Gene:
NAT2
N-acetyltransferase 2 (arylamine N-acetyltransferase)

PharmGKB contains no dosing guidelines for this . To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.

PharmGKB annotates drug labels containing pharmacogenetic information approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), the Pharmaceuticals and Medical Devices Agency, Japan (PMDA), and Health Canada (Santé Canada) (HCSC). PharmGKB annotations provide a brief summary of the PGx in the label, an excerpt from the label and a downloadable highlighted label PDF file. A list of genes and phenotypes found within the label is mapped to label section headers and listed at the end of each annotation. PharmGKB also attempts to interpret the level of action implied in each label with the "PGx Level" tag.

See the legend for more information about drug label sources and PGx Levels.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA, PMDA, HCSC or other Medicine Agencies around the world - please contact feedback.



last updated 10/25/2013

FDA Label for hydralazine, isosorbide dinitrate and NAT2

Informative PGx

Summary

Isosorbide dinitrate and hydralazine hydrochloride (Bidil) is metabolized by acetylation, and individuals who are 'fast acetylators' may have increased exposure to the drug, whereas individuals who are 'slow acetylators' may have increased drug bioavailability. Acetylation status of an individual can be determined by examining genetic variants in the NAT2 gene.

Annotation

Isosorbide dinitrate and hydralazine hydrochloride (Bidil) is indicated for the treatment of heart failure in self-identified Black patients, as an adjunct therapy to standard therapy. The genetics behind the mode of efficacy related to this population of patients is to our knowledge currently unknown.

NAT1 and NAT2 genes are biomarkers listed for the Isosorbide dinitrate and Hydralazine drug label in the FDA Table of Pharmacogenomic Biomarkers in Drug Labels table, however the latest drug label for Bidil available (updated on 03/27/2013) does not specifically mention genetic or biomarker testing for these genes. The label does contain information relating to the metabolism of hydralazine by acetylation. NAT1 and NAT2 are acetyltransferase enzymes. The label states that individuals who are 'fast acetylators' may have reduced exposure to hydralazine and those that are 'slow acetylators' may have higher bioavailability, although the clinical consequence of this is not mentioned. Acetylation status of an individual can be determined by examining genetic variants in the NAT2 gene (see NAT2 VIP summary).

Excerpt from the Hydralazine hydrochloride and isosorbide dinitrate (Bidil) drug label in the Pharmacokinetics section:

Hydralazine is metabolized by acetylation, ring oxidation and conjugation with endogenous compounds including pyruvic acid. Acetylation occurs predominantly during the first-pass after oral administration which explains the dependence of the absolute bioavailability on the acetylator phenotype. About 50% of patients are fast acetylators and have lower exposure.


In patients with heart failure, mean absolute bioavailability of a single oral dose of hydralazine 75 mg varies from 10 to 26%, with the higher percentages in slow acetylators.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Isosorbide and Hydralazine (BiDil) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Eye Diseases
    • Precautions section
    • source: PHONT
  • Heart Failure
    • Indications & usage section, Adverse reactions section
    • source: PHONT
  • Ischemia
    • Precautions section
    • source: PHONT

last updated 10/25/2013

FDA Label for isoniazid, pyrazinamide, rifampin and NAT2

Informative PGx

Summary

'Slow inactivators' of isoniazid may be more susceptible to drug toxicity when taking Rifator due to higher blood concentrations of the drug in these individuals. Acetylation status of an individual can be determined by examining genetic variants in the NAT2 gene.

Annotation

NAT1 and NAT2 genes are biomarkers listed for the Rifampin, Isoniazid and Pyrazinamide (Rifator) drug label in the FDA Table of Pharmacogenomic Biomarkers in Drug Labels table, however the latest available drug label for Rifator (updated on 27/02/2013) does not specifically mention genetic or biomarker testing for these genes. The label does contain information relating to the metabolism of isoniazid by acetylation and dehydrazination. NAT1 and NAT2 are acetyltransferase enzymes. The label states that slow acetylators may have higher blood levels of isoniazid. Acetylation status of an individual can be determined by examining genetic variants in the NAT2 gene (see NAT2 VIP summary).

The label also mentions that Rifampin and Isoniazid can induce or inhibit particular CYP450 enzymes, and therefore could affect the metabolism of drugs taken concomitantly that are metabolized via these enzymes.

Excerpts from the Rifampin, Isoniazid, Pyrazinamid (RIFATER) drug label:

The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of the drug, and thus, an increase in toxic reactions.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Rifampin, Isoniazid and Pyrazinamide drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Genes and/or phenotypes found in this label

  • Hepatitis, Toxic
    • Indications & usage section, Contraindications section, Warnings section, Precautions section
    • source: PHONT
  • HIV
    • Indications & usage section
    • source: PHONT
  • Leukemia
    • Indications & usage section, Precautions section
    • source: PHONT
  • Toxic liver disease
    • Adverse reactions section, Precautions section
    • source: PHONT
  • Tuberculosis
    • Indications & usage section, Warnings section, Precautions section
    • source: PHONT

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the table.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

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.

List of all variant annotations for NAT2

Variant?
(144)
Alternate Names ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available CA VA *4 N/A N/A N/A
No VIP available CA VA *5 N/A N/A N/A
No VIP available No VIP available VA *5A N/A N/A N/A
No VIP available No VIP available VA *5B N/A N/A N/A
No VIP available No VIP available VA *5C N/A N/A N/A
No VIP available No VIP available VA *5D N/A N/A N/A
No VIP available CA VA *6 N/A N/A N/A
No VIP available No VIP available VA *6A N/A N/A N/A
No VIP available No VIP available VA *6B N/A N/A N/A
No VIP available No VIP available VA *6C N/A N/A N/A
No VIP available No VIP available VA *6J N/A N/A N/A
No VIP available No VIP available VA *6O N/A N/A N/A
No VIP available CA VA *7 N/A N/A N/A
No VIP available No VIP available VA *7A N/A N/A N/A
No VIP available No VIP available VA *7B N/A N/A N/A
No VIP available No VIP available VA *7G N/A N/A N/A
No VIP available No VIP available VA *11A N/A N/A N/A
No VIP available CA VA *12 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 *13 N/A N/A N/A
No VIP available No VIP available VA *13A N/A N/A N/A
No VIP available CA VA *14 N/A N/A N/A
No VIP available No VIP available VA *14A N/A N/A N/A
No VIP available No VIP available VA *14B N/A N/A N/A
No VIP available No VIP available VA *19 N/A N/A N/A
No VIP available No Clinical Annotations available NAT2 deficiency
NAT2 deficiency N/A N/A N/A
rs1041983 14041C>T, 18257795C>T, 282C>T, 6115941C>T, NAT2:282C>T, Tyr94=, signature SNP for NAT2*13 allelic group
C > T
Synonymous
Tyr94Tyr
rs1208 14562G>A, 18258316G>A, 18400806G>A, 803G>A, Arg268Lys, NAT2:803A>G, NAT2:LYS268ARG, one of 3 variants comprising NAT2*5B, signature SNP for NAT2*12 allelic group
G > A
Missense
Arg268Lys
VIP No Clinical Annotations available No Variant Annotations available
rs1495741 18272881G>A, 6131027G>A, NC_000008.10:g.18272881
G > A
Not Available
rs1799929 14240C>T, 18257994C>T, 18400484C>T, 481C>T, KpnI, Leu161=, NAT2*14C. T allele defines "M1", NAT2:481C>T, signature SNP for NAT2*11 allelic group
C > T
Synonymous
Leu161Leu
rs1799930 14349G>A, 18258103G>A, 18400593G>A, 590G>A, Arg197Gln, NAT2:590G>A, NAT2:ARG197GLN, alleles and*14D. A allele defines "M2", signature SNP for NAT2*6 allelic group
G > A
Missense
Arg197Gln
rs1799931 14616G>A, 18258370G>A, 6116516G>A, 857G>A, NAT2:857G>A, NAT2:GLY286GLU, NAT2:rs1799931 A>G, NM_000015.2:c.857G>A, NP_000006.2:p.Gly286Glu, included in NAT2*7B. A allele defines "M3", signature SNP for NAT2*7 allelic group
G > A
Missense
Gly286Glu
VIP No Clinical Annotations available No Variant Annotations available
rs1801279 13950G>A, 18257704G>A, 191G>A, 6115850G>A, Arg64Gln, NAT2:191G>A, NAT2:ARG64GLN, NAT2:M4, signature SNP for NAT2*14 allelic group
G > A
Missense
Arg64Gln
rs1801280 14100T>C, 18257854T>C, 18400344T>C, 341T>C, Ile114Thr, NAT2:341T>C, NAT2:ILE114THR, signature SNP for NAT2*5 allelic group
T > C
Missense
Ile114Thr
rs4271002 -594G>C, 18248268G>C, 4514G>C, 6106414G>C, NAT2 -594G>C, NAT2(-9246)C>G
G > C
5' Flanking
No VIP available No Clinical Annotations available VA
rs45607939 14372A>T, 18258126A>T, 6116272A>T, 613A>T, Met205Leu
A > T
Missense
Met205Leu
rs4646244 -1144T>A, 18247718T>A, 3964T>A, 6105864T>A, NAT2(-9796)T>A
T > A
5' Flanking
No VIP available No Clinical Annotations available VA
rs4646267 -949A>G, 18247913A>G, 4159A>G, 6106059A>G, NAT2(-9601)A>G
A > G
5' Flanking
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 144

Overview

Alternate Names:  AAC2
Alternate Symbols:  None
PharmGKB Accession Id: PA18

Details

Cytogenetic Location: chr8 : p22 - p22
GP mRNA Boundary: chr8 : 18248755 - 18258723
GP Gene Boundary: chr8 : 18238755 - 18261723
Strand: plus

Visualization

UCSC has a Genome Browser that you can use to view PharmGKB annotations for this gene in context with many other sources of information.

