Biology:CYP2D6

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Short description: Human liver enzyme


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] 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.[1][2]

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.[3] 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.[4] Individuals who have ultrarapid polymorphism, however, may metabolize prodrugs, such as codeine or tramadol, to potentially fatal levels either through breast milk[5][6][7] such as treating post-cesarian section pain. These drugs may also cause serious toxicity in ultrarapid metabolizer patients when used to treat other post-operative pain, such as after tonsillectomy.[8][9][10] 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.[3]

Gene

The gene is located on chromosome 22q13.1. near two cytochrome P450 pseudogenes (CYP2D7P and CYP2D8P).[11] Among them, CYP2D7P originated from CYP2D6 in a stem lineage of great apes and humans,[12] the CYP2D8P originated from CYP2D6 in a stem lineage of Catarrhine and New World monkeys' stem lineage.[13] Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[14]

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.[15] The CYP2D6 function in any particular subject may be described as one of the following:[16]

  • 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).[17]

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.[18] Information about how human genetic variation of CYP2D6 affects response to medications can be found in databases such PharmGKB,[19] Clinical Pharmacogenetics Implementation Consortium (CPIC).[20]

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.[15] The current known alleles of CYP2D6 and their clinical function can be found in databases such as PharmVar.[21]

CYP2D6 enzyme activity for selected alleles[22][21]
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*44 none
CYP2D6*47 none
CYP2D6*50 decreased
CYP2D6*51 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 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.[23] The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among Middle Eastern and North African populations.[24][25]

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.[26]

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,[22] while approximately 50% of Asians possess the decreased functioning CYP2D6*10 allele.[22]

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.[27]
  • 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.[27]
  • 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.[27]
Selected inducers, inhibitors and substrates of CYP2D6
Substrates
↑ = bioactivation by CYP2D6		 Inhibitors Inducers

Strong

Moderate

Weak

Unspecified potency

Strong

Unspecified potency

Dopamine biosynthesis

{{Annotated image 4 | caption = {{{caption|In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid {{nowrap|L-phenylalanine}}.}}} | header_background = #F0F8FF | header = Biosynthetic pathways for catecholamines and trace amines in the human brain<ref name="Trace amine template 1">Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. </ref>[59][33] | alt = Graphic of catecholamine and trace amine biosynthesis | image = Catecholamine and trace amine biosynthesis.png | image-width = 580 | image-left = 5 | image-top = 0 | align = center | width = 590 | height = 585 | annot-font-size = 14 | annot-text-align = center | annotations =

{{annotation|50|565|{{if pagename|Adrenaline=Adrenaline|Epinephrine=Epinephrine|Catecholamine=Epinephrine|other=Epinephrine}}}}

{{annotation|245|60|{{if pagename|Phenethylamine=Phenethylamine|Trace amine=Phenethylamine|Neurobiological effects of physical exercise={{highlight|Phenethylamine}}|other=Phenethylamine}}}}

{{annotation|245|565|{{if pagename|Norepinephrine=Norepinephrine|Adrenaline=Noradrenaline|Catecholamine=Norepinephrine|other=Norepinephrine}}}}

