CYP2D6

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]
End	42,130,865 bp[1]
RNA expression pattern
	Top expressed in
	right lobe of liver; ; duodenum; ; sural nerve; ; right uterine tube; ; pituitary gland; ; right lobe of thyroid gland; ; left lobe of thyroid gland; ; nucleus accumbens; ; anterior pituitary; ; putamen;
	n/a
	More reference expression data
	; ;
	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; 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; heterocycle metabolic process; negative regulation of binding; monoterpenoid metabolic process; xenobiotic metabolic process; arachidonic acid metabolic process; negative regulation of cellular organofluorine metabolic process; long-chain fatty acid biosynthetic process; organic acid metabolic process;
	Sources:Amigo / QuickGO
Orthologs
	1565
	n/a
ENSG00000100197; ENSG00000275211; ENSG00000280905; ENSG00000282966; ENSG00000283284;
	ENSG00000272532
	n/a
	P10635
	n/a
	NM_000106; NM_001025161
	n/a
	NP_000097; NP_001020332
	n/a
	Wikidata
View/Edit Human

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, 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 on chromosome 22q13.1. near two cytochrome P450 pseudogenes (CYP2D7P and CYP2D8P).[7] Among them, CYP2D7P originated from CYP2D6 in a stem lineage of great apes and humans,[8] the CYP2D8P originated from CYP2D6 in a stem lineage of Catarrhine and New World monkeys' stem lineage.[9] Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[10]

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.[11] The CYP2D6 function in any particular subject may be described as one of the following:[12]

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).[13]

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.[14] Information about how human genetic variation of CYP2D6 affects response to medications can be found in databases such PharmGKB,[15] Clinical Pharmacogenetics Implementation Consortium (CPIC).[16]

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.[11] The current known alleles of CYP2D6 and their clinical function can be found in databases such as PharmVar.[17]

CYP2D6 enzyme activity for selected alleles[18][17]
Allele	CYP2D6 activity
CYP2D61*	normal
CYP2D62*	normal
CYP2D63*	none
CYP2D64*	none
CYP2D65*	none
CYP2D66*	none
CYP2D67*	none
CYP2D68*	none
CYP2D69*	decreased
CYP2D610*	decreased
CYP2D611*	none
CYP2D612*	none
CYP2D613*	none
CYP2D614*	none
CYP2D615*	none
CYP2D617*	decreased
CYP2D619*	none
CYP2D620*	none
CYP2D621*	none
CYP2D629*	decreased
CYP2D631*	none
CYP2D638*	none
CYP2D640*	none
CYP2D641*	decreased
CYP2D642*	none
CYP2D644*	none
CYP2D647*	none
CYP2D650*	decreased
CYP2D651*	none
CYP2D668*	none
CYP2D692*	none
CYP2D6100*	none
CYP2D6101*	none
CYP2D6 duplication	increased

Ethnic factors in variability

Ethnicity 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.[19] The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among Middle Eastern and North African populations.[20]

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.[21]

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,[18] while approximately 50% of Asians possess the decreased functioning CYP2D6*10 allele.[18]

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.[22]
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.[22]
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.[22]

