important in preventing COPD progression, identifying patients with risk genotypes for particular smoking behaviors may aid in treatments to help patients reduce smoking [Article:21685187].

The CYP2A6 and CYP2B6 genes are closely localized within the CYP2 cluster on chromosome 19, suggesting potential linkage disequilibrium [Articles:11692077, 16041240]. Human liver CYP2A6 and CYP2B6 enzyme expression is correlated and they share some inducers and substrates (as discussed in [Article:20307138]). Examining the contribution of CYP2B6 genotype on a potentially common substrate (i.e. nicotine, efavirenz) should take into consideration CYP2A6 status, and vice-versa. For example, the association seen between CYP2B6 and nicotine C-oxidation in vitro is abrogated after controlling for CYP2A6 protein levels [Article:20307138].

Table 1: CYP2A6 polymorphisms and nicotine associations

CYP2A6 allele Effect on nicotine metabolism Association with smoking behavior and response to nicotine replacement therapy
CYP2A6*1B Greater nicotine clearance in individuals with alleles *1B1-15 compared to wildtype homozygotes *1A/ *1A [Article:17522595] Genotype *1B/*1B genotype is associated with increased cpd compared to *1A/*1A, but not significantly associated with smoking status or ability to quit [Article:15940289]. Increased likelihood of being a smoker [Article:14981342]
CYP2A6*1X2 1X2A: Higher levels of exhaled carbon monoxide compared to *1/*2, *2/*2, *1/*4, and higher cotinine plasma levels compared to *1/*1 or *1/*2, *2/*2, *1/*4 [Article:10999944]#. 1X2B: increased nicotine metabolism compared to *1/*1 (ns), measured by cotinine/nicotine ratios [Article:17267622] 1X2A: Greater smoking intensity (CO per cpd, COT per cpd) compared to *1/*1 or *1/*2, *2/*2, *1/*4 [Article:10999944]#
CYP2A6*2 Longer half-life of nicotine and cotinine, and reduced nicotine metabolism [Article:16952495], [Article:17112802]# In adolescents, increased risk of becoming nicotine dependent, but slower progression and lower cigarette consumption once dependent [Articles:15564629, 17130279]#. Fewer compared to normal nicotine metabolizers [Articles:15475735, 10999944, 15564629]# [Article:20418888]. Fewer cpd and lower FTND [Article:21747048]#. Increased ability to quit smoking (ns) [Article:19279561]#. Better response to extended transdermal nicotine replacement therapy [Article:20336063]#
CYP2A6*4 Reduced nicotine metabolism and altered metabolite profile [Articles:10448083, 15265511, 17220563, 12445030, 16952495] In adolescents, increased risk of becoming nicotine dependent, but slower progression and lower cigarette consumption once dependent [Articles:15564629, 17130279]#. Reduced risk of being a smoker [Article:14981342], reduced cpd [Articles:21205058, 15308589, 10999944, 15475735, 10999944, 15564629]#, [Articles:12223434, 12832682], and increased ability to quit smoking (ns) [Article:19279561]#. Though in other studies, not significantly associated with smoker status, age started smoking, cpd or ability to quit [Articles:12749606, 11241319, 11725533, 15940289]. Fewer cpd and lower FTND [Article:21747048]#. Better response to extended transdermal nicotine replacement therapy [Article:20336063]#
CYP2A6*7 Reduced nicotine metabolism [Articles:16952495, 17220563, 11779172, 12445030, 15900015]. T1412C SNP (rs5031016): Reduced nicotine metabolism [Article:11237731] Fewer cpd, later onset of smoking, shorter smoking duration, but reduced likelihood of smoking cessation [Articles:21205058, 15308589]#
CYP2A6*9 Reduced nicotine metabolism and clearance [Articles:16952495, 12844137], [Article:17112802]# Fewer cpd [Articles:15475735, 21205058, 21205058, 21747048]#, lower FTND [Article:21747048]#, later onset of smoking, shorter smoking duration, but reduced likelihood of smoking cessation [Article:21205058]#. Better response to extended transdermal nicotine replacement therapy [Article:20336063]#
CYP2A6*10 Reduced nicotine metabolism [Articles:16952495, 11779172, 12445030] Reduced cpd [Articles:21205058, 15308589]#
CYP2A6*12 *1/ *12 genotype is associated with normal nicotine metabolism, but *9/*12 is associated with reduced metabolism [Article:17112802]# Fewer cpd [Articles:15475735, 21747048]#, lower FTND [Article:21747048]#. Better response to extended transdermal nicotine replacement therapy [Article:20336063]#
CYP2A6*17 Reduced nicotine metabolism and clearance [Articles:15592323, 16952495] Increased ability to quit smoking (ns) [Article:19279561]#
CYP2A6*35 Reduced nicotine metabolism [Article:19365400] Increased ability to quit smoking (ns) [Article:19279561]#

Table Key:
#=studies that analyze combined genotypes, or analyze this allele combined with other alleles in a phenotype category, e.g. reduced activity alleles.
cpd = Cigarettes per day
FTND: Fagerstrom Test for Nicotine Dependence
ns = not significant

CYP2A6 and caffeine
CYP2A6 plays a part in caffeine metabolism, as the major enzyme required to convert paraxanthine (1,7-dimethylxanthine, 17X) into 1,7-dimethyluric acid (17U) via 8-hydroxylation [Article:15980104] (see the PharmGKB Caffeine Pathway, Pharmacokinetics). Human liver microsomes (HLMs) with the CYP2A6 genotype *1/*4, *4/*9 or *1/*9 display significantly reduced 8-hydroxylase enzyme activity against paraxanthine, and *4/*4 samples have undetectable activity, compared to *1/*1 wildtype samples [Article:15980104]. Kinetic assays with CYP2A6 protein fractions demonstrate *7, *10 and *11 alleles confer reduced 8-hydroxylation activity [Article:15980104]. Amongst non-smokers, CYP2A6 intermediate and poor metabolizer genotypes have lower paraxanthine metabolism compared to 'normal metabolizers' (Table 2) [Article:20155256]. In addition to CYP2A6 genotype, cigarette smoking significantly reduces paraxanthine metabolism (17U/ 17X ratio in urine), and may be due to competition between paraxanthine and nicotine [Article:20155256], or via the impact of current smoking status which decreases CYP2A6 activity [Article:11197315]. Therefore, both smoking and CYP2A6 genotype influences CYP2A6 8-hydroxylation activity against caffeine, contributing to the inter-individual variability observed [Article:20155256]. By measuring 17U/17X ratios, caffeine has been proposed as a potentially more suitable substrate for studying the functional effects of CYP2A6 polymorphisms in vivo than nicotine or coumarin [Article:15980104], although further characterization of the timing, dose and association with genotype is required.

CYP2A6 and cancer therapeutics
CYP2A6 has a key role in the metabolism of several drugs involved in cancer treatment. Associations between CYP2A6 genotype, rate of drug metabolism and treatment efficacy are detailed below and in Table 2. CYP2A6 genotype is also associated with risk of developing cancer [Article:19823875], see the 'CYP2A6 and toxicology' section below.

Tegafur
The prodrug tegafur is initially metabolized into 5' hydroxytegafur, which rapidly breaks down into 5-fluorouracil (5 FU) and is further processed into active metabolites with anti-cancer properties (see the PharmGKB Fluoropyrimidine Pathway, Pharmacokinetics and the Fluoropyrimidine (PD) Pathway) [Article:20601926]. Although several CYP-450 proteins have a role in the biotransformation of tegafur into 5 FU, including CYP1A2, CYP2C8, CYP2C9 and CYP1A1, CYP2A6 has a principle role [Articles:11095583, 11106261]. In human liver microsomes, 5 FU formation correlates significantly with coumarin 7-hydroxylation and with CYP2A6 expression [Articles:11095583, 11106261]. Selective inhibition of CYP2A6 activity drastically attenuates 5 FU formation [Articles:11095583, 11106261, 15618749]. Genetic variants that affect CYP2A6 expression and function are associated with altered metabolism of tegafur and clinical outcome. The CYP2A6*4 gene deletion allele significantly reduces CYP2A6 mRNA and protein levels in human liver samples, which correlates with a reduced rate of tegafur metabolism in vitro [Article:21521021] and in vivo the *4C and *11 alleles confer poor tegafur metabolism [Article:12042667]. Conversely, a novel *1B allele is associated with increased CYP2A6 protein expression and significantly higher rates of 5 FU formation in human liver microsome (HLM) samples, compared to samples without the haplotype (Table 2) [Article:21521021].

To optimize 5 FU efficacy and reduce the toxicity of side effects, tegafur is combined with 5-chloro-2,4-dihydroxypyridine (CDHP) (inhibits degradation of 5 FU) and potassium oxonate (prevents gastrointestinal toxicity), to form the oral drug S-1 [Article:8862723]. In cancer patients treated with S-1, genotypes containing CYP2A6*4, *7, *9 and *10 alleles are associated with reduced metabolism of tegafur compared to wildtype CYP2A6, in cancer patients treated with S-1 (Table 2) [Articles:20596643, 21326246, 18212800, 18380793]. Those with two variant CYP2A6 alleles (*4/*4, *4/*7 or *7/*7) have significantly lower oral clearance of tegafur compared to wildtype homozygotes [Article:18380793]. Those without the *4C allele have significantly lower tegafur and higher 5 FU plasma concentrations compared to those with the allele [Article:18212800]. However, other studies find no association between 5 FU plasma concentrations and CYP2A6 genotype, with 5 FU levels correlating instead with CDHP concentrations [Articles:20596643, 18380793].