View on UCSC Browser
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.

Background

Function and expression

Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes for which three distinct enzymatic activities have been described. The first (EC 2.3.1.5) involves the acetyl coenzyme A (CoA) dependent N-acetylation of arylamines and arylhydrazines, a reaction usually associated with xenobiotic detoxification. The second (EC 2.3.1.118) is also acetyl-CoA dependent and involves O-acetylation of N-hydroxyarylamines [Article:19379125], typically generated through N-oxidation of arylamines by cytochrome P450 enzymes. The third (EC 2.3.1.56) is an acetyl-CoA independent N,O-acetyltransfer performed on N-arylhydroxamic acids, generating highly reactive mutagenic compounds that bind to DNA. NATs have important roles in the metabolism and detoxification of xenobiotics and therapeutic drugs, and are implicated in cancer risk due to their role in the activation or detoxification of carcinogens and their interaction with environmental chemicals [Articles:19018723, 22776642, 18852012].

Two NAT genes (NAT1 and NAT2) have been characterized in humans, which differ in gene structure, extent of genetic variation, pattern of developmental and tissue expression [Articles:23497148, 24467436, 18680469]. Their protein products have different physiological roles, and despite being structurally similar, differences in key residues result in different substrate profiles/ affinities [Articles:23497148, 24467436, 18680466]. NAT1 is ubiquitously expressed, and therefore may be involved in homeostasis and development, though levels of expression vary between cell types and tissues [Articles:19018723, 21401512, 17392017, 22090474, 18680469]. NAT2 expression is found predominantly in the liver, small intestine and colon tissues and thus is regarded as a typical xenobiotic metabolizing enzyme [Articles:17287389, 19018723, 21401512, 22090474, 18680469], though basal NAT2 mRNA levels can be found in most tissues [Article:19379125].

Genomic locus organization and protein structure

The genes NAT1, NAT2 and the nonfunctional pseudogene NATP (AACP) are found on chromosome 8p22 [Articles:19018723, 2340091, 8110178, 19379125]. NAT1 and NAT2 share 87.5% coding sequence homology, and around 80% with the corresponding sequence in NATP [Article:2340091]. The NAT1 gene contains eight non-coding exons upstream of the intronless open reading frame (ORF), resulting in differentially spliced transcripts with the same coding region that can be found in different tissues [Articles:15487985, 15853926, 15226672]. The NAT2 gene has one non-coding exon around 8.6kb upstream of the intronless ORF [Articles:15853926, 17287389, 1676262]. The two genes have ORFs of 870 nucleotides in length and they encode similar size proteins of 290 amino acids (~30 kDa) (GENEID: 9 and GENEID: 10). The crystal structure of human NAT1 and NAT2 proteins, 3-dimensional modeling and docking simulations, have provided insight into the functional properties of the two different isoenzymes, revealing a larger substrate binding pocket with a lip in NAT2 compared to NAT1, likely contributing to different substrate specificities [Articles:17656365, 18680466].

Genetic Polymorphisms and phenotype

Both NAT1 and NAT2 are polymorphic genes - to date (Jan 2014) 28 NAT1 alleles and 88 NAT2 alleles have been assigned official symbols by the Arylamine N-acetyltransferase Gene Nomenclature Committee, according to consensus guidelines [Article:18334921] (background). NAT1*4 and NAT2*4 are the reference (or "wildtype") alleles for the respective genes, and most variant alleles differ from these by one or more single nucleotide polymorphisms (SNPs).

Many NAT1 alleles result in a phenotype equivalent to that of reference NAT1*4 (*20, *21, *23, *24, *25, *27), some confer a "slow" acetylation phenotype (*14A, *14B, *17, *22), or result in truncated proteins with no enzymatic activity (*15, *19A, *19B), and others are undetermined. Despite these polymorphisms, looking across global human populations the NAT1 sequence seems to be highly conserved, though variation in the 3'-untranslated region (3'UTR) has been maintained [Articles:16416399, 21995608, 21081654].

In contrast, the NAT2 gene has a high frequency of functional variation, differing amongst populations that are ethnically diverse, and has high levels of haplotype diversity [Articles:16416399, 21995608]. SNPs within the NAT2 gene can affect NAT2 function by resulting in reduced enzyme stability, altered affinity for substrate, or a protein that is targeted for proteosome degradation [Articles:18680467, 19379125]. NAT2 genotypes can be grouped into three different phenotypes: "slow acetylator" (two slow alleles), "intermediate acetylator" (1 slow and 1 rapid allele), and "rapid" acetylator (2 rapid alleles, sometimes referred to as "fast") [Article:19018723]. Some papers simply report rapid (any genotypes containing NAT2*4) and slow (any non-carriers of NAT2*4) acetylators (for example [Article:17335581]). However, rapid alleles additional to NAT2*4 have been identified recently (e.g. *11A, *12A-C, *13A, *18), and heterozygous (intermediate) genotypes seem to display differences in phenotype compared to homozygous rapid (for examples see Section 4. Caffeine below). In addition, within the slow acetylator genotype group there is heterogeneity in phenotype due to variation in enzyme activity conferred by different alleles [Articles:22970273, 19379125, 7627960, 10335449] , which may affect the ability to detect significant associations [Article:24221535].

Early studies report a bimodal pattern of drug acetylation in a given population, and sulfamethazine (SMZ) was described as a suitable probe drug to divide individuals into a slow or rapid acetylator phenotype by plotting serum, urine or liver cytosol acetylation percentages [Articles:5365949, 7273597, 4029245, 2312737]. Now, many studies genotype NAT2 variants to define acetylator phenotype instead, and the SNPs investigated can vary between studies. An economic 4-SNP genotyping panel was reported to accurately predict NAT2 acetylator phenotype in different populations; rs1801280, rs1799930, rs1799931 and rs1801279 (See Variant Summaries) [Articles:22092036, 22676187] Hein & Doll Letter in response. Early genotyping methods based on PCR-RFLP typically used Kpn I (cuts wildtype allele C at position 481 rs1799929), Taq 1 (cuts wildtype allele G at position 590 rs1799930) and BamH I (cuts wildtype allele G at position 857 rs1799931) enzymes to distinguish NAT2*4 from the slow alleles described as *5, *6 and *7, respectively (for example [Articles:21261721, 12668988]) or defined as *5B, *6A, and *7B, respectively (for example [Articles:21856096, 21753138]). However, such approaches may lead to misclassification as the three SNPs they detect are present in numerous NAT2* alleles (see Variant Summaries). The methodology is also unable to detect other NAT2 slow alleles, such as NAT2*14A and *14B.

Several studies examining the diversity of NAT2 haplotypes between different populations and ethnicities support the hypothesis suggesting the NAT2 slow acetylator phenotype was positively selected for in the transition to an agricultural/ pastoral lifestyle from a hunter-gatherer/ nomadic lifestyle, resulting in changes in diet and thus exposure to different xenobiotics [Articles:16786516, 18043717, 18304320, 18773084, 21494681, 16416399]. For example, slow acetylator status is higher amongst Tajik populations (agriculturists) compared to Kirghiz populations (nomads) in Central Asia [Article:18043717], and a high frequency of rapid or intermediate status is observed in hunter-gatherer populations in Western/ Southern Africa (Kung San, Bakola Pygmy, Biaka Pygmy populations) [Articles:16786516, 21995608]. In India, the frequency of slow acetylators (based on genotype) is higher than rapid acetylators in areas where a vegetarian diet dominates, and the converse is observed in areas where non-vegetarian diet is more frequent [Article:23394391]. Worldwide NAT2 allele frequencies are detailed in the individual Variant Summaries (see links below).

It should be noted that the phenotype associated with a particular variant or allele may be specific to particular drugs, and that the designated phenotypes of NAT1 and NAT2 alleles are not always consistent in all studies (discussed in detail in [Article:18680467]). For example, compared with the product of the NAT1*4 reference allele, the enzyme conferred by NAT1*11 (as determined by genotyping 445G>A, 459G>A, 640T>G) displays increased acetylation activity against p-aminobenzoic acid. However, this effect seems to be substrate specific, as the difference in activity is not statistically significant with the carcinogen N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP) [Article:17909564]. Other studies report contradicting results (as discussed in [Article:17909564]). Another example of inconsistent phenotype is seen with the NAT2*7 signature variant rs1799931 857G>A, which displays decreased N-acetylation of sulfamethazine (SMZ) and decreased O-acetylation of the carcinogen N-OH-4-aminobiphenyl in vitro, indicating a slow acetylator phenotype. However O-acetylation activity against N-OH-PhIP does not differ from NAT2 4 [Article:17434923]. These results are also reflected in cells which express the NAT2*7B allele (rs1799931 857G>A and rs1041983 282C>T) [Article:17434923]. Regulatory mechanisms, substrate interaction, exposure to xenobiotics and other environmental factors may also influence NAT1 and NAT2 allele expression and activity [Articles:18680469, 18680470].