**Selected inducers, inhibitors and substrates of CYP2D6**
Substrates ↑ = bioactivation by CYP2D6	Inhibitors	Inducers
All[23] tricyclic antidepressants, e.g. imipramine[22] amitriptyline[22] etc. Most[23] SSRIs (antidepressant), e.g. fluoxetine[22] paroxetine[22] fluvoxamine[22] venlafaxine[22][23] (SNRI antidepressant) duloxetine[22] (SNRI, moderate sensitive substrates of CYP2D6[22]) mianserin[23] (tetracyclic antidepressant) mirtazapine[23] (antidepressant) opioids codeine[22][23] ↑[into morphine][24] tramadol[22][23] ↑[into O-desmethyltramadol][24] O-desmethyltramadol ↑[into N,O-didesmethyltramadol] N-desmethyltramadol [inactive] ↑[into N,O-didesmethyltramadol] oxycodone[22] hydrocodone ↑[into hydromorphone][25] tapentadol antipsychotics, e.g. haloperidol[22][23] risperidone[22][23] perphenazine[22][23] thioridazine[22][23] zuclopenthixol[22][23] iloperidone[22][23] aripiprazole[22][23] chlorpromazine[22][23] levomepromazine[23] remoxipride[23] minaprine[22] (RIMA antidepressant) tamoxifen[22][23] ↑[into hydroxytamoxifen][26] (SERM) beta-blockers metoprolol[22][23] timolol[22][23] alprenolol[22][23] carvedilol[22] bufuralol[22] nebivolol[22] propranolol[22] debrisoquine[22] (antihypertensive) Class I antiarrhythmics flecainide[22][23] propafenone[22][23] encainide[22][23] mexiletine[22][23] lidocaine[22] sparteine[22] ondansetron[22][23] (antiemetic) donepezil[22][23] (acetylcholinesterase inhibitor) phenformin[22][23] (antidiabetic) tropisetron[23] (5-HT3 receptor antagonist) stimulants amphetamine[22] methoxyamphetamine[22] dextromethamphetamine[22] Lisdexamfetamine NRI atomoxetine (Sensitive substrate of CYP2D6) [22] chlorphenamine[22] (antihistamine) dexfenfluramine[22] (serotoninergic anorectic) dextromethorphan[22] ↑[into dextrorphan] (antitussive) metoclopramide[22] (dopamine antagonist) perhexiline[22] (antianginal agent) phenacetin[22] (analgesic) promethazine[22] (antihistamine antiemetic) m-tyramine[27] p-tyramine[27] Lysergic acid diethylamide (LSD)[28] 5-methoxy-N,N-dimethyltryptamine[29] Calcium channel blocker diltiazem (minor/moderate sensitive substrate) [30] nifedipine (minor/moderate sensitive substrate)[31]	Strong Certain SSRIs fluoxetine[22][23] paroxetine[22][23] bupropion[22][32] (non-SSRI antidepressant) quinidine[22][23] (class I antiarrhythmic agent) quinine[33] cinacalcet[22] (calcimimetic) ritonavir[23] (antiretroviral) cannabidiol[34] Moderate duloxetine[22] (SNRI) terbinafine[22] (antifungal) Weak amiodarone[22] (antiarrhythmic) buprenorphine[35] (in opioid addiction) cimetidine[22] (H2-receptor antagonist) citalopram[22][36] (SSRI) escitalopram[22][36][37] (SSRI) fluvoxamine[38] (SSRI) methylphenidate[39] diltiazem[30] felodipine[40][41][42] mirtazapine[43] sertraline[38] (SSRI) Unspecified potency antipsychotics haloperidol[44][22] perphenazine[22][44] thioridazine[44] zuclopenthixol[44] chlorpromazine[22] antihistamines (H1-receptor antagonists) promethazine[45] (antipsychotic) chlorphenamine[22] diphenhydramine[22] hydroxyzine[22] tripelennamine[22] berberine[46][47][48] (an alkaloid found in plants like berberis) celecoxib[22] (NSAID) clemastine[22] (antihistamine and anticholinergic) clomipramine[22] (tricyclic antidepressant) cocaine[22] (stimulant) doxepin[22] (tricyclic antidepressant, anxiolytic) doxorubicin[22] (chemotherapeutic) halofantrine[22] (in malaria) hyperforin (St. Johns Wort)[49] levomepromazine[22] (antipsychotic) methadone[22] (analgesic and anti-addictive) metoclopramide[22] (antiemetic, prokinetic) mibefradil[22] (calcium channel blocker) midodrine[22] (α₁ agonist) moclobemide[22] (antidepressant) niacin[50] (nicotinic acid) and its form – niacinamide (nicotinamide), collectively called as vitamin B3 sesame[51] (seeds, oil) ticlopidine[22] (antiplatelet)	Strong glutethimide (hypnotic sedative) Unspecified potency haloperidol[52] (typical antipsychotic)

Dopamine biosynthesis

Biosynthetic pathways for catecholamines and trace amines in the human brain[53][54][27]

L-Phenylalanine

L-Tyrosine

N-Methylphenethylamine

N-Methyltyramine

3-Methoxytyramine

primary
pathway

brain
CYP2D6

minor
pathway

COMT

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.[27] Similarly, CYP2D6 also metabolizes m-tyramine into dopamine.[27]

References

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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.