Examining clinical outcome rather than 5FU blood concentrations suggests that the influence of CYP2A6 genetic variants on tegafur's pharmacokinetics (PK) may have clinical importance. S-1 and cisplatin-treated patients with two CYP2A6 variant alleles *4, *7, *9, *10, or the *1/*4 genotype, have significantly lower treatment response rates, increased risk of disease progression and increased likelihood of reduced overall survival time than other genotypes [Article:21364592]. Similar findings are observed in a study treating patients with S-1 and docetaxel; those with two CYP2A6 variant alleles (*4, *7, *9 or *10) display a 5-fold increased risk of cancer progression [Article:19604090]. However, in this study overall survival is not significantly associated with genotype, possibly due to switching to alternative chemotherapy upon tumor progression (as discussed in [Article:19604090]). Whether the association between CYP2A6 variants and reduced tegafur treatment efficacy is due to reduced formation of 5 FU cannot be concluded due to a lack of parallel PK studies [Articles:19604090, 21364592]. Significantly higher 5 FU plasma concentrations are found in responders to S-1 treatment compared to non-responders, and although no direct significant association between CYP2A6 genotype and treatment response is found in this study, those with one variant CYP2A6 allele have significantly higher 5 FU and significantly lower tegafur plasma concentrations compared to those with two variant alleles [Article:19921195].

Combining these results suggests that a poor-metabolizer CYP2A6 genotype is associated with reduced tegafur metabolism to 5 FU and thus reduced anti-tumor efficacy [Articles:19921195, 21364592, 19604090]. CYP2A6 genotype does not seem to influence treatment side effects, such as hematological toxicity [Articles:19921195, 21364592, 19604090]. Although these associations remain to be investigated further in studies that combine PK and clinical outcome in large sample sizes, current findings suggest that CYP2A6 genotype may be a useful addition to tegafur dosing guidelines to increase treatment efficacy.

Letrozole
Letrozole is a daily oral treatment for estrogen- or progesterone-receptor positive breast cancer in postmenopausal women, and suppresses estrogen synthesis by inhibiting the aromatase enzyme [Article:12802030]. Letrozole plasma levels, elimination rate and clearance show high inter-individual variation, and may contribute to adverse drug reactions or differences in treatment efficacy [Articles:21975350, 21494765]. CYP2A6 has a major role in the breakdown of letrozole into its inactive carbinol metabolite [Articles:19845430, 19198839] (see also the letrozole (Femara) tablet drug label, Novartis Pharmaceuticals Corporation ). In vitro, HLM samples from individuals with CYP2A6 genotypes *1/*4, *4/*4, *4/*9 and *1/*7 have significantly reduced letrozole oxidation compared to *1/*1 wildtype samples [Article:19845430]. Clinical studies in healthy postmenopausal women show that clearance of letrozole is lower in individuals with a CYP2A6 variant allele (*4, *9, *7) compared to *1 (see Table 2) [Article:21494765]. In a cohort of breast cancer patients, CYP2A6 genotype is significantly related to letrozole plasma concentrations, explaining around 26% of the inter-individual variability observed [Article:21975350]. CYP2A6 genotypes defined as conferring slow and intermediate metabolism are associated with significantly higher plasma concentrations of letrozole compared to the wildtype genotype (*1/*1) [Article:21975350] (see Table 2). The ability to predict letrozole plasma concentration using CYP2A6 genotype is further improved by integrating age and body mass index (BMI) variables, explaining 32.3% of inter-individual variation [Article:21975350]. As both CYP2A6 genotype and body weight influence letrozole levels, together they may explain some of the differences in letrozole PK parameters seen between Asian and Caucasian individuals [Article:21494765]. Overall, these studies provide evidence to suggest that CYP2A6 genotyping, along with BMI and age, could be useful for predicting exposure to letrozole in patients [Articles:21975350, 21494765, 19845430].

CYP2A6 and treatment of infectious diseases
CYP2A6 has a role in the metabolism of several drugs involved in the treatment of infectious diseases, as outlined below and detailed in Table 2. When treating individuals for co-infections, such as HIV and malaria infection, the added complication of drug-drug interactions and induction or inhibition of CYP-450 enzymes by these drugs should be considered when assessing the pharmacogenetic effect [Articles:19926036, 21625331].

Efavirenz
Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that suppresses viral replication and is used as a component in highly active anti-retroviral therapy (HAART) regimens for HIV-infected patients [Article:20001610]. High inter-individual variability of EFV plasma levels exists between patients receiving a fixed daily dose, and this has clinical implications; higher EFV plasma levels are associated with increased risk of central nervous system (CNS) side effects, whereas significantly lower levels are associated with failure to suppress viral replication [Articles:15167626, 11192870, 12545140, 19659438]. Demographic factors sex, age, body mass index, or co-medication, cannot explain this variability [Articles:11192870, 12545140, 19659438], and instead genetic variants underlie a high proportion of the inter-individual variation in EFV plasma concentrations (discussed below). Genotyping may therefore aid EFV dosing, help avoid virolic failure and CNS related adverse reactions.

CYP2B6 has a key role in EFV metabolism, predominantly forming the major metabolite 8-hydroxyefavirenz (the product of over 90% of EFV oxidation) [Articles:12676886, 17559344, 19238117], and a high percentage of inter-individual variation in EFV PK is attributed to CYP2B6 genetic variation [Articles:19225447, 19371316, 19779319, 20860463, 15864119, 19659438, 19238117]. CYP2B6 and CYP2A6 contribute to the 7-hydroxylation of EFV (represents less than 10% of EFV oxidation) [Articles:17559344, 19238117, 12676886]. CYP2A6 genetic variation therefore also plays a role in the variability of EFV PK seen in patients, the effects of which are particularly prominent in CYP2B6 slow metabolizers [Articles:19225447, 19238117, 19371316]. These studies are detailed below and in Table 2.

In small studies of 50-65 individuals, there is no statistically significant association between EFV PK parameters and the SNPs rs8192726 (1836 G>T, *9b) or rs28399454 (5065 G>A, *17) [Articles:20860463, 19371316], though rs8192726 is associated with higher EFV plasma levels when the study size is increased to 94 individuals [Article:19779319]. A trend for higher EFV plasma concentrations in rs28399433 T/G (CYP2A6*1/*9) heterozygotes compared to TT homozygotes does not reach significance after correcting for multiple comparisons in a small study of 45 individuals [Article:19659438]. The lack of significant association in these studies may be due to low allele frequencies of the variants examined, small sample sizes, the relatively smaller contribution of CYP2A6 to EFV PK and/ or a weak association; for instance, in Kwara et al. a significant association between EFV PK parameters and CYP2A6 was observed when individuals with one or more copies of CYP2A6*9b (rs8192726) and CYP2A6*17 (rs28399454) were grouped together, but not when the SNPs were analyzed individually [Article:19371316].

Individuals with two CYP2A6 loss-of-function alleles, two decreased function CYP2A6 alleles, or one of each (Table 2) have significantly higher EFV plasma concentrations, compared to those without these alleles, in individuals carrying CYP2B6 reference alleles [Article:19238117]. Stratifying for both CYP2A6 and CYP2B6 genotype, a trend for lower 7-hydroxy-EFV metabolite levels is seen in patients with two loss of function CYP2B6 alleles and two CYP2A6 loss or decrease function alleles, and higher levels of the CYP-450 independent metabolite N-glucuronide-EFV [Article:19238117]. Individuals with CYP2A6 loss-of-function alleles have lower clearance of EFV, and this is more pronounced in those who also have CYP2B6 loss-of-function alleles [Article:19225447]. In multiple regression analysis, incorporating multiple variants, CYP2A6 rs8192726 and/ or rs28399454 status independently contributes to EFV inter-individual plasma concentrations, accounting for around 10% (8.6-12%), with CYP2B6 rs3745274 genotype TT contributing 36-45.2%, and UGT2B7 *1a genotype also significantly contributing [Articles:19371316, 19779319]. To conclude, genetic variation in the CYP2B6, CYP2A6, CYP3A4 and UGT2B7 genes contributes to inter-individual variation of EFV clearance [Articles:19225447, 19371316, 19779319], and the effect of carrying CYP2A6 loss-of-function alleles on EFV clearance is more pronounced in people who are also CYP2B6 slow metabolizers [Articles:19225447, 19238117, 19371316]. The clinical consequence of CYP2A6 genotypes is not reported in the studies above, although higher plasma concentrations of EFV are associated with both increased viral suppression and increased likelihood of CNS adverse reactions [Articles:11192870, 12545140, 15167626]. The CYP2A6 enzyme may have a role in the metabolism of other HAART drugs prescribed alongside EFV, for example Zidovudine (see the PharmGKB Zidovudine Pathway, PK/PD) [Article:9586947], which could affect overall clinical outcome of viral suppression or adverse drug effects.

Artemisinin and derivatives
Artemisinin and its derivatives are drugs used to fight malaria infection [Articles:19851082, 19926036]. Recombinant CYP2A6 metabolizes artemisinin and CYP2A6 inhibition attenuates the rate of drug disappearance in human microsomes in vitro [Article:10583023]. However, CYP2B6 and CYP3A4 enzymes are thought to have a greater role in artemisinin metabolism [Article:10583023] (see the PharmGKB Artemisinin and Derivatives Pathway, Pharmacokinetics). Artemisinin derivatives (arteether, artemether, artesunate) were developed to enhance drug bioavailability, and are used in combination with a second unrelated slower acting drug, in order to initially rapidly eradicate malaria parasites within red blood cells, and then kill any residual parasites [Articles:19851082, 19926036]. CYP2A6 is the major CYP450 enzyme involved in artesunate metabolism, forming dihydro-artemisinin, which is then inactivated by UGT enzymes (see the PharmGKB Artemisinin and Derivatives Pathway, Pharmacokinetics) [Articles:12920490, 19926036]. Therefore, CYP2A6 alleles which confer loss-of-function or decreased function may affect metabolism of these anti-malarial drugs. However, studies investigating urinary metabolites after dosing with artemisinin or derivatives, and use concurrent coumarin or nicotine probe drugs, see no clear correlation between CYP2A6 genotype and an effect on PK or enzyme activity [Articles:18064444, 18979093]. Artemisinin and derivatives induce CYP2B6 expression [Article:18350255; 12844133], further complicating CYP2A6 association studies. Studies controlling for CYP2B6 status and with larger numbers are therefore required to investigate the clinical implications of CYP2A6 genotype on the metabolism of artemisinin and its derivatives.

