Annotated PGx Gene Information for CYP2D6

Citation: Cytochrome P450 2D6. Owen RP, Sangkuhl K, Klein TE, Altman RB. Pharmacogenet Genomics. 2009 Jul;19(7):559-62. PMID: 19512959 .

PharmGKB VIP Submitted by: Ryan Owen, Katrin Sangkuhl (PharmGKB)
PharmGKB Submission date: October 5, 2007
PharmGKB VIP Updated: February 14, 2009
PharmGKB VIP Reviewed: February 14, 2009

Gene HGNC Name:	CYP2D6
Gene Common Name:	CYP2D6
Introductory Information:	Introduction The cytochrome P450 2D6 (CYP2D6) is an enzyme of great historical importance for pharmacogenetics and is now thought to be involved in the metabolism of up to 25% of the drugs that are in common use in the clinic [18001838]. Several years before the gene was cloned, researchers observed that Caucasian subjects responded in a bimodal pattern to certain drugs such as debrisoquine and sparteine [71400, 499318], with most patients exhibiting "normal" pharmacokinetics, whereas others seemed to have great difficulty in metabolizing debrisoquine or sparteine. Debrisoquine and sparteine became examples of so-called probe drugs, and were used to phenotype patients [6644761]. This finding led researchers to conclude that there were common polymorphisms in an as yet unidentified metabolic gene that contributed to the variable pharmacokinetics of these drugs. The protein responsible for the altered metabolism was later purified from human liver microsomes by Distlerath et al. [4019462]. The gene encoding this protein was initially localized to chromosome 22 by Eichelbaum et al. [3472585]. The cDNA was cloned by Gonzalez et al. [3123997, 3410476] from human liver cDNA libraries using an antibody against the rat ortholog. The deduced human protein revealed 73% sequence similarity with the rat protein and by use of human-rodent somatic cell hybrids the gene was localized to human chromosome 22 [3410476], confirming the earlier study [3472585]. This gene came to be called CYP2D6, and is part of the cytochrome P450 gene family - a group of enzymes that is responsible for Phase I metabolism and elimination of numerous endogenous substrates and a diverse array of drugs. Among the drug-metabolizing CYPs, CYP2D6 is the only non-inducible enzyme, which results in a large contribution of genetic variation to the interindividual variation in enzyme activity [18001838]. CYP2D6 is highly polymorphic, with over 90 known allelic variants [8807658]. A selection of these variants and haplotypes is described in this summary, and the full list of all named alleles can be found at: http://www.cypalleles.ki.se/cyp2d6.htm. CYP2D6 metabolizer classes CYP2D6 became an object of intense research following its identification as the gene responsible for the altered activity observed with debrisoquine and other drugs. It soon became apparent that there were many different polymorphisms in all parts of the world that impacted CYP2D6 activity [17301689]. There were alleles that led to a complete loss of CYP2D6 activity, which were common in the initially studied Caucasian populations [12959412]; however, studies in populations of other ethnic origins revealed reduced function and even hyperfunctional CYP2D6 alleles [7903454, 3410476]. A system of assigned patients into four categories based on their ability to metabolize CYP2D6 substrates began to emerge. They are, listed in order of highest functioning to lowest: ultrarapid metabolizers (UM), extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM) [16968950, 14618296]. An individual's highest functioning CYP2D6 allele predicts his/her phenotypic activity [16968950, 14618296] (e.g. EM allele and PM allele results in an EM phenotype, UM allele and EM allele results in UM phenotype, IM allele and PM allele results in IM phenotype, etc.). EMs possess at least one fully functional CYP2D6 allele, and are thought of as phenotypically normal. IMs (two reduced function or one reduced and one non-functional allele) and PMs (two non-functional alleles) are not able to metabolize CYP2D6 substrates as well as their EM counterparts, and may be at increased risk for adverse effects resulting from higher plasma levels of the parent drug, or lack of efficacy resulting from an inability to form an active metabolite [16968950]. UMs, or ultrarapid metabolizers, possess multiple functional copies of a single CYP2D6 gene [12571261]. The CYP2D6 copy number has been found to be from 2-13 [12571261]. Each functional copy of CYP2D6 that is present increases the rate of metabolism of CYP2D6 substrates significantly [12571261]. CYP2D6 allele distributions exhibit significant interethnic differences. According to a review by Ingelman-Sundberg et al. [18001838], PMs are mainly found in Europe, and UMs are mainly found in North Africa and Oceania. Due to the high Asian prevalence of the CYP2D610* allele, IMs are located to a great extent in Asia [18001838, 15492763]. CYP2D6 substrates and therapeutic implications CYP2D6 polymorphisms have implications across many different therapeutic areas, as a diverse array of clinically used drugs are metabolized by CYP2D6 [16968950] (see Drugs/Substrates section for references). Examples of CYP2D6 substrates can be found in antidepressants (amitriptyline, citalopram, clomipramine, desipramine, doxepin, fluvoxamine, imipramine, maprotiline, mianserin, nortriptyline, fluoxetine, paroxetine), antipsychotics (chlorpromazine, clozapine, haloperidol, perphenazine, risperidone, thioridazine, zuclopenthixol), antiarrhythmics (flecainide, mexiletine, propafenone), beta-blockers (carvedilol, metoprolol, yohimbine, timolol), opioid analgesics (codeine, dihydrocodeine, morphine, tramadol), anticancer agents (debrisoquine, gefitinib, sparteine, tamoxifen), and assorted other drugs (atomoxetine, dextromethorphan, perhexilline, tolterodine). The impact that a CYP2D6 polymorphism has on therapy with any of the aforementioned drugs is related to the resulting metabolizer status that the polymorphism(s) cause in the individual receiving therapy, as well as whether the parent drug is active or if it requires CYP2D6 to metabolize it into an active metabolite. If the parent drug is active, then UMs may suffer from a lack of efficacy whereas IMs and PMs may suffer from complications resulting from higher than desired plasma concentrations of the drug [12571261]. If the parent drug must be converted to an active metabolite in order to relieve symptoms, then IMs and PMs may be deficient in the formation of the metabolite, and therefore not receive symptomatic relief [12571261]. Phenocopying and Autophenocopying Therapy with CYP2D6 substrates can be complex, not only due to genetic variation, but also due to drug-drug interactions. Many drugs are CYP2D6 inhibitors (such as the statins [8737761]), and taking an inhibitory drug along with a CYP2D6 substrate can alter the apparent phenotype of the patient. This phenomenon is known as phenocopying [16968950 12870705]. When this situation occurs, an EM can appear to be a IM or a PM because most of the available enzyme is being inhibited by a confounding drug. A related phenotype that can occur with chronic dosing of a CYP2D6 drug is called autophenocopying, in which a CYP2D6 substrate can inhibit its own metabolism over time as the concentration of the drug approaches steady state [16968950]. The pharmacokinetic profile of a single dose and of repeated dosing for drugs that exhibit phenocopying can therefore differ markedly [16968950]. CYP2D6 SNPs and Haplotypes Traditionally, allele frequency is reported with respect to an individual SNP, and haplotypes are constructed from a collection of those polymorphic sites. However, in the CYP2D6 literature, allele frequencies are usually reported in terms of haplotypes. We have therefore included the CYP2D6 allele frequency table in the haplotype section of this summary. CYP2D6 genotyping has traditionally been done according to an algorithm that appears in Gaedigk et al [10634130] in which several SNPs are tested for, and if none are found, then the algorithm defaults to either CYP2D61* or CYP2D62. We have classified the SNPs that are used to differentiate the haplotypes that we have summarized, and indicated whether that SNP has any role in the altered function when possible. Since most of the CYP2D6 literature is focused on determining an individual's metabolic status, we have chosen the haplotypes that most commonly result in altered CYP2D6 function, although many more exist. The CYP2D6* variant page should therefore serve mainly as a guide to determining the CYP2D6 haplotype, which should in turn serve as a guide to determining the metabolizer status and allele frequency.
Key PubMed IDs:	11972444 17301689 6644761 6754206 6849780 4019462 2574001 3410476 16033950 12959412 16550211 16249913 16968950 14618296 12571261 10634130 8737761 12870705
Key Pathways:	Antiestrogen Pathway (Tamoxifen PK) , Celecoxib Pathway , Codeine and Morphine Pathway (PK) , Gefitinib Pathway , Statin Pathway (Fluvastatin PK) , Statin Pathway (PK)
Drugs/Substrates:	amitriptyline [3956053] , atomoxetine[12485958] , carvedilol[7768074] , chlorpheniramine[11994058] , chlorpromazine[8739822] , citalopram [9110356] , clomipramine [10460069], clozapine [7640149] , codeine [1782973], debrisoquine [11823760] , desipramine[3533565] dextromethorphan [12152006] , dihydrocodeine [7586928], doxepin [12360109], flecainide [2498026], fluoxetine [8941024], fluvoxamine [8823236] , gefitinib [15788367] , haloperidol [1867960] , imipramine [3533565], maprotiline [8018460], metoprolol [7138751], mexiletine [1958440], mianserin[8062494] , morphine [8351162] , nortriptyline[9585799] , paroxetine[1531950] , perhexiline[6694182] , perphenazine [2743709], propafenone, [2713973] risperidone[11985287] , sparteine [2211621] , tamoxifen [14652237] , thioridazine [2007317], timolol [2859048], tolterodine[10583026] , tramadol[8988065] , yohimbine [15289791] , zuclopenthixol [1927573]
Phenotypes/Diseases:	Depression , Pain , Schizophrenia , Hypertension , Neoplasms , Cystic Fibrosis , Parkinson Disease
Important Variants:	CYP2D6 100C>T , CYP2D6 1023C>T , CYP2D6 1659G>A , CYP2D6 1707 del T , CYP2D6 1846G>A , CYP2D6 2549 del A , CYP2D6 2613-2615 del AGA , CYP2D6 2850C>T , CYP2D6 2988G>A , CYP2D6 3183G>A
Important Haplotypes:	CYP2D61 , CYP2D62 , CYP2D63, CYP2D64 , CYP2D65 , CYP2D66 , CYP2D69 , CYP2D610 , CYP2D617 , CYP2D629 , CYP2D6*41, CYP2D6UM

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