Another issue is determining phenotype from genotype. NAT2 alleles are often reported by examining a single SNP, however genotyping for other positions is required to confirm that it is the only variant in order to rule out other positions, and the number of SNPs covered by studies differs (also discussed in [Article:18680468]. This is particularly important for SNPs that are in NAT2 alleles with different phenotypes; for example rs1799929 allele T (the signature SNP for NAT2*11) is present in several slow and rapid alleles but alone does not seem to affect acetylation activity (see Variant Summaries) [Article:17434923].

Pharmacogenetics

Below we describe some of the important pharmacogenetic associations between NAT1 and NAT2 genetic variants and drug response, arranged by drug indication. Pharmacogenetic associations between NAT polymorphisms and drug responses are predominantly described for NAT2, because of its role in the metabolism of numerous pharmaceuticals. Please note that some studies do not mention NAT genotyping or the specific NAT enzyme involved in metabolism, simply reporting acetylation phenotype. However, where possible, we provide specific details for studies that do describe the specific enzyme or genetic variant.

1. Anti-infective agents

1.1 Isoniazid (INH)

The vast majority of NAT2 pharmacogenetic studies are those that report an association (or lack of) with anti-tuberculosis (anti-TB) drug-induced hepatotoxicity (ATDH), liver injury (DILI), or hepatitis. Standard therapy for TB infection involves a treatment regimen of INH, pyrazinamide, and rifampicin, sometimes with ethambutol or streptomycin, for 2 months, then INH and rifampicin for an additional 4 months [Articles:16503745, 17995946]. Latent infections can be treated with INH alone [Article:16503745]. NAT2 has a major role in the metabolism of INH, mediating its biotransformation to the metabolite acetyl-INH, which is hydrolyzed to isonicotinic acid or acetyl-hydrazine [Articles:18220565, 17995946, 21412230, 22037847, 21913872]. Acetyl-hydrazine can be further acetylated to the non-toxic diacetylhydrazine, or hydrolyzed to hydrazine [Articles:18220565, 17995946, 21412230, 22037847, 21913872]. Liver toxicity of INH treatment derives from INH itself (a hydrazine derivative) and its metabolites, including acetyl-hydrazine, hydrazine and ammonia, and is thought to involve the formation of reactive oxygen species that can cause necrosis and autoimmunity [Articles:21412230, 17995946, 18544910, 18220565, 1149365] and may also involve epigenetic effects [Article:17156885].

Due to reduced metabolism, NAT2 slow acetylators have increased exposure to INH and hydrazine compared to rapid acetylators [Articles:18544910, 17021358, 24383060, 23091716, 22695364, 24492365]. NAT2 slow acetylator profile (or two slow NAT2 alleles) has therefore been associated with an increased risk of hepatotoxicity/ liver injury/ hepatitis induced by anti-TB drug treatment as compared to rapid acetylators (and sometimes intermediates) in many studies [Articles:18421452, 17950035, 20392357, 22012226, 23190413, 22020825, 21047300, 18330759, 23407048, 10751073, 11915035, 12668988, 16246623, 21261721, 22162992, 22506592, 21753138, 21856096, 22788240, 23875638, 23394127]. Individual NAT2 SNPs have also been associated with ATDH (see Variant Summaries below).

However, there are numerous contradictory studies that do not find an association between increased risk of ATDH and slow NAT2 acetylator genotype in TB patients [Articles:19761367, 22947533, 22283902, 16677176, 16770646, 21753138], or NAT2 genotype with INH-induced adverse reactions in healthy individuals, despite an association seen between genotype and acetylator phenotype [Article:21479500]. Meta-analyses suggest there is a significantly increased risk of anti-TB drug induced liver injury/ hepatotoxicity in NAT2 slow acetylators [Articles:23082213, 23277397, 18713495, 22409928], but a publication bias for positive results in smaller studies is reported [Articles:23082213, 23277397]. This, along with allele frequency, definition of hepatotoxicity, study exclusion criteria, drug combination, other genetic variants, population ethnicity, genotyping method, haplotype reconstruction/ allele definition method, and grouping of genotypes into acetylator status, are all factors that may contribute to the differences seen in study outcome.

Despite these inconsistencies, a recent randomized control trial that compared standard INH dosing (n=52) with pharmacogenetic-based dosing (n=47) in Japanese patients supports an association between acetylator status (determined by NAT2 genotype) and INH treatment outcome. A significant decrease in the incidence of DILI in slow-acetylators and a reduced incidence of persistent positive TB culture (indicating efficacy) in rapid acetylators was observed compared to the corresponding genotype groups on standard dose [Article:23150149]. Combined, the relative risk of unfavorable events was significantly lower in the pharmacogenetic-based treatment group compared to the standard treatment group, suggesting that NAT2-based dosing may be of clinical relevance to enhance INH treatment efficacy and reduce toxicity, though further and more extensive studies in other populations are required [Article:23150149].

FDA-approved drug labels for INH differ slightly between manufacturers. One does not directly mention the NAT2 gene, but does mention that slow acetylation may result in higher levels of the drug and therefore an increase in toxic reactions (Remedyrepack Inc). Another mentions that rate of acetylation is genetically determined, different ethnicities display differences in rate of inactivation, and that slow acetylation may result in higher blood levels of the drug and therefore an increase in toxic reactions (Mikart Inc.). Rifater drug labels (a combination of rifampin, INH, pyrazinamide) contain similar information. All labels contain a boxed warning regarding hepatitis associated with INH treatment, but none mention this with regard to NAT2 or genetic testing.

1.2 Sulfamethoxazole

Sulfamethoxazole is acetylated to N-acetylsulfamethoxazole, or oxidized to sulfamethoxazole hydroxylamine (a reactive metabolite which may result in toxicity) by CYP450 enzymes [Article:18190954]. Recent studies have shown an association between NAT2 genotypes and sulfamethoxazole pharmacokinetics (PK). In renal transplant patients treated with an immunosuppressive regimen, significantly higher sulfamethoxazole concentrations in slow acetylators (defined as homozygotes or compound heterozygotes for NAT2*5, *6, or *7 variants) are seen compared to rapid acetylators (homozygous NAT2*4/*4), though the clinical relevance of this is not clear as toxic side effects in this study were not observed [Article:22106207].

Pneumocystis fungi is commonly found in the respiratory tract of most healthy individuals; however it can cause pneumonia in those who are immune-compromised or receiving immunosuppressive drugs, and is one of the most common infections associated with acquired immunodeficiency syndrome (AIDS) in HIV-infected patients [Article:22167405]. Co-trimoxazole (sulfamethoxazole combined with trimethoprim) is the choice medication for prophylaxis and treatment of Pneumocystis pneumonia; however it is associated with several significant side effects including skin rash, Stevens-Johnson syndrome and hepatic impairment [Article:22167405]. Different rates of co-trimoxazole induced adverse reactions are reported between ethnicities/ races (higher in Caucasians/ White patients), indicating a possible underlying pharmacogenetic association [Articles:8686712, 10509585]. Susceptibility to toxicity has been investigated in relation to NAT2 genotype due to the role of NAT2 in sulfamethoxazole PK. In a study of 48 Caucasian children under 3 years of age, 60% developed adverse reactions when treated with co-trimoxazole for pneumonia infection [Article:9923584]. NAT2 variants rs1799930 allele A and rs1799931 allele A were independently found at a significantly higher frequency in children with co-trimoxazole-induced adverse drug reactions (ADRs) compared to those without. Conversely, a significantly higher number of children with no variant alleles were found in the group without ADRs (absence of variant alleles rs1799929 481T, rs1208 803G, rs1799930 590A, rs1799931 857A) [Article:9923584]. In systemic lupus erythematosus (SLE) patients in Japan who were treated with co-trimoxazole, slow acetylator status (determined in this study by NAT2 genotypes *6A/*6A, *6A/*7B, *7B/*7B) was associated with an increased risk of adverse events, compared to rapid acetylators (genotypes NAT2*4/*4, *4/*5B, *4/*5E, *4/*6A, *4/*7B) [Article:17335581]. However, when sequencing the NAT2 gene, a matched case-control study excluding immuno-compromised patients found no association with individual NAT2 variants or slow acetylator genotype and risk of hypersensitivity to co-trimoxazole [Article:22850190]. Some adverse reactions with underlying auto-immune responses are not concentration-dependent, for example carbamazepine-induced Stevens Johnson Syndrome for which individuals with the HLA-B*5201 allele are at high risk [Article:23695185]. This may therefore be a factor underlying the lack of association between NAT2 genotype and hypersensitivity to co-trimoxazole.