CYP2A6 and other therapeutic drugs

Valproic acid
The antiepileptic drug valproic acid (VPA) is also used to treat migraines and schizophrenia, and could be a potential anti-cancer drug [Article:20798865]. In vitro studies demonstrate CYP2C9 is the principle enzyme in VPA metabolism, however CYP2A6 contributes to around 50% of VPA 3-hydroxylation in human microsomes [Article:16945988] and can contribute to 4-ene-VPA formation, a metabolite of VPA thought to cause hepatotoxicity [Articles:9353388; 16945988, 3101178, 6437960]. CYP2A6 activity against coumarin is inhibited by VPA treatment, therefore VPA may affect responses to drugs metabolized by CYP2A6 taken concurrently [Article:11736863]. Individuals with the *4 gene deletion allele have significantly increased plasma levels of VPA, likely due to decreased CYP2A6 enzyme metabolic activity, and may result in increased drug exposure [Article:20089352].

Pilocarpine
Pilocarpine is used for the treatment of glaucoma and xerostomia [Article:17178767]. CYP2A6 is the principle enzyme involved in 3-hydroxypilocarpine formation from pilocarpine in HLMs [Article:17178767]. Poor metabolizers with two inactive CYP2A6 alleles have significantly increased pilocarpine plasma concentrations and a trend for higher excretion in the urine, with concurrent reductions of the metabolite 3-hydroxypilocarpine compared to non-poor metabolizers [Article:18698229]. Despite these significant differences in metabolism, no severe adverse effects are observed, and the authors suggest CYP2A6 poor metabolizers likely use alternative renal clearance pathways [Article:18698229].

SM-12502 (3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one)
SM-12502 is a platelet activating factor (PAF) receptor antagonist and has potential for use in asthma therapy [Article:19075994]. CYP2A6 is the major metabolizer enzyme of SM-12502 in human microsomes in vitro [Article:8627557], and the compound has been used to identify CYP2A6 polymorphisms that confer poor and extensive metabolizer phenotypes in vivo [Article:10087035].

CYP2A6 is involved to a varying extent in the metabolism of numerous other therapeutic drugs (see [Article:19702528] for an extensive list of substrates). These include the antitumour drugs ifosfamide (see the PharmGKB Ifosfamide Pathway, Pharmacokinetics) and cyclophosphamide (see the PharmGKB cyclophosphamide Pathway, Pharmacokinetics), the epilepsy treatments phenytoin (see the PharmGKB Phenytoin Pathway, Pharmacokinetics [Article:11038165]), carbamazepine (see the PharmGKB Carbamazepine Pathway, Pharmacokinetics) [Articles:21738081, 12386121], and losigamone [Articles:8886611, 14704462]. CYP2A6 also has a secondary role in metabolism of the anaesthesia halothane [Article:19442086]. Therefore, CYP2A6 polymorphisms may affect additional pharmaceuticals, however the extent of CYP2A6's role in the metabolism/ clearance of these drugs may be minor and/ or redundant, and other genetic variants including those in CYP-450 genes may play a more prominent role in the overall outcome.

CYP2A6 and toxicology
CYP2A6 polymorphisms have not only been associated with extent of nicotine metabolism and effect on smoking behaviors (as discussed previously and outlined in Table 1), but also with activation of carcinogens from tobacco and xenobiotics [Articles:19018727, 19702528]. Tobacco-specific nitrosamines, including nitrosamine 4-(methylnitrosamino)1(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN), are present in tobacco and cigarette smoke, and hydroxlylation by CYP2A6, CYP2A13 and other CYPs activates NNK and NNN into metabolites that can then react with DNA to form adducts [Articles:19018727, 19702528]. CYP2A6 is involved in the activation of herbicides and pollutants such as hexamethylphosphoramide, dichlorobenzonitrile, aflatoxin B1, naphthalene, methyl tert-butyl ether, and N-nitro-sobenzylmethylamine (NBzMA) [Articles:12919726, 19702528], which are also procarcinogens.

CYP2A6 polymorphisms conferring lower enzyme activity are associated with reduced risk of lung, oral, head and neck, and upper aerodigestive cancers, particularly in tobacco users [Articles:19479063, 21791872, 15308589, 17259654, 1940642, 11960911, 19339270]. The association between CYP2A6 and lung cancer is especially prominent among those who smoke 20 or fewer cigarettes per day [Article:21747048]. Higher CYP2A6 enzyme activity is associated with increased risk of pancreatic cancer (adjusted for smoking status) [Article:19454817]. The results of different association studies are mixed, often due to a lack of statistical power or failure to adjust for smoking status and behaviors [Articles:19018727, 19823875]. The relative contribution of CYP2A6 polymorphisms to cancer risk through smoking behavior versus carcinogen activation is difficult to define [Articles:19823875, 11805739, 19018727], though studies controlling for the amount of cigarette exposure suggest that carcinogen bioactivation is a significant contributor [Articles:21747048, 15308589]. Inhibition of CYP2A6 could potentially reduce cancer risk [Articles:19823875, 11805739, 19018727].

