CYP2D6

Cytochrome P450, family 2, subfamily D, polypeptide 6
PDB rendering based on 2f9q.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2F9Q​, 3QM4​, 3TBG​, 3TDA​, 4WNT​, 4WNU​, 4WNV​, 4WNW​
Identifiers
Symbols	CYP2D6 ; CPD6; CYP2D; CYP2D7AP; CYP2D7BP; CYP2D7P2; CYP2D8P2; CYP2DL1; CYPIID6; P450-DB1; P450C2D; P450DB1
External IDs	OMIM: 124030 MGI: 1929474 HomoloGene: 133550 GeneCards: CYP2D6 Gene
EC number	1.14.14.1
Gene ontology Molecular function • monooxygenase activity • iron ion binding • drug binding • arachidonic acid epoxygenase activity • steroid hydroxylase activity • oxidoreductase activity • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen • oxygen binding • heme binding • aromatase activity Cellular component • cytoplasm • mitochondrion • endoplasmic reticulum • endoplasmic reticulum membrane Biological process • xenobiotic metabolic process • steroid metabolic process • coumarin metabolic process • alkaloid metabolic process • alkaloid catabolic process • monoterpenoid metabolic process • drug metabolic process • arachidonic acid metabolic process • isoquinoline alkaloid metabolic process • drug catabolic process • exogenous drug catabolic process • small molecule metabolic process • heterocycle metabolic process • negative regulation of binding • oxidation-reduction process • oxidative demethylation • negative regulation of cellular organofluorine metabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1565	13101
Ensembl	ENSG00000100197	ENSMUSG00000094806
UniProt	P10635	P24456
RefSeq (mRNA)	NM_000106	NM_010005
RefSeq (protein)	NP_000097	NP_034135
Location (UCSC)	Chr 22: 42.13 – 42.13 Mb	Chr 15: 82.4 – 82.41 Mb
PubMed search

Cytochrome P450 2D6 is an enzyme that in humans is encoded by the CYP2D6 gene. CYP2D6 is primarily expressed in the liver. It is also highly expressed in areas of the CNS, including the substantia nigra.

CYP2D6, a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. In particular, CYP2D6 is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, in a process referred to as O-demethylation.^[1] This enzyme also metabolizes several endogenous substances such as hydroxytryptamines and neurosteroids.^[1]

There is considerable variation in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence for drugs that are metabolized by CYP2D6 (that is, are CYP2D6 substrates), certain individuals will eliminate these drugs quickly (ultrarapid metabolizers) while others slowly (poor metabolizers). If a drug is metabolized too quickly, it may decrease the drug's efficacy while if the drug is metabolized too slowly, toxicity may result.^[2] Hence the dose of the drug may have to be adjusted to take into account of the speed at which it is metabolized by CYP2D6.^[3]

In addition, other drugs may function as inhibitors of CYP2D6 activity or inducers of CYP2D6 enzyme expression that will lead to decreased or increased CYP2D6 activity respectively. If such a drug is taken at the same time a second drug that is a CYP2D6 substrate, the first drug may affect the elimination rate of the second through what is known as a drug-drug interaction.^[2]

Gene

The gene is located near two cytochrome P450 pseudogenes on chromosome 22q13.1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.^[4]

Genotype/phenotype variability

CYP2D6 shows the largest phenotypical variability among the CYPs, largely due to genetic polymorphism. The genotype accounts for normal, reduced, and non-existent CYP2D6 function in subjects. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice.^[5] The CYP2D6 function in any particular subject may be described as one of the following:^[6]

• poor metabolizer – little or no CYP2D6 function
• intermediate metabolizers – metabolize drugs at a rate somewhere between the poor and extensive metabolizers
• extensive metabolizer – normal CYP2D6 function
• ultrarapid metabolizer – multiple copies of the CYP2D6 gene are expressed, and therefore greater-than-normal CYP2D6 function

A patient's CYP2D6 phenotype is often clinically determined via the administration of debrisoquine (a selective CYP2D6 substrate) and subsequent plasma concentration assay of the debrisoquine metabolite (4-hydroxydebrisoquine).^[7]

The type of CYP2D6 function of an individual may influence the person's response to different doses of drugs that CYP2D6 metabolizes. The nature of the effect on the drug response depends not only on the type of CYP2D6 function, but also on the extent to which processing of the drug by CYP2D6 results in a chemical that has an effect that is similar, stronger, or weaker than the original drug, or no effect at all. For example, if CYP2D6 converts a drug that has a strong effect into a substance that has a weaker effect, then poor metabolizers (weak CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects; conversely, if CYP2D6 converts a different drug into a substance that has a greater effect than its parent chemical, then ultrarapid metabolizers (strong CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects.^[8]

