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.
Quick Facts Available structures, PDB ...
CYP2D6 |
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Identifiers |
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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 |
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External IDs | OMIM: 124030; MGI: 1929474; HomoloGene: 133550; GeneCards: CYP2D6; OMA:CYP2D6 - orthologs |
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Bgee | Human | Mouse (ortholog) |
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Top expressed in | - right lobe of liver
- duodenum
- sural nerve
- right hemisphere of cerebellum
- right uterine tube
- pituitary gland
- right lobe of thyroid gland
- left lobe of thyroid gland
- nucleus accumbens
- anterior pituitary
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| Top expressed in | - left lobe of liver
- extraocular muscle
- cerebellar cortex
- sciatic nerve
- lumbar subsegment of spinal cord
- superior frontal gyrus
- primary visual cortex
- vestibular membrane of cochlear duct
- neural layer of retina
- muscle of thigh
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BioGPS | |
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Wikidata |
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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.[5] CYP2D6 also activates some prodrugs. This enzyme also metabolizes several endogenous substances, such as N,N-Dimethyltryptamine, hydroxytryptamines, neurosteroids, and both m-tyramine and p-tyramine which CYP2D6 metabolizes into dopamine in the brain and liver.[5][6][7]
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.[8] 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.[9] Individuals who exhibit an ultrarapid metabolizer phenotype, metabolize prodrugs, such as codeine or tramadol, more rapidly, leading to higher than therapeutic levels.[10][11] A case study of the death of an infant breastfed by an ultrarapid metabolizer mother taking codeine impacted postnatal pain relief clinical practices, but was later debunked.[12] These drugs may also cause serious toxicity in ultrarapid metabolizer patients when used to treat other post-operative pain, such as after tonsillectomy.[13][14][15] 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.[8]
The gene is located on chromosome 22q13.1. near two cytochrome P450 pseudogenes (CYP2D7P and CYP2D8P).[16] Among them, CYP2D7P originated from CYP2D6 in a stem lineage of great apes and humans,[17] the CYP2D8P originated from CYP2D6 in a stem lineage of Catarrhine and New World monkeys' stem lineage.[18] Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[19]
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.[20]
The CYP2D6 function in any particular subject may be described as one of the following:[21]
- 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).[22]
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.[23] Information about how human genetic variation of CYP2D6 affects response to medications can be found in databases such PharmGKB,[24] Clinical Pharmacogenetics Implementation Consortium (CPIC).[25]
The variability in metabolism is due to multiple different polymorphisms of 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.[20] The current known alleles of CYP2D6 and their clinical function can be found in databases such as PharmVar.[26]
Ethnicity is a factor in the occurrence of CYP2D6 variability. The reduction 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. A complete lack of CYP2D6 enzyme activity, wherein the individual has two copies of the polymorphisms that result in no CYP2D6 activity at all, is said to be about 1-2% of the population.[27] The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among Middle Eastern and North African populations.[28][29]
Caucasians with European descent predominantly (around 71%) have the functional group of CYP2D6 alleles, producing extensive metabolism, while functional alleles represent only around 50% of the allele frequency in populations of Asian descent.[30]
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 one (heterozygous) non-functional CYP2D6*4 allele,[31] while approximately 50% of Asians possess the decreased functioning CYP2D6*10 allele.[31]
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.[32]
- 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.[32]
- 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.[32]
More information Substrates ↑ = bioactivation by CYP2D6, Inhibitors ...
Selected inducers, inhibitors and substrates of CYP2D6
Substrates ↑ = bioactivation by CYP2D6 | Inhibitors | Inducers |
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Dopamine biosynthesis
primary pathway
brain CYP2D6
minor pathway
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. [41] Similarly, CYP2D6 also metabolizes m-tyramine into dopamine. [41]
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ENSG00000275211, ENSG00000280905, ENSG00000282966, ENSG00000283284, ENSG00000272532 GRCh38: Ensembl release 89: ENSG00000100197, ENSG00000275211, ENSG00000280905, ENSG00000282966, ENSG00000283284, ENSG00000272532 – Ensembl, May 2017
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 Metabolism Reviews. 41 (4): 573–643. doi:10.1080/03602530903118729. PMID 19645588. S2CID 41857580.
Teh LK, Bertilsson L (2012). "Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance". Drug Metabolism and Pharmacokinetics. 27 (1): 55–67. doi:10.2133/dmpk.DMPK-11-RV-121. PMID 22185816.