Table 2: CYP2A6 polymorphisms and association with therapeutic drug response

CYP2A6 Allele or Genotype Details of genotyping Drug Association Reference and study details
*1/*4 or *4/*4 or *4/*9 or *1/*9 # Caffeine Significantly reduced metabolism of paraxanthine compared to *1/*1 (not detectable in *4/*4 samples) [Article:15980104] in vitro study, n=42 human liver microsomes
*7 or *10 or *11 #CaffeineReduced activity against paraxanthine [Article:15980104] in vitro study, CYP2A6 transfected into E. coli, fractions then incubated with paraxanthine
Intermediate metabolizers: *1A/*4, *1A/*9, *1B1/*4, *1B1/*9 Poor metabolizers: *4/*9, *9/*9 *4: gene deletion *9: g.-48T>G (rs28399433) *1x2 gene duplication, *1B1 gene conversion in 3' region CaffeineReduced metabolism of paraxanthine into 17U compared to extensive metabolizers (*1A/*1A, *1A/*1B1, *1A1/*1B1x2, *1B1/*1B1) [Article:20155256] n=100 Serbian, healthy volunteers
rs8192725 Genotype CC g.1620T>C Intron 2 Method: direct gene sequencing, provide details of primers and #. Reference sequences used: NG_00008.7 and NP_000753.3 Tegafur Significantly increased mRNA expression and a trend for increased rate of 5 FU formation (ns), compared to genotype TT [Article:21521021] in vitro, (n=45) Chinese HLM and liver tissue samples
rs8192720 Genotype C/T or TT c.22C>T (NM_000762.5) Leu8Leu exon 1 Method: direct gene sequencing, provide details of primers and # Reference sequences used: NG_00008.7 and NP_000753.3 Tegafur Increased CYP2A6 mRNA expression and an increased rate of 5 FU formation, compared to genotype CC [Article:21521021] In vitro, (n=45) Chinese HLM and liver tissue samples
rs28399433 Genotype G/T or GG g. -48T>G Method: direct gene sequencing, provide details of primers and #. Reference sequences used: NG_00008.7 and NP_000753.3 Tegafur A trend for reduced CYP2A6 mRNA and protein expression, and reduced rate of 5 FU formation (ns), compared to genotype TT [Article:21521021]
*4 Allele defined by: CYP2A6 gene deletion. Method: direct gene sequencing, provide details of primers and #. Reference sequences used: NG_00008.7 and NP_000753.3 Tegafur Significantly reduced CYP2A6 mRNA and protein expression, and significantly reduced rate of 5 FU formation, compared to those without the *4 allele [Article:21521021] In vitro, (n=45) Chinese HLM and liver tissue samples
Two alleles with a gene conversion in the 3' UTR Method: direct gene sequencing, provide details of primers and #. Reference sequences used: NG_00008.7 and NP_000753.3 Tegafur Associated with a trend for reduced CYP2A6 expression and a trend for reduced rate of 5 FU formation, compared to those with no alleles with a gene conversion in the 3'UTR [Article:21521021] In vitro, (n=45) Chinese HLM and liver tissue samples
*1B (haplotype 14) Haplotype defined by: gene conversion in the CYP2A6 3' UTR, and the SNPs 22C>T (rs8192720) and 1620T>C (rs8192725) Method: direct gene sequencing, provide details of primers and #. Reference sequences used: NG_00008.7 and NP_000753.3 Tegafur significantly increased CYP2A6 mRNA expression, and significantly increased rates of 5 FU formation, compared to those without the allele. [Article:21521021] In vitro, (n=45) Chinese HLM and liver tissue samples
Genotype *1/*1 Sequenced for *9 at -48T>G (rs28399433), *10 at 6600G>T ) rs28399468), *7 at 6558T>C (rs5031016). *4 gene deletion #. Therefore *1 was defined as wildtype with none of the above variants. S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate combination) and oxaliplatin Associated with increased tegafur metabolism and a trend for higher 5 FU plasma concentrations compared to individuals with one or two variant alleles (*4, *7, *9, *10 combined) (p values were not given), but not associated with increased likelihood of diarrhea or neutropenia. [Article:21326246] Study: Biliary tract cancer patients, (n=48)
*4C and *11 combined Alleles defined by: *4C: Gene deletion (identical to *4A according to The Human CYP-450 Nomenclature Committee). *11: c.670T>C, g.3391T>C, Ser244Pro (rs111033610). Method: #, amplification of exon 8 to 3'UTR, restriction digest analysis. Amplification and sequencing of exon 5 Tegafur Reduced metabolism compared to four other patients. [Article:12042667] A case study of a gastric cancer patient subsequently found to have both alleles, and follow-up in vitro experiments.
Allele *7 g.6558T>C (Ile471Thr) (rs5031016) and gene conversion with CYP2A7 in the 3' UTR # Tegafur Reduced 5 FU formation rate compared to *1A/*1A [Article:15900015] In vitro kinetic assays, using transformed E. coli membrane preparations (n=3)
Allele *18 Single SNP rs1809810 (g. 5668A>T, Tyr392Phe). Allele specific primers used for genotyping.Tegafur Slightly reduced 5 FU formation rate compared to *1A/*1A[Article:15900015] In vitro kinetic assays, using transformed E. coli membrane preparations (n=3)
Allele *19 g.5668A>T (Tyr392Phe) (rs1809810) and g.6354T>C (intron 8), 6558T>C (Ile471Thr) (rs5031016) and gene conversion with CYP2A7 in the 3' UTR. Allele specific primers used for genotyping. Tegafur Reduced 5 FU formation rate compared to *1A/*1A[Article:15900015] In vitro kinetic assays, using transformed E. coli membrane preparations (n=3)
Individuals with two variant alleles (*4/*4, *7/*7 or *4/*7) *4A: # *7: # with some modifications, c.1412T>C, Ile471Thr (rs5031016) S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate combination) Significantly reduced oral clearance of tegafur, compared to *1/*1 [Article:18380793] n=54 Japanese patients
*4CAlleles defined by: *4C, *7, *9. Method: # amplification S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate combination) Significantly reduced metabolism of tegafur, compared to individuals without the allele [Article:18212800] n=46 Japanese patients with non-small-cell lung cancer.
Individuals with two variant alleles, (combined genotypes): *4/*4 *4/*7 *4/*9 *7/*9 *9/*9 Alleles defined by: *4: entire gene deletion #, Positions genotyped: g.-48T>G (for *9) (rs28399433), g. 6558T>C (rs5031016 Ile471Thr) (for *7, *10), and g. 6600G>T (rs28399468, Arg485Leu ) (for *10) S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate combination) Reduced treatment efficacy compared to individuals with one or two wildtype *1 alleles. Increased risk of disease progression and reduced progression-free survival, as measured by significantly reduced probability of tumor response [Article:19604090] n= 50 Korean patients with metastatic gastric cancer
Two variant alleles, (combined genotypes): *4A/*4A *4A/*7 *4A/*9 *7/*7 *7/*9 *9/*9 # (introduction describes *7 as c.1412T>C (rs5031016 Ile471Thr), and *9 as g.-48T>G (rs28399433), and *4 as complete lack of activity.) S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate combination) Associated with significantly reduced tegafur clearance, compared to *1/*1 or heterozygotes with one variant allele (tegafur plasma concentrations did not correlate with 5 FU concentrations) [Article:20596643] n=57 Japanese patients with solid tumors.
Individuals with two variant alleles, (combined genotypes): *4A/*4A *4A/*9 *4A/*10 *7/*9 *9/*9 *9/*10 Alleles defined by: *4 gene deletion *7: c.1412T>C , Ile471Thr (rs5031016) *9: g.-48T>G (rs28399433) S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate combination) Associated with higher tegafur and significantly lower 5 FU plasma concentrations compared to heterozygote patients (*1/*4A, *1/*7, *1/*9, *1/*11 combined genotypes). No significant association with adverse effects or treatment response were found [Article:19921195] n=34 patients with solid tumors.
Individuals with one or two variant alleles, (combined genotypes): *4/*7 *4/*9 *4/*10 *9/*9 *1/*4 Alleles defined by: *4 entire gene deletion, positions genotyped: g.-48T>G (rs28399433) (for *9), g.6558T>C (rs5031016 Ile471Thr) (for *7, *10), and g.6600G>T (rs28399468, Arg485Leu ) (for *10). # S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate combination) and cisplatin Significantly associated with lower response rate, increased risk of disease progression and reduced overall survival time.[Article:21364592] n=106, Korean patients, with metastatic gastric cancer
*1/*4 or *4/*4 or *4/*9 or *1/*7 # Letrozole Significantly associated with reduced metabolism compared with *1/*1 wildtype [Article:19845430] In vitro study using Japanese HLM samples (n=31)
*1A/*1A *1A/*1B *1B/*1B # *4, *7, *9 LetrozoleIncreased clearance compared to heterozyogous or homozygous individuals with variant alleles (*4, *9, *7)[Article:21494765] n=22 healthy Japanese postmenopausal women
Slow metabolizers = 2 copies of decrease-of-function alleles (*9, *12) or 1 or 2 copies of loss-of-function alleles (*2, *4, *7, *10, *17, *20, *23-*27, *35) or 1 decrease-of-function allele and 1 loss-of-function allele # *2: 1799 T>A; *4E: gene deletion (intron 7); *7: 6558 T>C; *9: -48 T>G; *10: 6558 T>C, 6600 G>T; *12: exon 1-2 CYP2A7, exon 3-9 CYP2A6; *17: 5065 G>A; *23: 2161 C>T; *24: 594 G>C; (if *25 is positive then perform *26 & *27 assays) *26: 1711 T>G; *27: 2162-2163 GC>A frameshift; *35: 6458 A>T.LetrozoleSignificantly higher plasma levels of drug compared to normal metabolizers (genotype *1/*1)[Article:21975350] n=259 mixed population, postmenopausal women with hormone receptor positive breast cancer
Intermediate metabolizer = one copy of decrease-of-function alleles *9, *12 # *2: 1799 T>A; *4E: gene deletion (intron 7); *7: 6558 T>C; *9: -48 T>G; *10: 6558 T>C, 6600 G>T; *12: exon 1-2 CYP2A7, exon 3-9 CYP2A6; *17: 5065 G>A; *23: 2161 C>T; *24: 594 G>C; (if *25 is positive then perform *26 & *27 assays) *26: 1711 T>G; *27: 2162-2163 GC>A frameshift; *35: 6458 A>T.LetrozoleSignificantly higher plasma levels of drug compared to normal metabolizers (genotype *1/*1) [Article:21975350] n=259 mixed population, postmenopausal women with hormone receptor positive breast cancer
Two loss-of-function alleles (*2, *4A-F, *5, *34) or two reduced function alleles (*1H, *1J, *7, *9, *10, *12, *13, *15, *17, *19) or one of each # for novel variants. *1X2A, *1X2B: gene duplication, *1H and *1J rs61663607 g.-745A>G, *2: rs1801272 g.1799T>A *4A *4F: intron 8 gene conversion with CYP2A7 - gene deletion. *5: rs5031017 g.6582G>T, *7, *10, *19: rs5031016 g.6558T>C, *9, *13, *15: rs28399433 g.-48T>G, *17: rs28399454 g.5065G>A, *12: intron 2 gene conversion with CYP2A7, *34: intron 4, gene conversion with CYP2A7 Efavirenz Reduced EFV metabolism - significantly higher EFV plasma AUC compared to those without variant alleles (in individuals with CYP2B6 reference alleles - please note reference alleles were not stated in the study). [Article:19238117] n=169 mixed population, HIV-infected individuals, The Swiss HIV Cohort Study. (Please note, the phenotype categories included different allele groupings from those described in [Article:19225447]).
loss-of-function alleles (*2, *4) and/ or diminished function alleles (*1H, *1J, *5, *7, *9, *10, *12, *13, *15, *17, *19, *34)#Efavirenz Reduced clearance of the drug irrespective of CYP2B6 status, however more pronounced in homozygotes with CYP2B6 loss-of-function alleles.[Article:19225447] n=169 mixed population, HIV-infected individuals, The Swiss HIV Cohort Study. (Please note, the phenotype categories included different allele groupings from those described in [Article:19238117]).
*9B allele rs8192726 g.1836G>T (genotyped only rs8192726 and no other SNPs which make up the *9B allele) # Efavirenz Slow metabolism of EFV (significantly increased plasma concentrations) compared to those without the allele. CYP2B6 genotype status was not accounted for in the initial analysis. [Article:19779319] n=94 Ghanaian patients with HIV-infection, some also with TB coinfection. Please note; this was the same study cohort as [Article:19371316] but more patients
*17 rs28399454 genotype AA+GA, g. 5065G>A, Val365Met (genotyped only rs28399454 and no other SNPs which make up the *17 allele) Efavirenz Not associated with slow metabolism of EFV (not statistically significant higher plasma concentrations) compared to those without the allele. CYP2B6 genotype status was not accounted for in the initial analysis. [Article:19779319] n=94 Ghanaian patients with HIV-infection, some also with TB coinfection. Please note; this was the same study cohort as [Article:19371316] but more patients
*9B and/ or *17 rs8192726 or rs28399454 (genotyped only rs8192726 and rs28399454, and no other SNPs which make up the *9B and *17 alleles) Efavirenz Slow metabolism of EFV (significantly increased plasma concentrations) compared to indivduals without the alleles. CYP2B6 genotype status was not accounted for in the initial analysis but in multiple regression analysis, CYP2A6 genotype status independently contributed to EFV variation, along with CYP2B6 and UGT2B7 genotype. [Article:19779319] n=94 Ghanaian patients with HIV-infection, some also with TB coinfection. Please note; this was the same study cohort as [Article:19371316] but more patients
*9B genotype TG vs GG rs8192726 g.1836G>T (genotyped only this position and no other SNPs which make up the *9B allele) Efavirenz Not associated with EFV plasma or cell concentrations (CYP2B6 status not considered in this initial analysis) [Article:20860463] n=50 a mixed population of patients with HIV-infection.
*17 Genotype GA vs GG rs28399454 g.5065 G>A, Val365Met (genotyped only this position and no other SNPs which make up the *17 allele) Efavirenz Not associated with EFV plasma concentration, peripheral blood mononuclear cell concentrations or accumulation ratio. (CYP2B6 status was not considered in this initial analysis) [Article:20860463] n=50 a mixed population of patients with HIV-infection.
*9 rs28399433 Genotype T/G Efavirenz A trend for higher EFV plasma concentrations compared to genotype T/T (not considering CYP2B6 status), although this was not statistically significant after Bonferroni correction for multiple comparisons.[Article:19659438] n=45, Haitians of African decent, with HIV-infection.
*4# Valproic acid Significantly higher steady state plasma concentrations (reduced metabolism) in individuals with the *4 allele compared to those without the allele [Article:20089352] n=179 Northern Han Chinese epilepsy patients
Genotype *7/*9 or *4A/*7 or *4A/*9 or *4A/*10 # *4A (entire gene deletion), *7: Ile471Thr (rs5031016), *8: Arg485Leu (rs28399468), *9: g.-48T>G (rs28399433), *10: Ile471Thr (rs5031016) and Arg485Leu (rs28399468) Pilocarpine Poor metabolism and low clearance. [Article:18698229] study 1 n=20, study 2 n=8, healthy Japanese individuals administered with a single dose of pilocarpine hydrochloride.