Genetic basis of variability

The genetic basis for CYP2D6-mediated metabolic variability is the CYP2D6 allele, located on chromosome 22. Subjects possessing certain allelic variants will show normal, decreased, or no CYP2D6 function, depending on the allele. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice.^[5]

CYP2D6 enzyme activity for selected alles[9][10]
Allele	CYP2D6 activity
CYP2D6*1	normal
CYP2D6*2	normal
CYP2D6*3	none
CYP2D6*4	none
CYP2D6*5	none
CYP2D6*6	none
CYP2D6*7	none
CYP2D6*8	none
CYP2D6*9	decreased
CYP2D6*10	decreased
CYP2D6*11	none
CYP2D6*12	none
CYP2D6*13	none
CYP2D6*14	none
CYP2D6*15	none
CYP2D6*17	decreased
CYP2D6*19	none
CYP2D6*20	none
CYP2D6*21	none
CYP2D6*29	decreased
CYP2D6*31	none
CYP2D6*38	none
CYP2D6*40	none
CYP2D6*41	decreased
CYP2D6*42	none
CYP2D6*68	none
CYP2D6*92	none
CYP2D6*100	none
CYP2D6*101	none
CYP2D6 duplication	increased

Ethnic factors in variability

Ethnicity is a factor in the occurrence of CYP2D6 variability. The prevalence of CYP2D6 poor metabolizers is approximately 6–10% in white populations, but is lower in most other ethnic groups such as Asians (2%).^[11] In African-Americans, the frequency of poor metabolizers is greater than for whites.^[12] The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among Middle Eastern and North African populations.^[13]

Caucasians with European descent predominantly (around 71%) have the functional group of CYP2D6 alleles, while functional alleles represent only around 50% of the allele frequency in populations of Asian descent.^[14]

This variability is accounted for by the differences in the prevalence of various CYP2D6 alleles among the populations–approximately 10% of whites are intermediate metabolizers, due to decreased CYP2D6 function, because they appear to have the non-functional CYP2D6*4 allele,^[9] while approximately 50% of Asians possess the decreased functioning CYP2D6*10 allele.^[9]

Ligands

Following is a table of selected substrates, inducers and inhibitors of CYP2D6. Where classes of agents are listed, there may be exceptions within the class.

Inhibitors of CYP2D6 can be classified by their potency, such as:

• Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance.^[15]
• Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.^[15]
• Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20-50% decrease in clearance.^[15]

Selected inducers, inhibitors and substrates of CYP2D6

Substrates ↑ = bioactivation by CYP2D6	Inhibitors	Inducers
All[16] tricyclic antidepressants, e.g. imipramine[15] amitriptyline[15] etc. Most[16] SSRIs (antidepressant), e.g. fluoxetine[15] paroxetine[15] fluvoxamine[15] venlafaxine[15][16] (SNRI antidepressant) duloxetine[15] (SNRI) mianserin[16] (tetracyclic antidepressant) mirtazapine[16] (antidepressant) opioids codeine[15][16] ↑[17] [into morphine] tramadol[15][16] ↑ [17] [into O-desmethyltramadol] O-desmethyltramadol ↑ [into N,O-didesmethyltramadol] N-desmethyltramadol [inactive] ↑ [into N,O-didesmethyltramadol] oxycodone [15] hydrocodone ↑[18] [into hydromorphone] tapentadol antipsychotics, e.g. haloperidol[15][16] risperidone[15][16] perphenazine[15][16] thioridazine[15][16] zuclopenthixol[15][16] iloperidone[15][16] aripiprazole[15][16] chlorpromazine[15][16] levomepromazine[16] remoxipride[16] minaprine[15] (RIMA antidepressant) tamoxifen[15][16] ↑[19] into hydroxytamoxifen (SERM) beta-blockers metoprolol[15][16] timolol[15][16] alprenolol[15][16] carvedilol[15] bufuralol[15] nebivolol[15] propranolol[15] debrisoquine[15] (antihypertensive) Class I antiarrhythmics flecainide[15][16] propafenone[15][16] encainide[15][16] mexiletine[15][16] lidocaine (mainly by 3A4)[15] sparteine[15] ondansetron[15][16] (antiemetic) donepezil[15][16] (acetylcholinesterase inhibitor) phenformin[15][16] (antidiabetic) tropisetron[16] (5-HT3 receptor antagonist) stimulants amphetamine[15] methoxyamphetamine[15] dextromethamphetamine[15] atomoxetine[15] chlorphenamine[15] (antihistamine) dexfenfluramine[15] (serotoninergic anorectic) dextromethorphan[15] (antitussive) [into dextrorphan] metoclopramide[15] (dopamine antagonist) perhexiline[15] (antianginal agent) phenacetin[15] (analgesic) promethazine[15] (antihistamine antiemetic)	Strong Certain SSRIs fluoxetine[15][16] paroxetine[15][16] bupropion[15][20] (non-SSRI antidepressant) quinidine[15][16] (class I antiarrhythmic agent) cinacalcet[15] (calcimimetic) ritonavir[16] (antiretroviral) Moderate sertraline[15] (SSRI) duloxetine[15] (SNRI) terbinafine[15] (antifungal) Weak amiodarone[15] (antiarrhythmic) buprenorphine[21] (in opioid addiction) cimetidine[15] (H2-receptor antagonist) citalopram[15][22] (SSRI) escitalopram[15][23] (SSRI) Unspecified potency antipsychotics haloperidol[24][15] perphenazine[15][24] thioridazine[24] zuclopenthixol[24] risperidone[24] chlorpromazine[15] hyperforin (St. Johns Wort)[25] antihistamines (H1-receptor antagonists) * promethazine[26](antipsychotic) chlorphenamine[15] diphenhydramine[15] hydroxyzine[15] tripelennamine[15] clemastine[15] (antihistamine and anticholinergic) celecoxib[15] (NSAID) clomipramine[15] (tricyclic antidepressant) cocaine[15] (stimulant) doxorubicin[15] (chemotherapeutic) metoclopramide[15] (antiemetic, prokinetic) methadone[15] (analgesic and anti-addictive) moclobemide[15] (antidepressant) doxepin[15] (tricyclic antidepressant, anxiolytic) halofantrine[15] (in malaria) levomepromazine[15] (antipsychotic) mibefradil[15] (calcium channel blocker) midodrine[15] (α1 agonist) ticlopidine[15] (antiplatelet) cannabidiol[27] (phytocannabinoid)	Strong glutethimide (hypnotic sedative) Unspecified potency dexamethasone[15] (glucocorticoid) rifampicin[15] (bactericidal)

