CYP2D6

Cytochrome P450 2D6 (CYP2D6) 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 central nervous system, including the substantia nigra.

CYP2D6
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 2F9Q, 3QM4, 3TBG, 3TDA, 4WNT, 4WNU, 4WNV, 4WNW, 4XRY, 4XRZ
Identifiers
Aliases	CYP2D6, CPD6, CYP2D, CYP2D7AP, CYP2D7BP, CYP2D7P2, CYP2D8P2, CYP2DL1, CYPIID6, P450-DB1, P450C2D, P450DB1, cytochrome P450 family 2 subfamily D member 6, Cytochrome P450 2D6
External IDs	OMIM: 124030 HomoloGene: 133550 GeneCards: CYP2D6
Gene location (Human) Chr. Chromosome 22 (human)[1] Band 22q13.2 Start 42,126,499 bp[1] End 42,130,881 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • iron ion binding • metal ion binding • heme binding • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen • drug binding • oxidoreductase activity • aromatase 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 • steroid hydroxylase activity • monooxygenase activity Cellular component • organelle membrane • endoplasmic reticulum membrane • membrane • intracellular membrane-bounded organelle • endoplasmic reticulum • mitochondrion • cytoplasm Biological process • steroid metabolic process • alkaloid metabolic process • coumarin metabolic process • lipid metabolism • isoquinoline alkaloid metabolic process • alkaloid catabolic process • oxidative demethylation • drug catabolic process • heterocycle metabolic process • negative regulation of binding • drug metabolic process • monoterpenoid metabolic process • xenobiotic metabolic process • oxidation-reduction process • arachidonic acid metabolic process • negative regulation of cellular organofluorine metabolic process • long-chain fatty acid biosynthetic process • organic acid metabolic process • exogenous drug catabolic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1565	n/a
Ensembl	ENSG00000100197 ENSG00000275211 ENSG00000280905 ENSG00000282966 ENSG00000283284 ENSG00000272532	n/a
UniProt	P10635	n/a
RefSeq (mRNA)	NM_000106 NM_001025161	n/a
RefSeq (protein)	NP_000097 NP_001020332	n/a
Location (UCSC)	Chr 22: 42.13 – 42.13 Mb	n/a
PubMed search	[2]	n/a
Wikidata
View/Edit Human

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, via the addition or removal of certain functional groups – specifically, hydroxylation, demethylation, and dealkylation.[3] CYP2D6 also activates some prodrugs. This enzyme also metabolizes several endogenous substances, such as hydroxytryptamines, neurosteroids, and both m-tyramine and p-tyramine which CYP2D6 metabolizes into dopamine in the brain and liver.[3][4]

Considerable variation exists 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.[5] So, the dose of the drug may have to be adjusted to take into account of the speed at which it is metabolized by CYP2D6.[6]

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 as 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.[5]

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.[7]

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.[8] The CYP2D6 function in any particular subject may be described as one of the following:[9]

• 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, so greater-than-normal CYP2D6 function occurs

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).[10]

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.[11]

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.[8]

CYP2D6 enzyme activity for selected alles[12][13]
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

Race is a factor in the occurrence of CYP2D6 variability. The lack of the liver cytochrome CYP2D6 enzyme occurs approximately in 7–10% in white populations, and is lower in most other ethnic groups such as Asians and African-Americans at 2% each.[14] The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among Middle Eastern and North African populations.[15]

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.[16]

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,[12] while approximately 50% of Asians possess the decreased functioning CYP2D6*10 allele.[12]

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 of sensitive substrates metabolized through CYP2D6, or more than 80% decrease in clearance thereof.[17]
• Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values of sensitive substrates metabolized through CYP2D6, or 50-80% decrease in clearance thereof.[17]
• Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values of sensitive substrates metabolized through CYP2D6, or 20-50% decrease in clearance thereof.[17]