{{annotation|440|295|p-Octopamine}}}}

primary
pathway
brain
CYP2D6
minor
pathway

References

  1. ↑ 1.0 1.1 "New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme". Drug Metabolism Reviews 41 (4): 573–643. 2009. doi:10.1080/03602530903118729. PMID 19645588. 
  2. ↑ "The endogenous substrates of brain CYP2D". European Journal of Pharmacology 724: 211–8. February 2014. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199. 
  3. ↑ 3.0 3.1 "Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance". Drug Metabolism and Pharmacokinetics 27 (1): 55–67. 2012. doi:10.2133/dmpk.DMPK-11-RV-121. PMID 22185816. 
  4. ↑ "Use of CYP2D6 genotyping in practice: tamoxifen dose adjustment". Pharmacogenomics 13 (6): 691–7. April 2012. doi:10.2217/pgs.12.27. PMID 22515611. 
  5. ↑ Tramadol Therapy and CYP2D6 Genotype. 2012. 
  6. ↑ Codeine Therapy and CYP2D6 Genotype. 2012. 
  7. ↑ "The Implausibility of Neonatal Opioid Toxicity from Breastfeeding". Clinical Pharmacology and Therapeutics 108 (5): 964–970. 2020. doi:10.1002/cpt.1882. PMID 32378749. 
  8. ↑ "Preventing opioid-related deaths in children undergoing surgery". Pain Med 13 (7): 982–3; author reply 984. July 2012. doi:10.1111/j.1526-4637.2012.01419.x. PMID 22694279. 
  9. ↑ "More codeine fatalities after tonsillectomy in North American children". Pediatrics 129 (5): e1343–7. May 2012. doi:10.1542/peds.2011-2538. PMID 22492761. 
  10. ↑ "Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study". Laryngoscope 124 (5): 1242–50. May 2014. doi:10.1002/lary.24455. PMID 24122716. 
  11. ↑ "In Silico Structural, Functional, and Phylogenetic Analysis of Cytochrome (CYPD) Protein Family". BioMed Research International 2021: 5574789. 2021. doi:10.1155/2021/5574789. PMID 34046497. 
  12. ↑ "CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme". Current Drug Metabolism 9 (7): 598–610. September 2008. doi:10.2174/138920008785821710. PMID 18781911. 
  13. ↑ "Evolution of the CYP2D gene cluster in humans and four non-human primates". Genes & Genetic Systems 86 (2): 109–116. 2011. doi:10.1266/ggs.86.109. PMID 21670550. 
  14. ↑ "Entrez Gene: CYP2D6 cytochrome P450, family 2, subfamily D, polypeptide 6". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1565. 
  15. ↑ 15.0 15.1 "The role of pharmacogenomic testing in psychiatry: Real world examples". The Australian and New Zealand Journal of Psychiatry 48 (8): 778. August 2014. doi:10.1177/0004867413520050. PMID 24413808. 
  16. ↑ "Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs". British Journal of Clinical Pharmacology 53 (2): 111–22. February 2002. doi:10.1046/j.0306-5251.2001.01548.x. PMID 11851634. 
  17. ↑ "Pharmacogenetics of debrisoquine and its use as a marker for CYP2D6 hydroxylation capacity". Pharmacogenomics 10 (1): 17–28. January 2009. doi:10.2217/14622416.10.1.17. PMID 19102711. 
  18. ↑ "The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects". American Family Physician 76 (3): 391–6. August 2007. PMID 17708140. 
  19. ↑ "PharmGKB" (in en). https://www.pharmgkb.org/gene/PA128/prescribingInfo. 
  20. ↑ "CYP2D6 CPIC guidelines" (in en-US). https://cpicpgx.org/gene/cyp2d6/. 
  21. ↑ 21.0 21.1 "PharmVar". https://www.pharmvar.org/gene/CYP2D6. 
  22. ↑ 22.0 22.1 22.2 "Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians". Pharmacogenetics 8 (4): 325–33. August 1998. doi:10.1097/00008571-199808000-00006. PMID 9731719. 
  23. ↑ Pharmacology and the Nursing Process. Toronto: Mosby Elsevier. 2007. pp. 25. ISBN 9780779699711. 