Side effects of co-trimoxazole are higher in those with HIV infection compared to those without [Article:18190954] (Septra drug label), though association with NAT2 acetylator status and toxicity in HIV patients has been inconsistent. In the majority of studies, no association with co-trimoxazole hypersensitivity (fever and/ or rash, including Stevens-Johnson syndrome) and NAT2 slow acetylator genotype or individual NAT2 slow allele frequencies in HIV patients is reported [Articles:11186133, 12580987, 12043950, 11191886]. A significant association with risk of co-trimoxazole-induced cutaneous reactions was however seen in AIDS patients with a combined NAT2 slow acetylator and GSTM1 null/null genotype [Article:11191886]. Using dapsone or caffeine as a probe drug, no association with slow acetylator phenotype and co-trimoxazole hypersensitivity is observed in HIV patients [Articles:12580987, 12043950, 8689813, 11191886] though one study reports HIV patients who experienced co-trimoxazole hypersensitivity were significantly more likely to have a slow acetylator phenotype than patients who did not experience toxicity [Article:8031511]. Meta-analyses show no significant difference in the frequency of slow acetylator phenotype (combining 4 studies) or genotype (combining 3 studies) in HIV patients with or without hypersensitivity to co-trimoxazole [Articles:12580987, 11186133].

It should be noted that discordance between NAT2 acetylator genotype and acetylator phenotype has been reported in HIV patients [Articles:11191886, 12043950, 12580987, 11191886]. Lower NAT2 activity has been observed in HIV-infected subjects compared to uninfected subjects [Articles:20084375, 18680474]. Genotyping may also be a factor influencing this discrepancy. In one study, discrepancy between genotype and phenotype (as measured by dapsone as a probe drug) in 8 patients could be resolved in half of the cases by sequencing for other variants, the others were slow genotypes with a borderline rapid phenotype - highlighting the importance of looking at variation across the NAT2 gene rather than a handful of variants [Article:12580987].

2. Cardiovascular and hematology agents

Hydralazine

Hydralazine is a vasodilator used to treat hypertension [Articles:344023, 21896152]. More recently, due to its epigenetic effects, one group has investigated its use in combination with valproic acid in clinical trials with the hypothesis of reducing tumor resistance and increasing anti-cancer chemotherapy efficacy [Articles:17761710, 17183730, 22427797]. Its beneficial epigenetic effects in cancer cells are thought to be as an inhibitor of DNA methyltransferase (DNMT) enzymes in order to reactivate tumor suppressor genes silenced by DNA methylation [Article:19072646], and may also inhibit histone methyltransferase activity [Article:22427797] and histone acetyltransferases [Article:17156885]. Hydralazine is thought to be metabolized by two pathways, both of which involve acetylation [Article:2860675]. One is via direct acetylation, forming the metabolite 3-methyl-s-triazolo(3,4-a)-phthalazine (MTP), and 3-OH-MTP [Articles:2860675, 7587931]. Another is via oxidation to form an unstable intermediate compound that is acetylated to form N-acetylhydrazinophthalazine (NAcHPZ) [Article:2860675].

Acetylation status has been associated with PK parameters of hydralazine. After oral dose, rapid acetylators display lower hydralazine plasma concentrations and area under the concentration-time curve (but no real difference in drug half life) compared to slow acetylators [Articles:344023, 2860675, 21781652]. MTP/ hydralazine ratio can be used to divide a population into slow and rapid acetylators, with a lower and higher ratio, respectively [Article:1396201]. In one study, patients with a slow acetylator genotype displayed significant reductions in blood pressure measurements at 24 hours before and after hydralazine, whereas significant effects were not observed in rapid or intermediate acetylators [Article:24444407]. Three out of a total of four patients who presented hydralazine-induced adverse reactions had a slow acetylator genotype [Article:24444407]. However, evidence for hydralazine dose adjustment based on acetylator status is not clear. In recent clinical trials in cancer patients, rapid acetylators (according to SMZ-acetylator phenotype) are given more than double the dose of hydralazine than that of slow acetylators. This resulted in similar plasma levels between the two acetylator groups in two studies [Articles:17183730, 21781652]; but significantly higher plasma levels in rapid acetylators in a third study by the same group [Article:17761710]. In a separate study examining blood pressure and cardiac output, using half doses of hydralazine in SMZ-slow acetylators was ineffective at changing peripheral resistance [Article:2244017]. A model incorporating multiple clinical factors including acetylator status may better predict dose required for better response to hydralazine [Article:2231320]. The FDA-approved BiDil® (contains isosorbide dinitrate and hydralazine hydrochloride) is indicated for the treatment of heart failure in self-identified Black patients (though the genetics behind the mode of efficacy is to our knowledge currently unknown), and the drug label contains information regarding acetylation status explaining that rapid acetylators have lower exposure to the drug; however changes to dosing according to this are not mentioned.

Hydralazine treatment is associated with an increased risk of systemic lupus erythematosus (SLE) [Articles:20840450, 21513360], and this has been associated with acetylator status, though again this lacks clear evidence (discussed in [Article:4029245]). Acetylator status may be related to disease severity, with an increased number of lesions seen in slow SMZ acetylators with discoid LE and SLE [Article:4029245]. Studies using bacterial strains suggest that hydralazine is detoxified by acetylation to MTP [Article:7587931]. Other studies also suggest that drug-induced toxic side effects are likely due to hydralazine itself rather than its metabolites - hydralazine and INH both inhibit complement component C4, whereas MTP and N-acetyl INH have little inhibitory effect - inhibitory effects on the complement system may contribute to impaired clearance of immune complexes and thus to SLE [Articles:6147500, 20005073, 24467436]. Development of anti-nuclear antibody positivity in patients treated with hydralazine has been reported to be more likely and more rapid in slow acetylators compared to rapid acetylators, with occurrence of lupus more likely in slow acetylators [Articles:344023, 2860675]. However, further evidence and studies determining the genetic variants behind this association are required. Another potential mechanism behind hydralazine-induced lupus is the reduction of B cell receptor gene rearrangements required for self-tolerance shown in mice models, and transfer of hydralazine treated bone marrow B cells to naive mice caused autoantibody production compared to vehicle control transferred cells [Article:17404230]. Slow acetylators may have reduced clearance of hydralazine and thus higher repression of this mechanism compared to rapid acetylators, but again this requires investigation. Another theory suggests hydralazine-derivative (including todralazine and INH) -induced liver injury is due to inhibition of histone acetylation (carried out by histone acetyltransferase (HAT) enzymes), affecting transcription and inhibiting proliferation and thus impairing liver regeneration after hepatotoxicity has occurred [Article:17156885]. This is supported by slow acetylator mouse models in which todralazine treatment did not induce liver failure on its own; however in mice with anti-CD95 induced liver injury, it resulted in mortality, smaller livers and impaired histone acetylation compared to controls despite similar alanine transaminase (ALT) levels [Article:17156885]. The role of HATs, their cofactors, and histone acetylation in liver regeneration after toxic injury has been shown in other studies [Articles:21319192, 21763259]. This may be another contributing factor to drug-induced liver injury that affects association with NAT2 genotype. Toxicity of hydralazine and related compounds is likely a combination of formation of reactive species, triggering of immune responses/ autoimmunity, and epigenetic effects.

3. Pain, anti-inflammatory and immunomodulating agents

Sulfasalazine

Sulfasalazine is indicated for the treatment of ulcerative colitis, Crohn's disease and as a second-line treatment for arthritis (DrugBank) [Article:15752]. It is a combination of 5-aminosalicyclic acid and sulfapyridine linked together by an azo bond [Articles:2860675, 15752]. Gut bacteria split the bond, a mechanism thought to deliver the two compounds at higher concentrations to the colon than if administered alone [Articles:15752, 4402374]. The effective derivative of sulfasalazine is considered to be 5-aminosalicylic acid, the majority of which remains in the colon where it is subject to N-acetylation by NAT1 [Article:2860675] (DrugBank). The second derivative, sulfapyridine, is readily absorbed and converted to N-acetyl-sulfapyridine, a process influenced by NAT2 acetylator status [Articles:2860675, 15752].

Sulfasalazine PK is not influenced by NAT2 polymorphisms; however, metabolism of sulfapyridine to N-acetyl-sulfapyridine is significantly reduced in slow acetylators (carriers of two variant alleles NAT2*5B, *6A, *7B or *5, *6 and *7) compared to both intermediate (one variant and one NAT2*4 allele) and rapid acetylators (NAT2*4/*4) [Articles:18167504, 19560446]. Slow acetylators have higher concentrations and elimination half-life of sulfapyridine (based on genotyping NAT2 SNPs rs1041983, rs1801280, rs1799929, rs1799930, rs1799931) [Article:20040334]. Plotting of the metabolic ratio N-acetyl-sulfapyridine/ sulfapyridine against NAT2 genotype gives two distinct groups: rapid and slow acetylators [Article:20040334]. There may therefore be an association between increased risk of sulfasalazine-induced toxicity and higher concentrations of sulfapyridine observed in slow acetylators [Articles:2860675, 15752]. A prospective study in Japan of female rheumatoid arthritis (RA) patients treated with sulfasalazine identified 4 patients who had adverse events in a one year period - none had the NAT2*4 allele, each carrying two variant alleles [Article:18398952].