Table Key:
5 FU = Fluorouracil
AUC = Area Under the Curve
EFV = efavirenz
HLM = Human Liver Microsomes
ns = not statistically significant
SNP = Single Nucleotide Polymorphism

#=give reference to other studies for the method of genotyping.
=refer to genotyping alleles in concordance with the Human Cytpchrome P450 Allele Nomeclature Committee website: CYP2A6
g. = gene nucleotide position according to NG_000008.7 (unless otherwise stated) as given by Human Cytpchrome P450 Allele Nomeclature Committee website: CYP2A6. Please note that this NCBI reference sequence has been removed.
c. = cDNA nucleotide position according to NM_000762.4 (unless otherwise stated) as given by the Human Cytpchrome P450 Allele Nomeclature Committee website: CYP2A6. Please note that this NCBI reference sequence has been updated.

Where possible, dbSNP rsID have been provided for variants, according to links from the Human Cytpchrome P450 Allele Nomeclature Committee website: CYP2A6 or from the cited journal. Please note, due to the reference sequences on the NCBI having been updated from those given by the CYP Allele Nomenclature Committee, the gene and cDNA nucleotide positions on dbSNP may differ, despite being consistent in amino acid position.

The CYP2A6 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations and haplotypes will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.

Citation PharmGKB summary: very important pharmacogene information for cytochrome P-450, family 2, subfamily A, polypeptide 6. Pharmacogenetics and genomics. 2012. McDonagh Ellen M, Wassenaar Catherine, David Sean P, Tyndale Rachel F, Altman Russ B, Whirl-Carrillo Michelle, Klein Teri E. PubMed
History

Submitted by Ellen M. McDonagh and Catherine Wassenaar (coauthors), Sean P. David, Rachel F. Tyndale, Russ B. Altman, Michelle Whirl-Carrillo, Teri E. Klein. Rewritten and updated 2012. Updated 2011: Sean P. David (PharmGKB), Catherine Wassenaar (PNAT), Rachel Tyndale (PNAT), - update of work by Manki Ho, Jill Mwenifumbo, Ryan Owen (PharmGKB), Rachel Tyndale (PNAT) (originally submitted Feb 28, 2007)

Variant Summaries rs1801272, rs28399433, rs28399444, rs28399454, rs28399468, rs5031016, rs8192726
Haplotype Summaries CYP2A6*1B, CYP2A6*1X2, CYP2A6 *2, CYP2A6*4, CYP2A6 *7, CYP2A6*9, CYP2A6*10, CYP2A6*12, CYP2A6 *17, CYP2A6 *20
Drugs
Pathways

Haplotype Overview

Haplotypes are derived from the Human Cytochrome P450 (CYP) Allele Nomenclature Database. The Human Cytochrome P450 (CYP) Allele Nomenclature Database states that nucleotide changes listed below are based on NCBI Reference Sequence NG_008377.1. For questions about nucleotide positions, please contact the Human Cytochrome P450 (CYP) Allele Nomenclature Database directly, as they are the authoritative source on cytochrome P450 nomenclature.

Notes for particular alleles:

  • Alleles CYP2A6*1B1-1B17, *5, *7, *8, *10, *19, have a gene conversion in the 3' flanking region.
  • Alleles CYP2A6*4A-*4H confer a gene deletion.
  • Allele CYP2A6*1X2A is a gene duplication with a breakpoint at intron 8 to the 3'UTR.
  • Allele CYP2A6*1X2B is a gene duplication with a breakpoint 5.2-5.6kb downstream from the stop codon.
  • Allele CYP2A6*1B3 was formerly named CYP2A6*1C.
  • Allele CYP2A6*3 is a CYP2A6/CYP2A7 gene hybrid.
  • Alleles CYP2A6*12A-12C have exons 1-2 of CYP2A7 origin and exons 3-9 of CYP2A6 origin.
  • Allele CYP2A6*34 has exons 1-4 of CYP2A7 origin and exons 5-9 of CYP2A6 origin.

Source: PharmGKB

All alleles in the download file are on the positive chromosomal strand. PharmGKB considers the first haplotype listed in each table as the reference haplotype for that set.

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

  1. Acetaminophen Pathway, Pharmacokinetics
    Stylized diagram showing acetaminophen metabolism and transport in the liver and kidney.
  1. Caffeine Pathway, Pharmacokinetics
    Stylized liver cell showing candidate genes involved in the metabolism of caffeine.
  1. Carbamazepine Pathway, Pharmacokinetics
    Stylized liver cell depicting candidate genes involved in the pharmacokinetics of carbamazepine.
  1. Cyclophosphamide Pathway, Pharmacokinetics
    Model human liver cell showing genes involved in the metabolism of cyclophosphamide.
  1. Efavirenz Pathway, Pharmacokinetics/Pharmacodynamics
    Schematic representation of efavirenz metabolism and mechanism of action against HIV.
  1. Fluoropyrimidine Pathway, Pharmacokinetics
    Representation of the metabolic pathways for fluoropyrimidines.
  1. Ifosfamide Pathway, Pharmacokinetics
    Model human liver cell showing genes involved in the metabolism of ifosfamide.
  1. Nicotine Pathway, Pharmacokinetics
    Summary of nicotine metabolism in human liver cell.
  1. Phenytoin Pathway, Pharmacokinetics
    Genes involved in the metabolism of phenytoin in the human liver cell.
  1. Valproic Acid Pathway, Pharmacokinetics
    Graphic representation of the candidate genes involved in valproic acid pharmacokinetics.
  1. Zidovudine Pathway, Pharmacokinetics/Pharmacodynamics
    Representation of candidate genes involved in the metabolism of zidovudine and its mechanism of antiviral action.

External Pathways

Links to non-PharmGKB pathways.

  1. Simple hydroxylation - (Reactome via Pathway Interaction Database)
  2. Xenobiotics - (Reactome via Pathway Interaction Database)
No related genes are available

Curated Information ?

Curated Information ?