Walko CM, McLeod H (April 2012). "Use of CYP2D6 genotyping in practice: tamoxifen dose adjustment". Pharmacogenomics. 13 (6): 691–697. doi:10.2217/pgs.12.27. PMID 22515611.
Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, et al. (2012). Tramadol Therapy and CYP2D6 Genotype. PMID 28520365.
Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, et al. (2012). Codeine Therapy and CYP2D6 Genotype. PMID 28520350.
Prows CA, Zhang X, Huth MM, Zhang K, Saldaña SN, Daraiseh NM, et al. (May 2014). "Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study". The Laryngoscope. 124 (5): 1242–1250. doi:10.1002/lary.24455. PMID 24122716. S2CID 5326129.
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.
Lynch T, Price A (August 2007). "The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects". American Family Physician. 76 (3): 391–396. PMID 17708140.
"PharmGKB". PharmGKB. Archived from the original on 3 October 2022. Retrieved 3 October 2022.
"PharmVar". www.pharmvar.org. Archived from the original on 19 May 2020. Retrieved 15 February 2024.
Lilley LL, Harrington S, Snyder JS, Swart B (2007). Pharmacology and the Nursing Process. Toronto: Mosby Elsevier. p. 25. ISBN 9780779699711.
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): 187–191. doi:10.1097/00008571-199706000-00003. PMID 9241658.
Droll K, Bruce-Mensah K, Otton SV, Gaedigk A, Sellers EM, Tyndale RF (August 1998). "Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians". Pharmacogenetics. 8 (4): 325–333. doi:10.1097/00008571-199808000-00006. PMID 9731719.
Zhao Y, Hellum BH, Liang A, Nilsen OG (June 2015). "Inhibitory Mechanisms of Human CYPs by Three Alkaloids Isolated from Traditional Chinese Herbs". Phytotherapy Research. 29 (6): 825–834. doi:10.1002/ptr.5285. PMID 25640685. S2CID 24002845.
Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM (June 2003). "Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro". Drug Metabolism and Disposition. 31 (6): 768–772. doi:10.1124/dmd.31.6.768. PMID 12756210.
Bailey DG, Bend JR, Arnold JM, Tran LT, Spence JD (July 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. PMID 8689808. S2CID 1246705.
Guengerich FP, Brian WR, Iwasaki M, Sari MA, Bäärnhielm C, Berntsson P (June 1991). "Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 IIIA4". Journal of Medicinal Chemistry. 34 (6): 1838–1844. doi:10.1021/jm00110a012. PMID 2061924.
Spina E, D'Arrigo C, Migliardi G, Morgante L, Zoccali R, Ancione M, et al. (August 2004). "Plasma risperidone concentrations during combined treatment with sertraline". Therapeutic Drug Monitoring. 26 (4): 386–390. doi:10.1097/00007691-200408000-00008. PMID 15257068.
Sproule BA, Otton SV, Cheung SW, Zhong XH, Romach MK, Sellers EM (April 1997). "CYP2D6 inhibition in patients treated with sertraline". Journal of Clinical Psychopharmacology. 17 (2): 102–106. doi:10.1097/00004714-199704000-00007. PMID 10950472.
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". European Journal of Clinical Pharmacology. 57 (12): 847–851. doi:10.1007/s00228-001-0399-0. PMID 11936702. S2CID 601644.
Foster BC, Sockovie ER, Vandenhoek S, Bellefeuille N, Drouin CE, Krantis A, et al. (2008). "In Vitro Activity of St. John's Wort Against Cytochrome P450 Isozymes and P-Glycoprotein". Pharmaceutical Biology. 42 (2): 159–69. doi:10.1080/13880200490512034. S2CID 2366709.
- Smith G, Stubbins MJ, Harries LW, Wolf CR (December 1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 28 (12): 1129–1165. doi:10.1080/004982598238868. PMID 9890157.
- Wolf CR, Smith G (1999). "Cytochrome P450 CYP2D6". IARC Scientific Publications (148): 209–229. 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: 149–173. 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): 159–176. 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): 243–277. doi:10.1081/DMR-120034000. PMID 15237854. S2CID 11330784. Archived from the original on 29 June 2022. Retrieved 5 July 2019.
- Abraham JE, Maranian MJ, Driver KE, Platte R, Kalmyrzaev B, Baynes C, et al. (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, et al. (June 2011). "CYP2D6 gene variants and their association with breast cancer susceptibility". Cancer Epidemiology, Biomarkers & Prevention. 20 (6): 1255–1258. doi:10.1158/1055-9965.EPI-11-0321. PMID 21527579. S2CID 32846974.