  24. ↑ "Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians". Pharmacogenetics 7 (3): 187–91. June 1997. doi:10.1097/00008571-199706000-00003. PMID 9241658. 
  25. ↑ "Cytochrome P450 2D6". Pharmacogenet Genomics 19 (7): 559–62. July 2009. doi:10.1097/FPC.0b013e32832e0e97. PMID 19512959. 
  26. ↑ "CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants". Pharmacogenomics 3 (2): 229–43. March 2002. doi:10.1517/14622416.3.2.229. PMID 11972444. 
  27. ↑ 27.00 27.01 27.02 27.03 27.04 27.05 27.06 27.07 27.08 27.09 27.10 27.11 27.12 27.13 27.14 27.15 27.16 27.17 27.18 27.19 27.20 27.21 27.22 27.23 27.24 27.25 27.26 27.27 27.28 27.29 27.30 27.31 27.32 27.33 27.34 27.35 27.36 27.37 27.38 27.39 27.40 27.41 27.42 27.43 27.44 27.45 27.46 27.47 27.48 27.49 27.50 27.51 27.52 27.53 27.54 27.55 27.56 27.57 27.58 27.59 27.60 27.61 27.62 27.63 27.64 27.65 27.66 27.67 27.68 27.69 27.70 27.71 27.72 27.73 27.74 27.75 27.76 27.77 27.78 27.79 27.80 27.81 27.82 27.83 "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. 2007. http://medicine.iupui.edu/flockhart/table.htm.  Retrieved in July 2011
  28. ↑ 28.00 28.01 28.02 28.03 28.04 28.05 28.06 28.07 28.08 28.09 28.10 28.11 28.12 28.13 28.14 28.15 28.16 28.17 28.18 28.19 28.20 28.21 28.22 28.23 28.24 28.25 28.26 28.27 28.28 28.29 28.30 28.31 28.32 FASS (drug formulary): Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare), retrieved July 2011
  29. ↑ 29.0 29.1 "Pharmacogenetics and pharmacogenomics". Pediatric Clinics of North America 48 (3): 765–81. June 2001. doi:10.1016/S0031-3955(05)70338-2. PMID 11411304. 
  30. ↑ "Hydrocodone". Drugbank. http://www.drugbank.ca/drugs/DB00956. 
  31. ↑ "CYP2D6 and tamoxifen: DNA matters in breast cancer". Nature Reviews. Cancer 9 (8): 576–86. August 2009. doi:10.1038/nrc2683. PMID 19629072. 
  32. ↑ "Wakix pitolisant tablets Prescribing Information". https://www.wakixhcp.com/assets/pdf/WAKIX__pitolisant__tablets_PI_Dec_2022.pdf#page10. 
  33. ↑ 33.0 33.1 33.2 "The endogenous substrates of brain CYP2D". Eur. J. Pharmacol. 724: 211–218. February 2014. doi:10.1016/j.ejphar.2013.12.025. PMID 24374199. 
  34. ↑ "Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis". Scientific Reports 11 (1): 10851. May 2021. doi:10.1038/s41598-021-90343-y. PMID 34035391. Bibcode: 2021NatSR..1110851V. 
  35. ↑ "Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions". Current Drug Metabolism 11 (8): 659–666. October 2010. doi:10.2174/138920010794233495. PMID 20942780. 
  36. ↑ 36.0 36.1 "DILTIAZEM HCL CD- diltiazem hydrochloride capsule, coated, extended release". 1 February 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e39be50-ea17-4077-a2dc-668267049f6a. 
  37. ↑ "NIFEDIPINE EXTENDED RELEASE- nifedipine tablet, extended release". 29 November 2012. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4617417a-08df-4417-a944-dfc30de183db. 
  38. ↑ "Inhibition of CYP2D6 activity by bupropion". Journal of Clinical Psychopharmacology 25 (3): 226–9. June 2005. doi:10.1097/01.jcp.0000162805.46453.e3. PMID 15876900. 
  39. ↑ "Pathway-specific inhibition of primaquine metabolism by chloroquine/quinine". Malaria Journal 15 (1): 466. September 2016. doi:10.1186/s12936-016-1509-x. PMID 27618912. 
  40. ↑ "Medical Cannabis Adverse Effects & Drug Interactions". https://doh.dc.gov/sites/default/files/dc/sites/doh/publication/attachments/Medical%20Cannabis%20Adverse%20Effects%20and%20Drug%20Interactions_0.pdf. 