Publications related to CYP2A6: 180

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Development of a broad-based ADME panel for use in pharmacogenomic studies. Pharmacogenomics. 2014. Brown Andrew Mk, et al. PubMed
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Effects of methoxsalen, a CYP2A5/6 inhibitor, on nicotine dependence behaviors in mice. Neuropharmacology. 2014. Bagdas Deniz, et al. PubMed
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Functional CYP2B6 variants and virologic response to an efavirenz-containing regimen in Port-au-Prince, Haiti. The Journal of antimicrobial chemotherapy. 2014. Haas David W, et al. PubMed
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Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes. The Journal of antimicrobial chemotherapy. 2014. Haas David W, et al. PubMed
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The role of genetic polymorphisms in cytochrome P450 and effects of tuberculosis co-treatment on the predictive value of CYP2B6 SNPs and on efavirenz plasma levels in adult HIV patients. Antiviral research. 2014. Bienvenu Emile, et al. PubMed
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PharmGKB summary: ifosfamide pathways, pharmacokinetics and pharmacodynamics. Pharmacogenetics and genomics. 2014. Lowenberg Daniella, et al. PubMed
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Dependence of efavirenz- and rifampicin-isoniazid-based antituberculosis treatment drug-drug interaction on CYP2B6 and NAT2 genetic polymorphisms: ANRS 12154 study in Cambodia. The Journal of infectious diseases. 2014. Bertrand Julie, et al. PubMed
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Pharmacogenetics and clinical biomarkers for subtherapeutic plasma efavirenz concentration in HIV-1 infected Thai adults. Drug metabolism and pharmacokinetics. 2014. Sukasem Chonlaphat, et al. PubMed
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Impact of CYP polymorphisms, ethnicity and sex differences in metabolism on dosing strategies: the case of efavirenz. European journal of clinical pharmacology. 2014. Naidoo Panjasaram, et al. PubMed
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Variation in P450 oxidoreductase (POR) A503V and flavin-containing monooxygenase (FMO)-3 E158K is associated with minor alterations in nicotine metabolism, but does not alter cigarette consumption. Pharmacogenetics and genomics. 2014. Chenoweth Meghan J, et al. PubMed
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Novel CYP2A6 variants identified in African Americans are associated with slow nicotine metabolism in vitro and in vivo. Pharmacogenetics and genomics. 2013. Piliguian Mark, et al. PubMed
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Inhibitory Potency of 8-Methoxypsoralen on Cytochrome P450 2A6 (CYP2A6) Allelic Variants CYP2A6*15, CYP2A6*16, CYP2A6*21 and CYP2A6*22: Differential Susceptibility Due to Different Sequence Locations of the Mutations. PloS one. 2014. Tiong Kai Hung, et al. PubMed
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Pregnancy and pharmacogenomics in the context of drug metabolism and response. Pharmacogenomics. 2013. Helldén Anders, et al. PubMed
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Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects. British journal of cancer. 2013. Henry N L, et al. PubMed
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S-1 plus irinotecan and oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: a prospective phase II study and pharmacogenetic analysis. British journal of cancer. 2013. Kim S Y, et al. PubMed
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Inhibition of cytochrome p450 enzymes by the e- and z-isomers of norendoxifen. Drug metabolism and disposition: the biological fate of chemicals. 2013. Liu Jinzhong, et al. PubMed
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Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients. The Journal of antimicrobial chemotherapy. 2013. Sarfo Fred S, et al. PubMed
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Genetic and Pharmacokinetic Determinants of Response to Transdermal Nicotine in White, Black and Asian Non- Smokers. Clinical pharmacology and therapeutics. 2013. Dempsey Delia A, et al. PubMed
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Impact of pharmacogenetics on CNS side effects related to efavirenz. Pharmacogenomics. 2013. Sánchez Martín Almudena, et al. PubMed
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Pharmacogenetics of chronic obstructive pulmonary disease. Pharmacogenomics. 2013. Hizawa Nobuyuki. PubMed
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CHRNA5-A3-B4 genetic variants alter nicotine intake and interact with tobacco use to influence body weight in Alaska-Native tobacco users. Addiction (Abingdon, England). 2013. Zhu Andy Z X, et al. PubMed
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CYP2A6 Genotype but not Age Determines Cotinine Half-life in Infants and Children. Clinical pharmacology and therapeutics. 2013. Dempsey Delia A, et al. PubMed
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Genetic polymorphisms of enzymes related to oral tegafur/uracil therapeutic efficacy in patients with hepatocellular carcinoma. Anti-cancer drugs. 2013. Fushiya Nao, et al. PubMed
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Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer. Breast cancer research and treatment. 2013. Henry N Lynn, et al. PubMed
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CYP2A6 slow nicotine metabolism is associated with increased quitting by adolescent smokers. Pharmacogenetics and genomics. 2013. Chenoweth Meghan J, et al. PubMed
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Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenetics and genomics. 2013. Ghodke-Puranik Yogita, et al. PubMed
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Correlates of efavirenz exposure in Chilean patients affected with human immunodeficiency virus reveals a novel association with a polymorphism in the constitutive androstane receptor. Therapeutic drug monitoring. 2013. Cortes Claudia P, et al. PubMed
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The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race and sex. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2013. Zhu Andy Z X, et al. PubMed
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Influence of efavirenz pharmacokinetics and pharmacogenetics on neuropsychological disorders in Ugandan HIV-positive patients with or without tuberculosis: a prospective cohort study. BMC infectious diseases. 2013. Mukonzo Jackson K, et al. PubMed
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Pilot Study of CYP2B6 Genetic Variation to Explore the Contribution of Nitrosamine Activation to Lung Carcinogenesis. International journal of molecular sciences. 2013. Wassenaar Catherine A, et al. PubMed
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Cytochrome P450-mediated drug metabolism in the brain. Journal of psychiatry & neuroscience : JPN. 2012. Miksys Sharon, et al. PubMed
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Variation in trans-3'-hydroxycotinine glucuronidation does not alter the nicotine metabolite ratio or nicotine intake. PloS one. 2013. Zhu Andy Z X, et al. PubMed
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Multi-ethnic cytochrome-P450 copy number profiling: novel pharmacogenetic alleles and mechanism of copy number variation formation. The pharmacogenomics journal. 2012. Martis S, et al. PubMed
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Alaska Native smokers and smokeless tobacco users with slower CYP2A6 activity have lower tobacco consumption, lower tobacco specific nitrosamine exposure and lower tobacco specific nitrosamine bioactivation. Carcinogenesis. 2012. Zhu Andy Z X, et al. PubMed
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Differential Effects of Nicotine Treatment and Ethanol Self-administration on CYP2A6, CYP2B6 and Nicotine Pharmacokinetics in African Green Monkeys. The Journal of pharmacology and experimental therapeutics. 2012. Ferguson Charmaine S, et al. PubMed
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The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition. Pharmacological reviews. 2012. Michaud Veronique, et al. PubMed
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CYP2A6 genetic variation and dexmedetomidine disposition. European journal of clinical pharmacology. 2012. Kohli Utkarsh, et al. PubMed
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CYP2A6 and CYP2B6 genetic variation and its association with nicotine metabolism in South Western Alaska Native people. Pharmacogenetics and genomics. 2012. J Binnington Matthew, et al. PubMed
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PharmGKB summary: phenytoin pathway. Pharmacogenetics and genomics. 2012. Thorn Caroline F, et al. PubMed
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Genetic variation in CYP2A6 predicts neural reactivity to smoking cues as measured using fMRI. NeuroImage. 2012. Tang Deborah W, et al. PubMed
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PharmGKB summary: very important pharmacogene information for cytochrome P-450, family 2, subfamily A, polypeptide 6. Pharmacogenetics and genomics. 2012. McDonagh Ellen M, et al. PubMed
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Genetic polymorphisms are associated with variations in warfarin maintenance dose in Han Chinese patients with venous thromboembolism. Pharmacogenomics. 2012. Zhang Wei, et al. PubMed
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Associations Between ABCB1, CYP2A6, CYP2B6, CYP2D6, and CYP3A5 Alleles in Relation to Efavirenz and Nevirapine Pharmacokinetics in HIV-Infected Individuals. Therapeutic drug monitoring. 2012. Heil Sandra G, et al. PubMed
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Pharmacogenetics of smoking cessation: role of nicotine target and metabolism genes. Human genetics. 2012. Gold Allison B, et al. PubMed
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Association between daily cigarette consumption and hypertension moderated by CYP2A6 genotypes in Chinese male current smokers. Journal of human hypertension. 2012. Liu T, et al. PubMed
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PharmGKB summary: caffeine pathway. Pharmacogenetics and genomics. 2012. Thorn Caroline F, et al. PubMed
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Relationship Between Amounts of Daily Cigarette Consumption and Abdominal Obesity Moderated by CYP2A6 Genotypes in Chinese Male Current Smokers. Annals of behavioral medicine : a publication of the Society of Behavioral Medicine. 2011. Liu Tao, et al. PubMed
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Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age. Clinical pharmacology and therapeutics. 2011. Desta Z, et al. PubMed
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Interaction between heavy smoking and CYP2A6 genotypes on type 2 diabetes and its possible pathways. European journal of endocrinology / European Federation of Endocrine Societies. 2011. Liu Tao, et al. PubMed
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Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk. Journal of the National Cancer Institute. 2011. Wassenaar Catherine A, et al. PubMed
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The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans. Pharmacogenetics and genomics. 2011. Bloom Joseph, et al. PubMed
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Genistein alters caffeine exposure in healthy female volunteers. European journal of clinical pharmacology. 2011. Chen Yao, et al. PubMed
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Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women. European journal of clinical pharmacology. 2011. Tanii Hiromi, et al. PubMed
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Association analysis of CYP2A6 genotypes and haplotypes with 5-fluorouracil formation from tegafur in human liver microsomes. Pharmacogenomics. 2011. Wang Huijuan, et al. PubMed
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Copy number variants in pharmacogenetic genes. Trends in molecular medicine. 2011. He Yijing, et al. PubMed
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Phase II study of S-1 combined with oxaliplatin as therapy for patients with metastatic biliary tract cancer: influence of the CYP2A6 polymorphism on pharmacokinetics and clinical activity. British journal of cancer. 2011. Kim K-p, et al. PubMed
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Associations of CYP2A6 genotype with smoking behaviors in southern China. Addiction (Abingdon, England). 2010. Liu Tao, et al. PubMed
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Breaking Barriers in the Genomics and Pharmacogenetics of Drug Addiction. Clinical pharmacology and therapeutics. 2010. Ho M K, et al. PubMed
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Pharmocoepigenetics: a new approach to predicting individual drug responses and targeting new drugs. Pharmacological reports : PR. 2011. Baer-Dubowska Wanda, et al. PubMed