4. Caffeine

Paraxanthine, a metabolite of caffeine, can undergo acetylation by NAT2 to form 5-acetylamino-6-formylamino-3-methyluracil (AFMU) (see PharmGKB Caffeine Pathway, Pharmacokinetics) [Article:22293536]. Caffeine can be used as a non-toxic probe drug in vivo for predicting acetylator phenotype; by measuring metabolite ratio AFMU/1-methyl xanthine (1X) in urine after caffeine consumption, a bi- or tri-modal pattern in a given population is observed [Articles:6721992, 2312737, 8689813]. AFMU/AFMU+1X+1-methyluric acid (1U), AFMU+5-acetylamino-6-amino-3-methyluracil (AAMU)/AFMU+AAMU+1X+1U or AAMU/ AAMU+1X+1U metabolite ratios can also be used to determine acetylator phenotype [Articles:17221922, 22105431, 20801937, 14747882, 24306330]. Variability in NAT2 activity (as determined by caffeine AFMU/AFMU+1X+1U ratio) between different populations exists - significantly higher NAT2 activity is observed in Koreans compared to Swedes, and this may be due to a higher proportion of the NAT2*4 rapid allele in Koreans and the higher frequency of slow acetylator genotype in Swedes [Article:22105431]. Some studies report good concordance between acetylator phenotype determined by caffeine metabolite ratio and NAT2 genotype [Articles:17011540, 14747882]; however others show discordance [Articles:11191886, 20801937, 15558239, 11214777, 9333101, 7668286]. These discrepancies may be due to differences in sample collection and handling, laboratory techniques and conditions, genotyping method, differences in assignment of slow/intermediate/rapid to genotypes based on NAT2 allele combinations, whether heterozygotes are analyzed independently, as well as other genetic, disease state, environmental factors or use of drugs that could affect the caffeine metabolism pathway (as discussed in [Articles:15558239, 18680467, 8781741, 8866914, 12580991, 9333101]). In one study, up to 54% of the variation in acetylation activity determined by caffeine test could be explained by NAT2 genotype (homozygous wildtype, homozygous variant or heterozygous determined by PCR-RFLP), though phenotype variation was seen with homozygous wildtype [Article:8781741].

Cancer: NAT1 and NAT2 association with risk, treatment responses, treatment resistance and as drug targets

Due to their role in the activation or deactivation of xenobiotics, the NAT1 and NAT2 enzymes have been implicated in chemical carcinogenesis pathways. Polymorphisms in the NAT1 and NAT2 genes have therefore been investigated for an association with cancer risk, though findings are inconsistent, likely due to the complex nature of cancer etiology and the multiple factors that contribute to susceptibility.

For studies examining the risk of bladder cancer, some report a significant association with NAT2 slow acetylator genotype/ phenotype (e.g. [Article:22961351]), others do not after adjusting for multiple factors [Articles:24221535, 24092628]. Recent GWAS meta-analyses reveal multiple risk loci, including NAT2 [Article:24163127]. A meta-analysis of cases in the general population (n=5594) showed a significant association between NAT2 slow acetylation with risk of bladder cancer (OR=1.37, C.I.=1.22-1.54, p=2x10-7) [Article:17510073]. The rs1495741 AA genotype (located downstream of the NAT2 gene and associated with the slow acetylator status) was significantly associated with increased risk of bladder cancer in Europeans compared to those with AG or GG genotype [Article:20739907], and a GWAS meta-analysis consisting of 12,270 cases and 55,059 controls confirmed the association with the A risk allele, along with numerous other SNPs at other loci that contribute to risk [Article:24163127]. Furthermore, both an additive and multiplicative association was shown between smoking and rs1495741 allele A with risk of bladder cancer [Article:24163127]. This GWAS meta-analysis study did not identify risk alleles associated with NAT1, and a meta-analysis of 11 studies (n=3311 cases, n=3906 controls) found no association between bladder cancer and the NAT1*10 allele [Article:23569127]. However, NAT1*14A has been associated with increased risk of bladder cancer in Lebanese men [Articles:24319536, 23803105, 22956951].

Associations between NAT1/2 variants and susceptibly to other cancers also lacks clarity or require further study [Articles:18852012, 22090474, 16257833, 18680472]. For example, NAT2 slow acetylator genotype may be a small, low penetrance risk factor for head and neck cancer [Article:24338712]. Mixed results are reported for NAT2 genotype and risk of breast cancer [Articles:23628324, 24023296] and esophageal cancer [Articles:17661210, 19766908, 24586291]. The InterLymph Consortium found no association between NAT2 phenotype (based on genotype, 4421 cases, 4095 controls) or NAT1*10 (1528 cases, 1586 controls) and risk of non-hodgkin lymphoma [Article:23160945].

Gene-environment interactions for cancer risk have been reported in an attempt to identify risk factors [Article:18680472]. For example, individuals with a NAT1 rapid acetylator genotype (defined as homozygous for alleles NAT1*10, *11, or these alleles in combination with NAT1*3, *4), and AHR rs2066853 genotype GA or AA, and high meat consumption were found to have an increased risk of concurrent adenomatous and hyperplastic colorectal polyps [Article:18268115]. Conversely, meta-analyses show no statistically significant interaction between NAT1 acetylator phenotype and meat intake (2 studies), or NAT2 acetylator phenotype and meat intake (3 studies), with relation to risk of colorectal cancer [Article:23216531], though this may be due to low penetrance and the need to include multiple genetic risk factors.

As well as combinatorial environmental/ genetic factors, reaction context is also an important consideration - examining the site of action and specific reaction by NAT1/ NAT2 may make these associations clearer and more consistent. For example, O-acetylation by NAT1 can result in the formation of nitrenium ions from the unstable N-acetoxyarylamine which can react with DNA to cause mutations, whereas N-acetylation by NAT1 detoxifies aromatic amines [Articles:19379125, 22114069]. Similarly, O-acetylation of N-hydroxy-heterocyclic amine carcinogens by NAT2 in the colon can explain the association between rapid acetylator phenotype and colorectal cancer risk in those who consume well-done meat, whereas association with slow acetylator phenotype and bladder cancer in smokers or those exposed to chemical dyes can be explained by N-acetylation competing with N-hydroxylation by cytochrome P450 enzymes that produce aromatic amine carcinogens in the liver [Article:19379125]. N-acetylation of an aryldiamine (for example benzidine) could increase risk of bladder cancer due to enhancement of N-hydroxylation, whereas as N-acetylation of an arylmonoamine may have the opposite effect [Articles:19379125, 17510073]. It should also always be kept in mind that "slow" and "rapid" acetylator phenotype is not homogenous, and that if the underlying genetic polymorphisms affect enzyme-substrate affinity, then the resulting association may only be seen with some drugs/ chemicals and exposure levels [Article:19379125]. NAT1 activity is influenced by substrate-dependent down-regulation, the redox state of cells, and epigenetic regulation [Article:22090474], thus these may contribute to the lack of consistency seen between a direct association between NAT1 genotype and cancer risk, along with interacting environmental factors, other genetic polymorphisms, inconsistencies in allele-phenotype definitions or genotyping methods. For instance, attributing the rapid acetylation phenotype to the NAT1*10 and *11 alleles remains an issue of controversy among investigators and the phenotypic effects of many NAT1 polymorphisms (especially those in the 3' untranslated region of the gene) are still not well understood [Article:19379125]. Cell-specific expression of alleles, alternative NAT1 transcripts driven by different promoters or alternative polyadenylation site use may also be a factor, or if SNPs are missed in genotyping (for example misclassification of NAT1*10B for NAT1*10 [Articles:19379125, 22114069]).

Overexpression of NAT1 is a common finding in estrogen receptor positive breast tumors [Articles:18642144, 24467436]. Cells over-expressing NAT1 display resistance to etoposide in vitro [Article:14517345], and thus NAT1 activity may have implications in response to anti-cancer therapy - polymorphisms in the NAT1 gene that result in changes in enzyme activity could affect drug response, though this needs to be investigated. These, and studies that show an association between increased NAT1 expression/ activity and cancer cell proliferation, support the use of specific NAT1 probes as potential diagnostic tools and the development of direct NAT1 inhibitors as potential leads for cancer therapeutics [Articles:20170182, 22776642, 22090474, 21347396, 20100460, 19059786, 14517345, 24467436]. Though not their primary target, several current chemotherapeutics have been shown to inhibit NAT1 or N-acetyltransferase activity in vitro in human cancer cells: cisplatin [Article:18310302] and tamoxifen [Articles:12889515, 17564319].

Amonafide has anti-cancer properties but is no longer in clinical development due to failing to reach phase III clinical trial primary end points [Article:22272701]. The drug displayed variable and unpredictable toxic effects [Article:11259359]. NAT2 phenotype was one of the underlying genetic factors contributing to variation in myelosuppression severity; rapid acetylators (determined by caffeine test) were susceptible to greater toxicity and counter-intuitively displayed higher plasma concentrations of amonafide. This was thought to be due to production of the metabolite N-acetyl amonafide which inhibits the oxidation of amonafide by CYP1A2 [Articles:11259359, 1934870, 7884434]. Thus, higher and lower doses from the standard dosage were recommended in slow and rapid acetylators, respectively, and a pharmacodynamic model incorporating acetylator phenotype, gender and pre-treatment white blood cell count was developed [Articles:8485716, 8845865]. The story from this drug highlighted the importance of genetic influence on both drug pharmacokinetics and pharmacodynamics [Articles:11259359, 8845865].

NAT2 polymorphisms/ acetylator phenotype has been associated with risk of other complex multifactorial diseases (including asthma, Parkinson's Disease and diabetes), however the associations are inconclusive and further discussion of these is beyond the scope of this review [Articles:18680473, 18680475].