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[refGRCh38Ensembl-1] ENSG00000275211, ENSG00000280905, ENSG00000282966, ENSG00000283284, ENSG00000272532 GRCh38: Ensembl release 89: ENSG00000100197, ENSG00000275211, ENSG00000280905, ENSG00000282966, ENSG00000283284, ENSG00000272532 - Ensembl, May 2017

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Cytochromes, oxygenases: cytochrome P450 (Most belong to EC 1.14)
CYP1	A1 A2 A5 B1
CYP2	A6 A7 A13 B6 C8 C9 C18 C19 D6 E1 F1 J2 R1 S1 U1 W1
CYP3 (CYP3A)	A4 A5 A7 A37 A43
CYP4	A11 A22 B1 F2 F3 F8 F11 F12 F22 V2 X1 Z1
CYP5-20	CYP5 (A1) CYP6 (G1, M2) CYP7 (A1, B1) CYP8 (A1, B1) CYP9 CYP10 CYP11 (A1, A2, B1, B2, B3, C1) CYP12 CYP13 CYP14 CYP15 CYP16 CYP17 (A1) CYP18 CYP19 (A1) CYP20 (A1)
CYP21-49	CYP21 (A2) CYP22 (A1) CYP23 CYP24 (A1) CYP25 CYP26 (A1, B1, C1) CYP27 (A1, B1, C1) CYP28 (A1) CYP29 CYP35 (B1) CYP39 (A1) CYP46 (A1)
CYP51-69	CYP51 (A1, F1) CYP52 CYP53 (A1) CYP55 CYP56A1 CYP61
CYP71-99	CYP71 (C1, C2, C3, C4, Z6, AJ4, AV1, BA1) CYP72A1 CYP73A1 CYP74 (D1) CYP75 (A1, B1) CYP76 (B6, M7) CYP79 (A1, A2, B1, B2, B3, D1, D2, D3, D4) CYP80 (A1, B1, G2) CYP81 (E1, E3, E7, E9) CYP88D6 CYP90C1 CYP93E1 CYP97C1 CYP99A3
CYP101-281	CYP101A1 CYP102A1 CYP105 A1 D7 CYP106A2 CYP107 A1 G1 CYP109 B1 E1 CYP111 CYP113A1 CYP119A1 CYP123 CYP125A1 CYP139 CYP152 A1 B1 CYP154C3 CYP158A CYP161C CYP170 A1 B1 CYP176A1 CYP183A CYP199A2 CYP255A
CYP301-499	CYP303A1 CYP305 M2 Halloween genes ( CYP302A1, CYP306A1, CYP307A1, CYP307A2, CYP314A1, CYP315A1) CYP318A1
CYP501-699	CYP503 CYP504B1
CYP701-999	CYP710 CYP720A1

Oxidoreductases: dioxygenases, including steroid hydroxylases (EC 1.14)
1.14.11: 2-oxoglutarate	Prolyl hydroxylase HIF prolyl-hydroxylase EGLN1 EGLN2 EGLN3 P4HTM Lysyl hydroxylase AlkB ALKBH1 FTO
1.14.13: NADH or NADPH	Flavin-containing monooxygenase FMO1 FMO2 FMO3 FMO4 FMO5 Nitric oxide synthase NOS1 NOS2 NOS3 Cholesterol 7 alpha-hydroxylase Methane monooxygenase 3A4 14α-demethylase 24-hydroxycholesterol 7α-hydroxylase
1.14.14: reduced flavin or flavoprotein	19A1 2D6 2E1
1.14.15: reduced iron–sulfur protein	11B1 11B2 11A1
1.14.16: reduced pteridine (BH4 dependent)	Phenylalanine hydroxylase Tyrosine hydroxylase Tryptophan hydroxylase
1.14.17: reduced ascorbate	Dopamine beta-hydroxylase
1.14.18-19: other	Tyrosinase Stearoyl-CoA desaturase-1
1.14.99 - miscellaneous	Cyclooxygenase Heme oxygenase (HMOX1) Squalene monooxygenase 17A1 21A2 Ecdysone 20-monooxygenase Deoxyhypusine monooxygenase

Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)