Selected inducers, inhibitors and substrates of CYP2D6

Substrates ↑ = bioactivation by CYP2D6	Inhibitors	Inducers
All[18] tricyclic antidepressants, e.g. imipramine[17] amitriptyline[17] etc. Most[18] SSRIs (antidepressant), e.g. fluoxetine[17] paroxetine[17] fluvoxamine[17] venlafaxine[17][18] (SNRI antidepressant) duloxetine[17] (SNRI, moderate sensitive substrates of CYP2D6[17]) mianserin[18] (tetracyclic antidepressant) mirtazapine[18] (antidepressant) opioids codeine[17][18] ↑[into morphine][19] tramadol[17][18] ↑[into O-desmethyltramadol][19] O-desmethyltramadol ↑[into N,O-didesmethyltramadol] N-desmethyltramadol [inactive] ↑[into N,O-didesmethyltramadol] oxycodone[17] hydrocodone ↑[into hydromorphone][20] tapentadol antipsychotics, e.g. haloperidol[17][18] risperidone[17][18] perphenazine[17][18] thioridazine[17][18] zuclopenthixol[17][18] iloperidone[17][18] aripiprazole[17][18] chlorpromazine[17][18] levomepromazine[18] remoxipride[18] minaprine[17] (RIMA antidepressant) tamoxifen[17][18] ↑[into hydroxytamoxifen][21] (SERM) beta-blockers metoprolol[17][18] timolol[17][18] alprenolol[17][18] carvedilol[17] bufuralol[17] nebivolol[17] propranolol[17] debrisoquine[17] (antihypertensive) Class I antiarrhythmics flecainide[17][18] propafenone[17][18] encainide[17][18] mexiletine[17][18] lidocaine [17] sparteine[17] ondansetron[17][18] (antiemetic) donepezil[17][18] (acetylcholinesterase inhibitor) phenformin[17][18] (antidiabetic) tropisetron[18] (5-HT3 receptor antagonist) stimulants amphetamine[17] methoxyamphetamine[17] dextromethamphetamine[17] NRI atomoxetine (Sensitive substrate of CYP2D6) [17] chlorphenamine[17] (antihistamine) dexfenfluramine[17] (serotoninergic anorectic) dextromethorphan[17] ↑[into dextrorphan] (antitussive) metoclopramide[17] (dopamine antagonist) perhexiline[17] (antianginal agent) phenacetin[17] (analgesic) promethazine[17] (antihistamine antiemetic) m-tyramine[22] p-tyramine[22] Calcium channel blocker diltiazem (minor/moderate sensitive substrate) [23] nifedipine (minor/moderate sensitive substrate)[24]	Strong Certain SSRIs fluoxetine[17][18] paroxetine[17][18] bupropion[17][25] (non-SSRI antidepressant) quinidine[17][18] (class I antiarrhythmic agent) quinine[26] cinacalcet[17] (calcimimetic) ritonavir[18] (antiretroviral) cannabidiol[27] Moderate duloxetine[17] (SNRI) terbinafine[17] (antifungal) Weak amiodarone[17] (antiarrhythmic) buprenorphine[28] (in opioid addiction) cimetidine[17] (H2-receptor antagonist) citalopram[17][29] (SSRI) escitalopram[17][29][30] (SSRI) fluvoxamine [31] (SSRI) methylphenidate [32] diltiazem [23] felodipine [33][34][35] mirtazapine[36] sertraline[31] (SSRI) Unspecified potency antipsychotics haloperidol[37][17] perphenazine[17][37] thioridazine[37] zuclopenthixol[37] chlorpromazine[17] hyperforin (St. Johns Wort)[38] antihistamines (H1-receptor antagonists) promethazine[39] (antipsychotic) chlorphenamine[17] diphenhydramine[17] hydroxyzine[17] tripelennamine[17] clemastine[17] (antihistamine and anticholinergic) celecoxib[17] (NSAID) clomipramine[17] (tricyclic antidepressant) cocaine[17] (stimulant) doxorubicin[17] (chemotherapeutic) metoclopramide[17] (antiemetic, prokinetic) methadone[17] (analgesic and anti-addictive) moclobemide[17] (antidepressant) niacin[40] (nicotinic acid) and its form – niacinamide (nicotinamide), collectively called as vitamin B3 doxepin[17] (tricyclic antidepressant, anxiolytic) halofantrine[17] (in malaria) levomepromazine[17] (antipsychotic) mibefradil[17] (calcium channel blocker) midodrine[17] (α1 agonist) ticlopidine[17] (antiplatelet) sesame[41] (seeds, oil)	Strong glutethimide (hypnotic sedative) Unspecified potency dexamethasone[17] (glucocorticoid) rifampicin[17] (bactericidal) haloperidol[42] (typical antipsychotic)