Summary

NAT1 and NAT2 are polymorphic enzymes with important roles in the deactivation or activation of numerous xenobiotics in humans. Due to expression of the isoenzyme in the liver, the genetic variants of NAT2 have primarily been associated with drug metabolism, response and toxicity. NAT2 genotype confers a slow, intermediate or rapid acetylation phenotype, resulting in differences in drug metabolic rates and susceptibility to drug toxicity. However, studies show inconsistencies for which NAT2 and NAT1 variants are genotyped and in the pooling of variants into phenotype groups, thus these factors along with how a patient's disease phenotype is defined, environmental factors, drug-drug interactions, and acetylation reaction context may contribute to the contradictory evidence for some pharmacogenetic and disease associations. Further studies are required to help determine whether genotyping of NAT2 is clinically useful for determining a patient's dosage for efficacy of treatment and to avoid drug toxicity.

Citation PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2. Pharmacogenetics and genomics. 2014. McDonagh Ellen M, Boukouvala Sotiria, Aklillu Eleni, Hein David W, Altman Russ B, Klein Teri E. PubMed
History

Submitted by Ellen M. McDonagh, Sotiria Boukouvala, Eleni Aklillu, David W. Hein, Russ B. Altman, Teri E. Klein, Ph.D. (Aug 2013)

Key Publications
  1. Arylamine N-acetyltransferases--from drug metabolism and pharmacogenetics to identification of novel targets for pharmacological intervention. Advances in pharmacology (San Diego, Calif.). 2012. Sim Edith, Fakis Giannoulis, Laurieri Nicola, Boukouvala Sotiria. PubMed
  2. Arylamine N-acetyltransferases: structural and functional implications of polymorphisms. Toxicology. 2008. Sim Edith, Lack Nathan, Wang Chan-Ju, Long Hilary, Westwood Isaac, Fullam Elizabeth, Kawamura Akane. PubMed
  3. Update on the pharmacogenetics of NATs: structural considerations. Pharmacogenomics. 2008. Stanley Lesley A, Sim Edith. PubMed
  4. N-acetylation pharmacogenetics. Pharmacological reviews. 1985. Weber W W, Hein D W. PubMed
Variant Summaries rs1041983, rs1208, rs1495741, rs1799929, rs1799930, rs1799931, rs1801279, rs1801280, rs4271002, rs4646244
Haplotype Summaries NAT2 *4
Drugs
Diseases
Pathways

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

  1. Caffeine Pathway, Pharmacokinetics
    Stylized liver cell showing candidate genes involved in the metabolism of caffeine.

External Pathways

Links to non-PharmGKB pathways.

  1. Acetylation - (Reactome via Pathway Interaction Database)
No related genes are available

Curated Information ?

Curated Information ?