References

1. Wang B, Yang LP, Zhang XZ, Huang SQ, Bartlam M, Zhou SF (2009). "New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme". Drug Metab. Rev. 41 (4): 573–643. doi:10.1080/03602530903118729. PMID 19645588.
2. Teh LK, Bertilsson L (2012). "Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance". Drug Metab. Pharmacokinet. 27 (1): 55–67. doi:10.2133/dmpk.DMPK-11-RV-121. PMID 22185816.
3. Walko CM, McLeod H (April 2012). "Use of CYP2D6 genotyping in practice: tamoxifen dose adjustment". Pharmacogenomics 13 (6): 691–7. doi:10.2217/pgs.12.27. PMID 22515611.
4. "Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6".
5. Ostille DO., Warren AM., Kulkarni, J. The role of pharmacogenomic testing in psychiatry. Aust New Zealand J Psychiatry 2014 Jan 10. PMID 24413808
6. Bertilsson L, Dahl ML, Dalén P, Al-Shurbaji A (February 2002). "Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs". Br J Clin Pharmacol 53 (2): 111–22. doi:10.1046/j.0306-5251.2001.01548.x. PMC 1874287. PMID 11851634.
7. Llerena A, Dorado P, Peñas-Lledó EM (January 2009). "Pharmacogenetics of debrisoquine and its use as a marker for CYP2D6 hydroxylation capacity". Pharmacogenomics 10 (1): 17–28. doi:10.2217/14622416.10.1.17. PMID 19102711.
8. Lynch T, Price A (August 2007). "The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects". Am Fam Physician 76 (3): 391–6. PMID 17708140.
9. Droll K, Bruce-Mensah K, Otton SV, Gaedigk A, Sellers EM, Tyndale RF (1998). "Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians". Pharmacogenetics 8 (4): 325–33. doi:10.1097/00008571-199808000-00006. PMID 9731719.
10. http://www.cypalleles.ki.se/cyp2d6.htm. Retrieved 5 February 2016. Missing or empty |title= (help)
11. Australian Medicines Handbook (AMH) 2004. ISBN 0-9578521-4-2
12. Gaedigk A, Bradford LD, Marcucci KA, Leeder JS (2002). "Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans". Clin. Pharmacol. Ther. 72 (1): 76–89. doi:10.1067/mcp.2002.125783. PMID 12152006.
13. McLellan RA, Oscarson M, Seidegård J, Evans DA, Ingelman-Sundberg M (June 1997). "Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians". Pharmacogenetics 7 (3): 187–91. doi:10.1097/00008571-199706000-00003. PMID 9241658.
14. Bradford LD (2002). "CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants". Pharmacogenomics 3 (2): 229–43. doi:10.1517/14622416.3.2.229. PMID 11972444.
15. Flockhart DA (2007). "Drug Interactions: Cytochrome P₄₅₀ Drug Interaction Table". Indiana University School of Medicine. Retrieved on July 2011
16. FASS (drug formulary): Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare), retrieved July 2011
17. PHARMACOGENETICS AND PHARMACOGENOMICS. J. Steven Leeder PharmD, PhD Pediatric Clinics of North America - Volume 48, Issue 3 (June 2001). doi:10.1016/S0031-3955%2805%2970338-2.
18. "Hydrocodone". Drugbank. Retrieved 14 June 2011.
19. Hoskins JM, Carey LA, McLeod HL (August 2009). "CYP2D6 and tamoxifen: DNA matters in breast cancer". Nat. Rev. Cancer 9 (8): 576–86. doi:10.1038/nrc2683. PMID 19629072.