  41. ↑ "Inhibitory Mechanisms of Human CYPs by Three Alkaloids Isolated from Traditional Chinese Herbs". Phytotherapy Research 29 (6): 825–34. June 2015. doi:10.1002/ptr.5285. PMID 25640685. 
  42. ↑ "Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions". Planta Medica 78 (13): 1458–77. September 2012. doi:10.1055/s-0032-1315117. PMID 22855269. 
  43. ↑ "The enhancement of cardiotoxicity that results from inhibiton of CYP 3A4 activity and hERG channel by berberine in combination with statins". Chemico-Biological Interactions 293: 115–123. September 2018. doi:10.1016/j.cbi.2018.07.022. PMID 30086269. 
  44. ↑ "Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro". Drug Metabolism and Disposition 31 (6): 768–72. June 2003. doi:10.1124/dmd.31.6.768. PMID 12756210. 
  45. ↑ 45.0 45.1 "Citalopram Oral Solution". Drugs.com. https://www.drugs.com/pro/citalopram-oral-solution.html. 
  46. ↑ "Escitalopram-drug-information". https://www.uptodate.com/contents/escitalopram-drug-information. 
  47. ↑ 47.0 47.1 "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". FDA. 26 May 2021. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. 
  48. ↑ "Methylphenidate and Its Under-recognized, Under- explained, and Serious Drug Interactions: A Review of the Literature with Heightened Concerns". German Journal of Psychiatry: 29–42. July 2013. http://www.gjpsy.uni-goettingen.de/gjp-article-nevels.pdf. Retrieved 31 August 2016. 
  49. ↑ "Erythromycin-felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice". Clinical Pharmacology and Therapeutics 60 (1): 25–33. July 1996. doi:10.1016/s0009-9236(96)90163-0. PMID 8689808. 
  50. ↑ "Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression". The Journal of Clinical Investigation 99 (10): 2545–53. May 1997. doi:10.1172/jci119439. PMID 9153299. 
  51. ↑ "Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 IIIA4". Journal of Medicinal Chemistry 34 (6): 1838–44. June 1991. doi:10.1021/jm00110a012. PMID 2061924. 
  52. ↑ "New antidepressants and the cytochrome P450 system: focus on venlafaxine, nefazodone, and mirtazapine". Depression and Anxiety 7 (Suppl 1): 24–32. 30 May 1998. doi:10.1002/(SICI)1520-6394(1998)7:1+<24::AID-DA7>3.0.CO;2-F. PMID 9597349. https://researchers.dellmed.utexas.edu/en/publications/new-antidepressants-and-the-cytochrome-psub450sub-system-focus-on. Retrieved 1 November 2019. 
  53. ↑ 53.0 53.1 53.2 53.3 FASS, The Swedish official drug catalog > Kodein Recip Last reviewed 8 April 2008
  54. ↑ "Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes". European Journal of Clinical Pharmacology 57 (12): 847–51. February 2002. doi:10.1007/s00228-001-0399-0. PMID 11936702. 
  55. ↑ "In Vitro Activity of St. John's Wort Against Cytochrome P450 Isozymes and P-Glycoprotein". Pharmaceutical Biology 42 (2): 159–69. 2008. doi:10.1080/13880200490512034. 
  56. ↑ "Inhibition of human P450 enzymes by nicotinic acid and nicotinamide". Biochemical and Biophysical Research Communications 317 (3): 950–956. May 2004. doi:10.1016/j.bbrc.2004.03.137. PMID 15081432. 
  57. ↑ "Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles". Pharmaceutics 10 (4): 277. December 2018. doi:10.3390/pharmaceutics10040277. PMID 30558213. 
  58. ↑ "Pharmacokinetics of haloperidol: an update". Clinical Pharmacokinetics 37 (6): 435–56. December 1999. doi:10.2165/00003088-199937060-00001. PMID 10628896. 
  59. ↑ "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. May 2005. doi:10.1016/j.tips.2005.03.007. PMID 15860375. 

Further reading

External links



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