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Influence of host genetic factors on efavirenz plasma and intracellular pharmacokinetics in HIV-1-infected patients. Pharmacogenomics. 2010. Elens Laure, et al. PubMed
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Can the 2-(13)C-uracil breath test be used to predict the effect of the antitumor drug S-1?. Cancer chemotherapy and pharmacology. 2010. Ishii Yukimoto, et al. PubMed
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Efavirenz primary and secondary metabolism in vitro and in vivo: identification of novel metabolic pathways and cytochrome P450 2A6 as the principal catalyst of efavirenz 7-hydroxylation. Drug metabolism and disposition: the biological fate of chemicals. 2010. Ogburn Evan T, et al. PubMed
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Nicotine addiction. The New England journal of medicine. 2010. Benowitz Neal L. PubMed
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The influence of cytochrome oxidase CYP2A6, CYP2B6, and CYP2C9 polymorphisms on the plasma concentrations of valproic acid in epileptic patients. Clinical neurology and neurosurgery. 2010. Tan Lan, et al. PubMed
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Genetic variation in nicotine metabolism predicts the efficacy of extended-duration transdermal nicotine therapy. Clinical pharmacology and therapeutics. 2010. Lerman C, et al. PubMed
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Effects of nicotine on cytochrome P450 2A6 and 2E1 activities. British journal of clinical pharmacology. 2010. Hukkanen Janne, et al. PubMed
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New CYP2A6 gene deletion and conversion variants in a population of Black African descent. Pharmacogenomics. 2010. Mwenifumbo Jill C, et al. PubMed
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Efavirenz in the therapy of HIV infection. Expert opinion on drug metabolism & toxicology. 2010. Rakhmanina Natella Y, et al. PubMed
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Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes. Xenobiotica; the fate of foreign compounds in biological systems. 2009. Murai K, et al. PubMed
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CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients. AIDS (London, England). 2009. Kwara Awewura, et al. PubMed
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Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4'-methanol-bisbenzonitrile in vitro. Cancer chemotherapy and pharmacology. 2009. Jeong Seongwook, et al. PubMed
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Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15. Human molecular genetics. 2009. Keskitalo Kaisu, et al. PubMed
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Structure, function, regulation and polymorphism of human cytochrome P450 2A6. Current drug metabolism. 2009. Di Yuan Ming, et al. PubMed
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CYP2B6 variants and plasma efavirenz concentrations during antiretroviral therapy in Port-au-Prince, Haiti. The Journal of infectious diseases. 2009. Leger Paul, et al. PubMed
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A novel CYP2A6 allele (CYP2A6*35) resulting in an amino-acid substitution (Asn438Tyr) is associated with lower CYP2A6 activity in vivo. The pharmacogenomics journal. 2009. Al Koudsi Nael, et al. PubMed
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Association of CYP2A6 polymorphisms with S-1 plus docetaxel therapy outcomes in metastatic gastric cancer. Pharmacogenomics. 2009. Kong Sun-Young, et al. PubMed
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Association of nicotine metabolite ratio and CYP2A6 genotype with smoking cessation treatment in African-American light smokers. Clinical pharmacology and therapeutics. 2009. Ho M K, et al. PubMed
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Pharmacogenetics-based population pharmacokinetic analysis of efavirenz in HIV-1-infected individuals. Clinical pharmacology and therapeutics. 2009. Arab-Alameddine M, et al. PubMed
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Genetic and environmental influences on the ratio of 3'hydroxycotinine to cotinine in plasma and urine. Pharmacogenetics and genomics. 2009. Swan Gary E, et al. PubMed
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CYP2B6 (c.516G-->T) and CYP2A6 (*9B and/or *17) polymorphisms are independent predictors of efavirenz plasma concentrations in HIV-infected patients. British journal of clinical pharmacology. 2009. Kwara Awewura, et al. PubMed
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Coffee intake, variants in genes involved in caffeine metabolism, and the risk of epithelial ovarian cancer. Cancer causes & control : CCC. 2009. Kotsopoulos Joanne, et al. PubMed
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Pharmacoepigenetics: its role in interindividual differences in drug response. Clinical pharmacology and therapeutics. 2009. Gomez A, et al. PubMed
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In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function. Pharmacogenetics and genomics. 2009. di Iulio Julia, et al. PubMed
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Polymorphic drug metabolism in anaesthesia. Current drug metabolism. 2009. Restrepo Juan G, et al. PubMed
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Application of pharmacogenomics to malaria: a holistic approach for successful chemotherapy. Pharmacogenomics. 2009. Mehlotra Rajeev K, et al. PubMed
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Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Analytical and bioanalytical chemistry. 2008. Zanger Ulrich M, et al. PubMed
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Toward personalized therapy for smoking cessation: a randomized placebo-controlled trial of bupropion. Clinical pharmacology and therapeutics. 2008. Patterson F, et al. PubMed
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Genetic polymorphisms of CYP2A6 affect the in-vivo pharmacokinetics of pilocarpine. Pharmacogenetics and genomics. 2008. Endo Takuro, et al. PubMed
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CYP2A6 and the plasma level of 5-chloro-2, 4-dihydroxypyridine are determinants of the pharmacokinetic variability of tegafur and 5-fluorouracil, respectively, in Japanese patients with cancer given S-1. Cancer science. 2008. Fujita Ken-ichi, et al. PubMed
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Novel and established CYP2A6 alleles impair in vivo nicotine metabolism in a population of Black African descent. Human mutation. 2008. Mwenifumbo Jill C, et al. PubMed
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Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction. Clinical pharmacology and therapeutics. 2008. Benowitz N L. PubMed
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The CYP2A6*4 allele is determinant of S-1 pharmacokinetics in Japanese patients with non-small-cell lung cancer. Clinical pharmacology and therapeutics. 2008. Kaida Y, et al. PubMed
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Dexamethasone-mediated up-regulation of human CYP2A6 involves the glucocorticoid receptor and increased binding of hepatic nuclear factor 4 alpha to the proximal promoter. Molecular pharmacology. 2008. Onica Tania, et al. PubMed
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Identification of novel CYP2A6*1B variants: the CYP2A6*1B allele is associated with faster in vivo nicotine metabolism. Clinical pharmacology and therapeutics. 2008. Mwenifumbo J C, et al. PubMed
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A novel CYP2A6 allele, CYP2A6*23, impairs enzyme function in vitro and in vivo and decreases smoking in a population of Black-African descent. Pharmacogenetics and genomics. 2008. Ho Man Ki, et al. PubMed
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Clinical pharmacology of artemisinin-based combination therapies. Clinical pharmacokinetics. 2008. German Polina I, et al. PubMed
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Pyrethroids: cytotoxicity and induction of CYP isoforms in human hepatocytes. Drug metabolism and drug interactions. 2008. Das Parikshit C, et al. PubMed
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Gene-gene interactions between CYP2B6 and CYP2A6 in nicotine metabolism. Pharmacogenetics and genomics. 2007. Ring Huijun Z, et al. PubMed
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Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacology & therapeutics. 2007. Ingelman-Sundberg Magnus, et al. PubMed
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Analysis of CYP2A contributions to metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human peripheral lung microsomes. Drug metabolism and disposition: the biological fate of chemicals. 2007. Brown Pamela J, et al. PubMed
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CYP2A13: variable expression and role in human lung microsomal metabolic activation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. The Journal of pharmacology and experimental therapeutics. 2007. Zhang Xiuling, et al. PubMed
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Human CYP2A6 is induced by estrogen via estrogen receptor. Drug metabolism and disposition: the biological fate of chemicals. 2007. Higashi Eriko, et al. PubMed
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Effects of eleven isothiocyanates on P450 2A6- and 2A13-catalyzed coumarin 7-hydroxylation. Chemical research in toxicology. 2007. von Weymarn Linda B, et al. PubMed
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Structure of the human lung cytochrome P450 2A13. The Journal of biological chemistry. 2007. Smith Brian D, et al. PubMed
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A novel duplication type of CYP2A6 gene in African-American population. Drug metabolism and disposition: the biological fate of chemicals. 2007. Fukami Tatsuki, et al. PubMed
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Involvement of CYP2A6 in the formation of a novel metabolite, 3-hydroxypilocarpine, from pilocarpine in human liver microsomes. Drug metabolism and disposition: the biological fate of chemicals. 2007. Endo Takuro, et al. PubMed
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Effects of the flavonoid biochanin A on gene expression in primary human hepatocytes and human intestinal cells. Molecular nutrition & food research. 2007. Moon Young Jin, et al. PubMed
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In vivo evaluation of CYP1A2, CYP2A6, NAT-2 and xanthine oxidase activities in a Greek population sample by the RP-HPLC monitoring of caffeine metabolic ratios. Biomedical chromatography : BMC. 2007. Begas E, et al. PubMed
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Population pharmacokinetics of nicotine and its metabolites I. Model development. Journal of pharmacokinetics and pharmacodynamics. 2007. Levi Micha, et al. PubMed
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CYP2A6 polymorphisms: is there a role for pharmacogenomics in preventing coumarin-induced hepatotoxicity in lymphedema patients?. Pharmacogenomics. 2007. Farinola Nicholas, et al. PubMed
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Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype. Toxicological sciences : an official journal of the Society of Toxicology. 2006. Kiang Tony K L, et al. PubMed
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CYP2A6 genotype and the metabolism and disposition kinetics of nicotine. Clinical pharmacology and therapeutics. 2006. Benowitz Neal L, et al. PubMed
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Effect of grapefruit juice on cytochrome P450 2A6 and nicotine renal clearance. Clinical pharmacology and therapeutics. 2006. Hukkanen Janne, et al. PubMed
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Determinants of the rate of nicotine metabolism and effects on smoking behavior. Clinical pharmacology and therapeutics. 2006. Johnstone Elaine, et al. PubMed
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Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations. Clinical pharmacology and therapeutics. 2006. Nakajima Miki, et al. PubMed
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New cytochrome P450 2D6*56 allele identified by genotype/phenotype analysis of cryopreserved human hepatocytes. Drug metabolism and disposition: the biological fate of chemicals. 2006. Li Li, et al. PubMed
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Characterization of the novel CYP2A6*21 allele using in vivo nicotine kinetics. European journal of clinical pharmacology. 2006. Al Koudsi Nael, et al. PubMed
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Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract. International journal of cancer. Journal international du cancer. 2006. He Xiao-Yang, et al. PubMed
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Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine levels from and usage of nicotine replacement therapy. Molecular psychiatry. 2006. Malaiyandi V, et al. PubMed