Publications related to NAT2: 158

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Genetic determinants of metamizole metabolism modify the risk of developing anaphylaxis. Pharmacogenetics and genomics. 2015. García-Martín Elena, et al. PubMed
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Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene. The Journal of clinical investigation. 2015. Knowles Joshua W, et al. PubMed
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Pharmacogenomics of antimicrobial agents. Pharmacogenomics. 2014. Aung Ar Kar, et al. PubMed
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N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group. European journal of clinical pharmacology. 2014. Ng Ching-Soon, et al. PubMed
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Genetic polymorphisms affect efficacy and adverse drug reactions of DMARDs in rheumatoid arthritis. Pharmacogenetics and genomics. 2014. Zhang Ling Ling, et al. PubMed
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Pharmacogenomics of NAT2 and ABCG2 influence the toxicity and efficacy of sulphasalazine containing DMARD regimens in early rheumatoid arthritis. The pharmacogenomics journal. 2014. Wiese M D, et al. PubMed
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An atlas of genetic influences on human blood metabolites. Nature genetics. 2014. Shin So-Youn, et al. PubMed
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PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2. Pharmacogenetics and genomics. 2014. McDonagh Ellen M, et al. PubMed
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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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Novel NAT2 haplotyping using allele-specific sequencing. Pharmacogenomics. 2014. Kang Seong-Ho, et al. PubMed
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Future of pharmacogenetics-based therapy for tuberculosis. Pharmacogenomics. 2014. Matsumoto Tomoshige, et al. PubMed
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Different phenotypes of the NAT2 gene influences hydralazine antihypertensive response in patients with resistant hypertension. Pharmacogenomics. 2014. Spinasse Lizania Borges, et al. PubMed
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Full-gene sequencing analysis of NAT2 and its relationship with isoniazid pharmacokinetics in Venezuelan children with tuberculosis. Pharmacogenomics. 2014. Verhagen Lilly M, et al. PubMed
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Pharmacogenomic assessment of cisplatin-based chemotherapy outcomes in ovarian cancer. Pharmacogenomics. 2014. Khrunin Andrey V, 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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Pregnancy and pharmacogenomics in the context of drug metabolism and response. Pharmacogenomics. 2013. Helldén Anders, et al. PubMed
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Association of N-acetyltransferase 2 and cytochrome P450 2E1 gene polymorphisms with antituberculosis drug-induced hepatotoxicity in Western India. Journal of gastroenterology and hepatology. 2013. Gupta Vinod H, et al. PubMed
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N-acetyl transferase 2 and cytochrome P450 2E1 genes and isoniazid-induced hepatotoxicity in Brazilian patients. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2013. Santos N P C, et al. PubMed
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Pharmacogenetics of disease-modifying antirheumatic drugs in rheumatoid arthritis: towards personalized medicine. Pharmacogenomics. 2013. Umićević Mirkov Maša, et al. PubMed
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NAT2 sequence polymorphisms and acetylation profiles in Indians. Pharmacogenomics. 2013. Khan Naazneen, et al. PubMed
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Relationship of NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms with mild elevation of liver enzymes in Brazilian individuals under anti-tuberculosis drug therapy. Clinica chimica acta; international journal of clinical chemistry. 2013. Forestiero Francisco Jose, et al. PubMed
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Slow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis. Molecular biology reports. 2013. Du Haijian, et al. PubMed
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Correlation of N-acetyltransferase 2 genotype with isoniazid acetylation in polish tuberculosis patients. BioMed research international. 2013. Zabost Anna, et al. PubMed
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NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy. European journal of clinical pharmacology. 2012. Azuma Junichi, et al. PubMed
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Sex, ethnicity and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs. Journal of gastroenterology and hepatology. 2012. Chamorro Julián G, et al. PubMed
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Comparison of N-acetyltransferase-2 enzyme genotype-phenotype and xanthine oxidase enzyme activity between Swedes and Koreans. Journal of clinical pharmacology. 2012. Djordjevic Natasa, et al. PubMed
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Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis. Pathologie-biologie. 2012. Ben Mahmoud L, et al. PubMed
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Genetic interaction between NAT2, GSTM1, GSTT1, CYP2E1, and environmental factors is associated with adverse reactions to anti-tuberculosis drugs. Molecular diagnosis & therapy. 2012. Costa Gustavo N O, et al. PubMed
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Evaluation of polymorphisms in the sulfonamide detoxification genes NAT2, CYB5A, and CYB5R3 in patients with sulfonamide hypersensitivity. Pharmacogenetics and genomics. 2012. Sacco James C, et al. PubMed
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NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients. Clinical and experimental pharmacology & physiology. 2012. An Hui-Ru, et al. PubMed
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Accuracy of NAT2 SNP genotyping panels to infer acetylator phenotypes in African, Asian, Amerindian and admixed populations. Pharmacogenomics. 2012. Suarez-Kurtz Guilherme, et al. PubMed
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NAT2 polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: a meta-analysis. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2012. Wang P-Y, et al. PubMed
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The pharmacogenetics of NAT2 enzyme maturation in perinatally HIV exposed infants receiving isoniazid. Journal of clinical pharmacology. 2012. Zhu Rui, et al. PubMed
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Novel tagging SNP rs1495741 and 2-SNPs (rs1041983 and rs1801280) yield a high prediction of the NAT2 genotype in HapMap samples. Pharmacogenetics and genomics. 2012. He Yi Jing, et al. PubMed
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Influence of NAT2 polymorphisms on sulfamethoxazole pharmacokinetics in renal transplant recipients. Antimicrobial agents and chemotherapy. 2012. Kagaya Hideaki, 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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Accuracy of various human NAT2 SNP genotyping panels to infer rapid, intermediate and slow acetylator phenotypes. Pharmacogenomics. 2012. Hein David W, et al. PubMed
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Arylamine N-acetyltransferases--from drug metabolism and pharmacogenetics to identification of novel targets for pharmacological intervention. Advances in pharmacology (San Diego, Calif.). 2012. Sim Edith, et al. PubMed
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NAT2 genetic polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Chinese community population. Annals of hepatology. 2012. Lv Xiaozhen, et al. PubMed
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Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis. PloS one. 2012. Cai Yu, et al. PubMed
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alcohol, smoking, and caffeine in relation to fecundability, with effect modification by NAT2. Annals of epidemiology. 2011. Taylor Kira C, et al. PubMed
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Characterization of genetic variation and natural selection at the arylamine N-acetyltransferase genes in global human populations. Pharmacogenomics. 2011. Mortensen Holly M, et al. PubMed
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N-acetyltransferase 2 polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity in Caucasians. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2011. Leiro-Fernandez V, et al. PubMed
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Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients. Memórias do Instituto Oswaldo Cruz. 2011. Teixeira Raquel Lima de Figueiredo, et al. PubMed
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Comparison between acetylator phenotype and genotype polymorphism of n-acetyltransferase-2 in tuberculosis patients. Hepatology international. 2011. Rana S V, et al. PubMed
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A fresh look at the mechanism of isoniazid-induced hepatotoxicity. Clinical pharmacology and therapeutics. 2011. Metushi I G, et al. PubMed
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Pharmacogenomics: the genetics of variable drug responses. Circulation. 2011. Roden Dan M, 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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A single nucleotide polymorphism tags variation in the arylamine N-acetyltransferase 2 phenotype in populations of European background. Pharmacogenetics and genomics. 2011. García-Closas Montserrat, et al. PubMed
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Genetic variation in the bioactivation pathway for polycyclic hydrocarbons and heterocyclic amines in relation to risk of colorectal neoplasia. Carcinogenesis. 2011. Wang Hansong, et al. PubMed
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Regulation of phase II biotransformation enzymes by steroid hormones. Current drug metabolism. 2011. Kohalmy Krisztina, et al. PubMed
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Association of N-acetyltransferase-2 genotypes and anti-tuberculosis induced liver injury; first case-controlled study from Iran. Current drug safety. 2011. Khalili Hossein, et al. PubMed
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NAT2, CYP2C9, CYP2C19, and CYP2E1 genetic polymorphisms in anti-TB drug-induced maculopapular eruption. European journal of clinical pharmacology. 2011. Kim Sang-Heon, et al. PubMed
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Global patterns of genetic diversity and signals of natural selection for human ADME genes. Human molecular genetics. 2011. Li Jing, et al. PubMed
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Databases in the area of pharmacogenetics. Human mutation. 2011. Sim Sarah C, et al. PubMed
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Role of polymorphic N-acetyl transferase2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis. Journal of gastroenterology and hepatology. 2011. Bose Purabi Deka, et al. PubMed
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Association of isoniazid-metabolizing enzyme genotypes and isoniazid-induced hepatotoxicity in tuberculosis patients. In vivo (Athens, Greece). 2011. Sotsuka Takayo, et al. PubMed
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Effects of single nucleotide polymorphisms on human N-acetyltransferase 2 structure and dynamics by molecular dynamics simulation. PloS one. 2011. Rajasekaran M, et al. PubMed
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Pharmacogenetic & pharmacokinetic biomarker for efavirenz based ARV and rifampicin based anti-TB drug induced liver injury in TB-HIV infected patients. PloS one. 2011. Yimer Getnet, et al. PubMed
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Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, et al. PubMed
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Caffeine, selected metabolic gene variants, and risk for neural tube defects. Birth defects research. Part A, Clinical and molecular teratology. 2010. Schmidt Rebecca J, et al. PubMed
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Polymorphisms of caffeine metabolism and estrogen receptor genes and risk of Parkinson's disease in men and women. Parkinsonism & related disorders. 2010. Palacios N, et al. PubMed
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Association analysis of N-acetyl transferase-2 polymorphisms with aspirin intolerance among asthmatics. Pharmacogenomics. 2010. Kim Jin-Moo, et al. PubMed
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A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform. The pharmacogenomics journal. 2010. Deeken J F, et al. PubMed
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Drug-induced liver injury: past, present and future. Pharmacogenomics. 2010. Daly Ann K. PubMed
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NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2010. Lee S-W, et al. PubMed
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Low N-acetyltransferase 2 activity in isoniazid-associated acute hepatitis requiring liver transplantation. Transplant international : official journal of the European Society for Organ Transplantation. 2010. Cramer Jakob P, et al. PubMed
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Phenotyping with sulfasalazine - time dependence and relation to NAT2 pharmacogenetics. International journal of clinical pharmacology and therapeutics. 2010. Kuhn U D, et al. PubMed
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Association of polymorphism in cytochrome P450 2D6 and N-acetyltransferase-2 with Parkinson's disease. Disease markers. 2010. Singh Madhu, et al. PubMed
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Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis. Pharmacogenomics. 2009. Kim Sang-Heon, et al. PubMed
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Effects of NAT2 polymorphism on SASP pharmacokinetics in Chinese population. Clinica chimica acta; international journal of clinical chemistry. 2009. Ma Jing-Jing, et al. PubMed
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Drug-induced liver injury: insights from genetic studies. Pharmacogenomics. 2009. Andrade Raúl J, et al. PubMed
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Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population. Pharmacogenomics. 2009. Yamada So, et al. PubMed
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N-acetyltransferase SNPs: emerging concepts serve as a paradigm for understanding complexities of personalized medicine. Expert opinion on drug metabolism & toxicology. 2009. Hein David W. PubMed
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Arylamine N-acetyltransferases: structural and functional implications of polymorphisms. Toxicology. 2008. Sim Edith, et al. PubMed
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Red meat intake, doneness, polymorphisms in genes that encode carcinogen-metabolizing enzymes, and colorectal cancer risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2008. Cotterchio Michelle, et al. PubMed
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Update on the pharmacogenetics of NATs: structural considerations. Pharmacogenomics. 2008. Stanley Lesley A, et al. PubMed
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Drug-metabolising enzyme polymorphisms and predisposition to anti-tuberculosis drug-induced liver injury: a meta-analysis. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2008. Sun F, et al. PubMed
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Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 (BCRP) gene polymorphisms in humans. Clinical pharmacology and therapeutics. 2008. Yamasaki Y, et al. PubMed
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Structure/function evaluations of single nucleotide polymorphisms in human N-acetyltransferase 2. Current drug metabolism. 2008. Walraven Jason M, et al. PubMed
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Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil. European journal of clinical pharmacology. 2008. Possuelo L G, et al. PubMed