Dopamine biosynthesis

Biosynthetic pathways for catecholamines and trace amines in the human brain[43][44][22] L-Phenylalanine L-Tyrosine L-DOPA Epinephrine Phenethylamine p-Tyramine Dopamine Norepinephrine N-Methylphenethylamine N-Methyltyramine p-Octopamine Synephrine 3-Methoxytyramine AADC AADC AADC primary pathway PNMT PNMT PNMT PNMT AAAH AAAH brain CYP2D6 minor pathway COMT DBH DBH In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid phenylalanine. It is well established that dopamine is produced from L-tyrosine via L-dopa; however, recent evidence has shown that CYP2D6 is expressed in the human brain and catalyzes the biosynthesis of dopamine from L-tyrosine via p-tyramine.[22] Similarly, CYP2D6 also metabolizes m-tyramine into dopamine.[22]

References

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15. 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.
16. Bradford LD (March 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.
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22. Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". European Journal of Pharmacology. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199.
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26. Fasinu PS, Tekwani BL, Avula B, Chaurasiya ND, Nanayakkara NP, Wang YH, Khan IA, Walker LA (September 2016). "Pathway-specific inhibition of primaquine metabolism by chloroquine/quinine". Malaria Journal. 15: 466. doi:10.1186/s12936-016-1509-x. PMC 5020452. PMID 27618912.
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33. Bailey, David G.; Bend, John R.; Arnold, J. Malcolm O.; Tran, Lan T.; Spence, J. David (1996). "Erythromycin-felodipine interaction: Magnitude, mechanism, and comparison with grapefruit juice*". Clinical Pharmacology and Therapeutics. 60 (1): 25–33. doi:10.1016/s0009-9236(96)90163-0. ISSN 0009-9236. PMID 8689808.
34. Lown, K S; Bailey, D G; Fontana, R J; Janardan, S K; Adair, C H; Fortlage, L A; Brown, M B; Guo, W; Watkins, P B (1997-05-15). "Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression". The Journal of Clinical Investigation. 99 (10): 2545–2553. doi:10.1172/jci119439. ISSN 0021-9738. PMC 508096. PMID 9153299.
35. Guengerich, FP; Brian, WR; Iwasaki, M; Sari, MA; Bäärnhielm, C; Berntsson, P (1991). "Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 IIIA4". Journal of Medicinal Chemistry. 34 (6): 1838–44. doi:10.1021/jm00110a012. ISSN 0022-2623. PMID 2061924.
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Further reading

• Smith G, Stubbins MJ, Harries LW, Wolf CR (December 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 Scientific Publications (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". Annual Review of Pharmacology and Toxicology. 43: 149–73. doi:10.1146/annurev.pharmtox.43.100901.140251. PMID 12171978.
• Lilienfeld S (2006). "Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease". CNS Drug Reviews. 8 (2): 159–76. doi:10.1111/j.1527-3458.2002.tb00221.x. PMC 6741688. PMID 12177686.
• Yu AM, Idle JR, Gonzalez FJ (May 2004). "Polymorphic cytochrome P450 2D6: humanized mouse model and endogenous substrates". Drug Metabolism Reviews. 36 (2): 243–77. doi:10.1081/DMR-120034000. PMID 15237854. S2CID 11330784.
• 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 Research. 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 (June 2011). "CYP2D6 gene variants and their association with breast cancer susceptibility". Cancer Epidemiology, Biomarkers & Prevention. 20 (6): 1255–8. doi:10.1158/1055-9965.EPI-11-0321. PMID 21527579. S2CID 32846974.

External links

• Flockhart Lab Cyp2D6 Substrates Page at IUPUI
• PharmGKB: Annotated PGx Gene Information for CYP2D6
• Human CYP2D6 genome location and CYP2D6 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P10635 (Cytochrome P450 2D6) at the PDBe-KB.