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3'-UTR polymorphism in the human CYP2A6 gene affects mRNA stability and enzyme expression. Biochemical and biophysical research communications. 2006. Wang Jue, et al. PubMed
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Limitation of cigarette consumption by CYP2A6*4, *7 and *9 polymorphisms. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 2006. Minematsu N, et al. PubMed
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Inactivation of CYP2A6 and CYP2A13 during nicotine metabolism. The Journal of pharmacology and experimental therapeutics. 2006. von Weymarn Linda B, et al. PubMed
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Identification of N-(hydroxymethyl) norcotinine as a major product of cytochrome P450 2A6, but not cytochrome P450 2A13-catalyzed cotinine metabolism. Chemical research in toxicology. 2005. Brown Kathryn M, et al. PubMed
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CYP2A6 AND CYP2B6 are involved in nornicotine formation from nicotine in humans: interindividual differences in these contributions. Drug metabolism and disposition: the biological fate of chemicals. 2005. Yamanaka Hiroyuki, et al. PubMed
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Cancer treatment and pharmacogenetics of cytochrome P450 enzymes. Investigational new drugs. 2005. van Schaik Ron H N. PubMed
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CYP2A6, MAOA, DBH, DRD4, and 5HT2A genotypes, smoking behaviour and cotinine levels in 1518 UK adolescents. Pharmacogenetics and genomics. 2005. Huang Shuwen, et al. PubMed
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Cytochrome P450s and other enzymes in drug metabolism and toxicity. The AAPS journal. 2006. Guengerich F Peter. PubMed
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CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation. The pharmacogenomics journal. 2006. Kubota T, et al. PubMed
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CYP2A7 polymorphic alleles confound the genotyping of CYP2A6*4A allele. The pharmacogenomics journal. 2006. Fukami T, et al. PubMed
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A novel CYP2A6*20 allele found in African-American population produces a truncated protein lacking enzymatic activity. Biochemical pharmacology. 2005. Fukami Tatsuki, et al. PubMed
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Cyp2a6 is a principal enzyme involved in hydroxylation of 1,7-dimethylxanthine, a main caffeine metabolite, in humans. Drug metabolism and disposition: the biological fate of chemicals. 2005. Kimura Miyuki, et al. PubMed
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Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen. Nature structural & molecular biology. 2005. Yano Jason K, et al. PubMed
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Three haplotypes associated with CYP2A6 phenotypes in Caucasians. Pharmacogenetics and genomics. 2005. Haberl Michael, et al. PubMed
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Characterization of novel CYP2A6 polymorphic alleles (CYP2A6*18 and CYP2A6*19) that affect enzymatic activity. Drug metabolism and disposition: the biological fate of chemicals. 2005. Fukami Tatsuki, et al. PubMed
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Nicotine 5'-oxidation and methyl oxidation by P450 2A enzymes. Drug metabolism and disposition: the biological fate of chemicals. 2005. Murphy Sharon E, et al. PubMed
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Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence. Clinical pharmacology and therapeutics. 2005. Malaiyandi Viba, et al. PubMed
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Ethnic variation in CYP2A6*7, CYP2A6*8 and CYP2A6*10 as assessed with a novel haplotyping method. Pharmacogenetics and genomics. 2005. Mwenifumbo Jill C, et al. PubMed
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Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence. Pharmacogenetics and genomics. 2005. Swan Gary E, et al. PubMed
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A novel polymorphism of human CYP2A6 gene CYP2A6*17 has an amino acid substitution (V365M) that decreases enzymatic activity in vitro and in vivo. Clinical pharmacology and therapeutics. 2004. Fukami Tatsuki, et al. PubMed
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Association of CYP2A6*1B genetic variant with the amount of smoking in French adults from the Stanislas cohort. The pharmacogenomics journal. 2005. Gambier N, et al. PubMed
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Genetically decreased CYP2A6 and the risk of tobacco dependence: a prospective study of novice smokers. Tobacco control. 2004. O'Loughlin J, et al. PubMed
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Identification of deletion-junction site of CYP2A6*4B allele lacking entire coding region of CYP2A6 in Japanese. Pharmacogenetics. 2004. Ariyoshi Noritaka, et al. PubMed
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Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics. 2004. Schoedel Kerri A, et al. PubMed
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Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13, the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK. Cancer research. 2003. Wang Haijian, et al. PubMed
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Decreased coumarin 7-hydroxylase activities and CYP2A6 expression levels in humans caused by genetic polymorphism in CYP2A6 promoter region (CYP2A6*9). Pharmacogenetics. 2003. Kiyotani Kazuma, et al. PubMed
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Effects of polymorphism in promoter region of human CYP2A6 gene (CYP2A6*9) on expression level of messenger ribonucleic acid and enzymatic activity in vivo and in vitro. Clinical pharmacology and therapeutics. 2003. Yoshida Ryoko, et al. PubMed
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Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annual review of pharmacology and toxicology. 2003. Ding Xinxin, et al. PubMed
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The contribution of cytochrome P450 to the metabolism of tegafur in human liver. Drug metabolism and pharmacokinetics. 2003. Kajita Jiro, et al. PubMed
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Genetic polymorphisms in human CYP2A6 gene causing impaired nicotine metabolism. British journal of clinical pharmacology. 2002. Yoshida Ryoko, et al. PubMed
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Characterization of a novel CYP2A7/CYP2A6 hybrid allele (CYP2A6*12) that causes reduced CYP2A6 activity. Human mutation. 2002. Oscarson Mikael, et al. PubMed
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Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Molecular pharmacology. 2002. Maglich Jodi M, et al. PubMed
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Characterization of a genotype previously designated as CYP2A6 D-type: CYP2A6*4B, another entire gene deletion allele of the CYP2A6 gene in Japanese. Pharmacogenetics. 2002. Ariyoshi Noritaka, et al. PubMed
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A novel mutant allele of the CYP2A6 gene (CYP2A6*11 ) found in a cancer patient who showed poor metabolic phenotype towards tegafur. Pharmacogenetics. 2002. Daigo Satoshi, et al. PubMed
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An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles. Biochemical and biophysical research communications. 2002. Xu C, et al. PubMed
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Twenty one novel single nucleotide polymorphisms (SNPs) of the CYP2A6 gene in Japanese and Caucasians. Drug metabolism and pharmacokinetics. 2002. Kiyotani Kazuma, et al. PubMed
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Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. The Journal of pharmacology and experimental therapeutics. 2001. Rae J M, et al. PubMed
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In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9). British journal of clinical pharmacology. 2001. Wen X, et al. PubMed
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Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity. Biochemical and biophysical research communications. 2001. Pitarque M, et al. PubMed
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CYP2A6*6, a novel polymorphism in cytochrome p450 2A6, has a single amino acid substitution (R128Q) that inactivates enzymatic activity. The Journal of biological chemistry. 2001. Kitagawa K, et al. PubMed
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Genetic polymorphisms of cytochrome P450 2A6 in a case-control study on lung cancer in a French population. Pharmacogenetics. 2001. Loriot M A, et al. PubMed
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Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans. Clinical pharmacology and therapeutics. 2001. Nakajima M, et al. PubMed
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Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug metabolism and disposition: the biological fate of chemicals. 2000. Komatsu T, et al. PubMed
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Bioactivation of tegafur to 5-fluorouracil is catalyzed by cytochrome P-450 2A6 in human liver microsomes in vitro. Clinical cancer research : an official journal of the American Association for Cancer Research. 2000. Ikeda K, et al. PubMed
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CYP2A5/CYP2A6 expression in mouse and human hepatocytes treated with various in vivo inducers. Drug metabolism and disposition: the biological fate of chemicals. 2000. Donato M T, et al. PubMed
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Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking. Molecular pharmacology. 2000. Rao Y, et al. PubMed
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Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer research. 2000. Su T, et al. PubMed
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Expression and induction of CYP1A1/1A2, CYP2A6 and CYP3A4 in primary cultures of human hepatocytes: a 10-year follow-up. Xenobiotica; the fate of foreign compounds in biological systems. 2000. Meunier V, et al. PubMed
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Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin. British journal of clinical pharmacology. 1999. Svensson U S, et al. PubMed
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Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism. FEBS letters. 1999. Oscarson M, et al. PubMed
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Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Archives of toxicology. 1999. Yamazaki H, et al. PubMed
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Genotyping of human cytochrome P450 2A6 (CYP2A6), a nicotine C-oxidase. FEBS letters. 1998. Oscarson M, et al. PubMed
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Human CYP2C9 and CYP2A6 mediate formation of the hepatotoxin 4-ene-valproic acid. The Journal of pharmacology and experimental therapeutics. 1997. Sadeque A J, et al. PubMed
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A single amino acid substitution (Leu160His) in cytochrome P450 CYP2A6 causes switching from 7-hydroxylation to 3-hydroxylation of coumarin. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 1997. Hadidi H, et al. PubMed
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Role of human cytochrome P4502A6 in C-oxidation of nicotine. Drug metabolism and disposition: the biological fate of chemicals. 1996. Nakajima M, et al. PubMed
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Characterization of CYP2A6 involved in 3'-hydroxylation of cotinine in human liver microsomes. The Journal of pharmacology and experimental therapeutics. 1996. Nakajima M, et al. PubMed
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Human cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. Drug metabolism and disposition: the biological fate of chemicals. 1995. Zhang Z, et al. PubMed
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Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. The Journal of pharmacology and experimental therapeutics. 1994. Shimada T, et al. PubMed
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O-demethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4. Molecular pharmacology. 1994. Relling M V, et al. PubMed
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Identification of the human liver cytochrome P-450 responsible for coumarin 7-hydroxylase activity. The Biochemical journal. 1990. Miles J S, et al. PubMed
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The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes. Biochemistry. 1990. Yamano S, et al. PubMed

LinkOuts

Entrez Gene:
1548
OMIM:
122700
122720
188890
211980
UCSC Genome Browser:
NM_000762
RefSeq RNA:
NM_000762
RefSeq Protein:
NP_000753
RefSeq DNA:
AC_000062
AC_000151
NC_000019
NG_000008
NG_008377
NT_011109
NW_001838496
NW_927217
ALFRED:
LO027806X
HuGE:
CYP2A6
Comparative Toxicogenomics Database:
1548
HumanCyc Gene:
HS10343
HGNC:
2610

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