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Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients. The Journal of toxicological sciences. 2008. Fukino Katsumi, et al. PubMed
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Changes in consensus arylamine N-acetyltransferase gene nomenclature. Pharmacogenetics and genomics. 2008. Hein David W, et al. PubMed
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Prospective study of the association between NAT2 gene haplotypes and severe adverse events with sulfasalazine therapy in patients with rheumatoid arthritis. The Journal of rheumatology. 2008. Soejima Makoto, et al. PubMed
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Pharmacogenomics of anti-TB drugs-related hepatotoxicity. Pharmacogenomics. 2008. Roy Puspita Das, et al. PubMed
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Population genetic diversity of the NAT2 gene supports a role of acetylation in human adaptation to farming in Central Asia. European journal of human genetics : EJHG. 2008. Magalon Hélène, et al. PubMed
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Antituberculosis drug-induced hepatotoxicity: concise up-to-date review. Journal of gastroenterology and hepatology. 2008. Tostmann Alma, et al. PubMed
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Worldwide distribution of NAT2 diversity: implications for NAT2 evolutionary history. BMC genetics. 2008. Sabbagh Audrey, et al. PubMed
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Isoniazid: metabolic aspects and toxicological correlates. Current drug metabolism. 2007. Preziosi Paolo. PubMed
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Genotype and phenotype of NAT2 and the occurrence of adverse drug reactions in Mexican individuals to an isoniazid-based prophylactic chemotherapy for tuberculosis. Molecular medicine reports. 2008. Díaz-Molina Raúl, et al. PubMed
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Determining the relation between N-acetyltransferase-2 acetylator phenotype and antituberculosis drug induced hepatitis by molecular biologic tests. Tüberküloz ve toraks. 2008. Bozok Cetintaş Vildan, et al. PubMed
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NAT2 6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis. World journal of gastroenterology : WJG. 2007. Higuchi Norihide, et al. PubMed
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Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis (Edinburgh, Scotland). 2007. Cho Hyun-Jung, et al. PubMed
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Contribution of the N-acetyltransferase 2 polymorphism NAT2*6A to age-related hearing impairment. Journal of medical genetics. 2007. Van Eyken E, et al. PubMed
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Functional characterization of single-nucleotide polymorphisms and haplotypes of human N-acetyltransferase 2. Carcinogenesis. 2007. Zang Yu, et al. PubMed
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Validation of the associations between single nucleotide polymorphisms or haplotypes and responses to disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a proposal for prospective pharmacogenomic study in clinical practice. Pharmacogenetics and genomics. 2007. Taniguchi Atsuo, et al. PubMed
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Analysis of nucleotide diversity of NAT2 coding region reveals homogeneity across Native American populations and high intra-population diversity. The pharmacogenomics journal. 2007. Fuselli S, 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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Concordance between the deduced acetylation status generated by high-speed: real-time PCR based NAT2 genotyping of seven single nucleotide polymorphisms and human NAT2 phenotypes determined by a caffeine assay. Clinica chimica acta; international journal of clinical chemistry. 2007. Rihs Hans-Peter, et al. PubMed
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Commentary: Reflections on G. M. Lower and colleagues' 1979 study associating slow acetylator phenotype with urinary bladder cancer: meta-analysis, historical refinements of the hypothesis, and lessons learned. International journal of epidemiology. 2007. Rothman Nathaniel, et al. PubMed
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Effect of common NAT2 variant alleles in the acetylation of the major clonazepam metabolite, 7-aminoclonazepam. Drug metabolism letters. 2007. Olivera M, et al. PubMed
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Association of the diplotype configuration at the N-acetyltransferase 2 gene with adverse events with co-trimoxazole in Japanese patients with systemic lupus erythematosus. Arthritis research & therapy. 2007. Soejima Makoto, et al. PubMed
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DNA microarray genotyping of N-acetyltransferase 2 polymorphism using carbodiimide as the linker for assessment of isoniazid hepatotoxicity. Tuberculosis (Edinburgh, Scotland). 2006. Shimizu Yasuo, et al. PubMed
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CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. European journal of clinical pharmacology. 2006. Vuilleumier Nicolas, et al. PubMed
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Predisposition of antituberculosis drug induced hepatotoxicity by cytochrome P450 2E1 genotype and haplotype in pediatric patients. Journal of gastroenterology and hepatology. 2006. Roy Bidyut, et al. PubMed
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The influence of NAT2 genotypes on the plasma concentration of isoniazid and acetylisoniazid in Chinese pulmonary tuberculosis patients. Clinica chimica acta; international journal of clinical chemistry. 2006. Chen Bing, et al. PubMed
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SNP selection at the NAT2 locus for an accurate prediction of the acetylation phenotype. Genetics in medicine : official journal of the American College of Medical Genetics. 2006. Sabbagh Audrey, et al. PubMed
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Acetylation genotype and phenotype in patients with systemic lupus erythematosus. Pharmacological reports : PR. 2006. Rychlik-Sych Mariola, et al. PubMed
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The role of Gilbert's syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine. The pharmacogenomics journal. 2006. Hermann R, et al. PubMed
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Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Archives of disease in childhood. 2005. Schaaf H S, et al. PubMed
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Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses?. Antimicrobial agents and chemotherapy. 2005. Kinzig-Schippers Martina, et al. PubMed
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Re-investigation of the concordance of human NAT2 phenotypes and genotypes. Archives of toxicology. 2005. Bolt Hermann M, et al. PubMed
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Lack of association between arylamine N-acetyltransferase 2 (NAT2) polymorphism and systemic sclerosis. European journal of clinical pharmacology. 2005. Skretkowicz K, et al. PubMed
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The T341C (Ile114Thr) polymorphism of N-acetyltransferase 2 yields slow acetylator phenotype by enhanced protein degradation. Pharmacogenetics. 2004. Zang Yu, et al. PubMed
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Pharmacogenetics of antihypertensive drug responses. American journal of pharmacogenomics : genomics-related research in drug development and clinical practice. 2004. Schwartz Gary L, et al. PubMed
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Effects of tamoxifen on DNA adduct formation and arylamines N-acetyltransferase activity in human breast cancer cells. Research communications in molecular pathology and pharmacology. 2004. Lee Jau-Hong, et al. PubMed
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Genotype and allele frequencies of TPMT, NAT2, GST, SULT1A1 and MDR-1 in the Egyptian population. British journal of clinical pharmacology. 2003. Hamdy Samar I, et al. PubMed
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NAT2 slow acetylator function as a risk indicator for age-related cataract formation. Pharmacogenetics. 2003. Meyer David, et al. PubMed
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Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology (Baltimore, Md.). 2003. Huang Yi-Shin, et al. PubMed
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Slow acetylator phenotype and genotype in HIV-positive patients with sulphamethoxazole hypersensitivity. British journal of clinical pharmacology. 2003. Alfirevic Ana, et al. PubMed
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Glutathione S-transferase M1 polymorphism and the risk of lung cancer. Anticancer research. 2003. Mohr Lawrence C, et al. PubMed
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Increased genotype frequency of N-acetyltransferase 2 slow acetylation in patients with rheumatoid arthritis. Clinical pharmacology and therapeutics. 2002. Pawlik Andrzej, et al. PubMed
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Effect of interferon alpha-ribavirin bitherapy on cytochrome P450 1A2 and 2D6 and N-acetyltransferase-2 activities in patients with chronic active hepatitis C. Clinical pharmacology and therapeutics. 2002. Becquemont Laurent, et al. PubMed
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Acetylator phenotype and genotype in HIV-infected patients with and without sulfonamide hypersensitivity. Journal of clinical pharmacology. 2002. O'Neil William M, et al. PubMed
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Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology (Baltimore, Md.). 2002. Huang Yi-Shin, et al. PubMed
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Analysis of six SNPs of NAT2 in Ngawbe and Embera Amerindians of Panama and determination of the Embera acetylation phenotype using caffeine. Pharmacogenetics. 2002. Jorge-Nebert Lucia F, et al. PubMed
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Arylamine N-acetyltransferase type 2 and glutathione S-transferases M1 and T1 polymorphisms in familial adenomatous polyposis. Pharmacogenetics. 2002. Lamberti Christof, et al. PubMed
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Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses. Obstetrics and gynecology. 2001. Signorello L B, et al. PubMed
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Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 'null' mutation. Journal of gastroenterology and hepatology. 2001. Roy B, et al. PubMed
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Prospective evaluation of detoxification pathways as markers of cutaneous adverse reactions to sulphonamides in AIDS. Pharmacogenetics. 2000. Wolkenstein P, et al. PubMed
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Tamoxifen inhibits arylamine N-acetyltransferase activity and DNA-2-aminofluorene adduct in human leukemia HL-60 cells. Research communications in molecular pathology and pharmacology. 2001. Lu K H, et al. PubMed
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Association analysis of drug metabolizing enzyme gene polymorphisms in HIV-positive patients with co-trimoxazole hypersensitivity. Pharmacogenetics. 2000. Pirmohamed M, et al. PubMed
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Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2000. Ohno M, et al. PubMed
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Polymorphisms of NAT2 in relation to sulphasalazine-induced agranulocytosis. Pharmacogenetics. 2000. Wadelius M, et al. PubMed
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Populations and genetic polymorphisms. Molecular diagnosis : a journal devoted to the understanding of human disease through the clinical application of molecular biology. 1999. Weber W W. PubMed
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Chromosomal aberrations in humans induced by urban air pollution: influence of DNA repair and polymorphisms of glutathione S-transferase M1 and N-acetyltransferase 2. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 1999. Knudsen L E, et al. PubMed
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Rate of caffeine metabolism and risk of spontaneous abortion. American journal of epidemiology. 1998. Fenster L, et al. PubMed
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The arylamine N-acetyltransferase (NAT2) polymorphism and the risk of adverse reactions to co-trimoxazole in children. European journal of clinical pharmacology. 1998. Zielińska E, et al. PubMed
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Meta-analysis of phenotype and genotype of NAT2 deficiency in Chinese populations. Pharmacogenetics. 1997. Xie H G, et al. PubMed
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Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism. Clinical pharmacology and therapeutics. 1997. Okumura K, et al. PubMed
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Human acetyltransferase polymorphisms. Mutation research. 1997. Grant D M, et al. PubMed
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N-acetyltransferases: pharmacogenetics and clinical consequences of polymorphic drug metabolism. Journal of pharmacokinetics and biopharmaceutics. 1996. Spielberg S P. PubMed
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N-acetyltransferase 2 polymorphism in patients infected with human immunodeficiency virus. Clinical pharmacology and therapeutics. 1996. Kaufmann G R, et al. PubMed
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Predictors of N-acetyltransferase activity: should caffeine phenotyping and NAT2 genotyping be used interchangeably in epidemiological studies?. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 1996. Le Marchand L, et al. PubMed
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CYP2D6, N-acetylation, and xanthine oxidase activity in cystic fibrosis. Pharmacotherapy. 1996. Bosso J A, et al. PubMed
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Acetylation and its role in the mutagenicity of the antihypertensive agent hydralazine. Drug metabolism and disposition: the biological fate of chemicals. 1995. Lemke L E, et al. PubMed
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Acetylation phenotype and cutaneous hypersensitivity to trimethoprim-sulphamethoxazole in HIV-infected patients. AIDS (London, England). 1994. Carr A, et al. PubMed
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The use of caffeine for enzyme assays: a critical appraisal. Clinical pharmacology and therapeutics. 1993. Kalow W, et al. PubMed
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Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics. 1992. Gu L, et al. PubMed
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Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proceedings of the National Academy of Sciences of the United States of America. 1991. Blum M, et al. PubMed
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Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clinical pharmacology and therapeutics. 1991. Rieder M J, et al. PubMed
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Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA and cell biology. 1990. Blum M, et al. PubMed
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N-acetylation pharmacogenetics. Pharmacological reviews. 1985. Weber W W, et al. PubMed
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Hydralazine-induced lupus: is there a toxic metabolic pathway?. European journal of clinical pharmacology. 1984. Timbrell J A, et al. PubMed
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Clonazepam acetylation in fast and slow acetylators. Clinical pharmacology and therapeutics. 1981. Miller M E, et al. PubMed
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Metabolism of hydralazine. Drug metabolism reviews. 1977. Israili Z H, et al. PubMed
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Clinical pharmacokinetics of sulphasalazine. Clinical pharmacokinetics. 1976. Das K M, et al. PubMed
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An improved and simplified method of detecting the acetylator phenotype. Journal of medical genetics. 1969. Evans D A. PubMed