20. Kotlyar M, Brauer LH, Tracy TS, Hatsukami DK, Harris J, Bronars CA, Adson DE (2005). "Inhibition of CYP2D6 activity by bupropion". J Clin Psychopharmacol 25 (3): 226–9. doi:10.1097/01.jcp.0000162805.46453.e3. PMID 15876900.
21. Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM (June 2003). "Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro". Drug Metab. Dispos. 31 (6): 768–72. doi:10.1124/dmd.31.6.768. PMID 12756210.
22. http://www.drugs.com/pro/citalopram-oral-solution.html. Retrieved 5 February 2016. Missing or empty |title= (help)
23. http://www.drugs.com/pro/escitalopram-oral-solution.html. Retrieved 5 February 2016. Missing or empty |title= (help)
24. FASS, The Swedish official drug catalog > Kodein Recip Last reviewed 2008-04-08
25. Foster BC, Sockovie ER, Vandenhoek S, Bellefeuille N, Drouin CE, Krantis A, Budzinski JW, Livesey J, and Arnason JT (2004). "In Vitro Activity of St. John's Wort Against Cytochrome P450 Isozymes and P-Glycoprotein". Pharmaceutical Biology 42 (2): 159–169. doi:10.1080/13880200490512034.
26. He N, Zhang WQ, Shockley D, Edeki T (February 2002). "Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes". Eur. J. Clin. Pharmacol. 57 (12): 847–51. doi:10.1007/s00228-001-0399-0. PMID 11936702.
27. Yamaori S, Okamoto Y, Yamamoto I, Watanabe K (2011). "Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6". Drug Metab Dispos 39 (11): 2049–56. doi:10.1124/dmd.111.041384. PMID 21821735.

Further reading

• Smith G, Stubbins MJ, Harries LW, Wolf CR (1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica 28 (12): 1129–65. doi:10.1080/004982598238868. PMID 9890157.
• Wolf CR, Smith G (1999). "Cytochrome P450 CYP2D6". IARC Sci. Publ. (148): 209–29. PMID 10493260.
• Ding X, Kaminsky LS (2003). "Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts". Annu. Rev. Pharmacol. Toxicol. 43 (1): 149–73. doi:10.1146/annurev.pharmtox.43.100901.140251. PMID 12171978.
• Lilienfeld S (2002). "Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease". CNS Drug Rev 8 (2): 159–76. doi:10.1111/j.1527-3458.2002.tb00221.x. PMID 12177686.
• Yu AM, Idle JR, Gonzalez FJ (2004). "Polymorphic cytochrome P450 2D6: humanized mouse model and endogenous substrates". Drug Metab. Rev. 36 (2): 243–77. doi:10.1081/DMR-120034000. PMID 15237854.
• Abraham JE, Maranian MJ, Driver KE, Platte R, Kalmyrzaev B, Baynes C, Luccarini C, Shah M, Ingle S, Greenberg D, Earl HM, Dunning AM, Pharoah PD, Caldas C (2010). "CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen". Breast Cancer Res. 12 (4): R64. doi:10.1186/bcr2629. PMC 2949659. PMID 20731819.
• Abraham JE, Maranian MJ, Driver KE, Platte R, Kalmyrzaev B, Baynes C, Luccarini C, Earl HM, Dunning AM, Pharoah PD, Caldas C (2011). "CYP2D6 gene variants and their association with breast cancer susceptibility". Cancer Epidemiol. Biomarkers Prev. 20 (6): 1255–8. doi:10.1158/1055-9965.EPI-11-0321. PMID 21527579.

External links

• Flockhart Lab Cyp2D6 Substrates Page at IUPUI
• PharmGKB: Annotated PGx Gene Information for CYP2D6