Biology:CYP2C19

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Short description: Mammalian protein found in humans


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

Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some proton pump inhibitors and antiepileptic drugs. In humans, it is the CYP2C19 gene that encodes the CYP2C19 protein.[1][2] CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use,[3] most notably the antiplatelet treatment clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.[4]

CYP2C19 has been annotated as (R)-limonene 6-monooxygenase and (S)-limonene 6-monooxygenase in UniProt.

Function

The gene encodes a member of the cytochrome P450 superfamily of enzymes. Enzymes in the CYP2C subfamily, including CYP2C19, account for approximately 20% of cytochrome P450 in the adult liver.[5] These proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize many drugs. Polymorphism within this gene is associated with variable ability to metabolize drugs. The gene is located within a cluster of cytochrome P450 genes on chromosome no.10 arm q24.[6]

CYP2C19 also possesses epoxygenase activity: it is one of the principal enzymes responsible for attacking various long-chain polyunsaturated fatty acids at their double (i.e. alkene) bonds to form epoxide products that act as signaling agents. It metabolizes:

  1. arachidonic acid to various epoxyeicosatrienoic acids (also termed EETs);
  2. linoleic acid to 9,10-epoxy octadecenoic acids (also termed vernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin);
  3. docosahexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and
  4. eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs).[7][8][9]

Along with CYP2C19, CYP2C8, CYP2C9, CYP2J2, and possibly CYP2S1 are the main producers of EETs and, very likely EEQs, EDPs, and the epoxides of linoleic acid.[8][10]

Pharmacogenomics

Pharmacogenomics is a study that analyzes how an individual's genetic makeup affects the response to drugs of this individual. There are many common genetic variations that affect the expression of the CYP2C19 gene, which in turn influences the enzyme activity in the metabolic pathways of those drugs in which this enzyme is involved.

The Pharmacogene Variation Consortium keeps the Human CYP Allele Nomenclature Database and assigns labels to known polymorphisms that affect drug response. A label consists of an asterisk (*) character followed by a number. The most common variant (also called wild type) has "CYP2C19*1" label. The variant genotypes of CYP2C19*2 (NM_000769.2:c.681GA; p.Pro227Pro; rs4244285), CYP2C19*3 (NM_000769.2:c.636G>A; p.Trp212Ter; rs4986893) and CYP2C19*17 (NM_000769.2:c.-806C>T; rs12248560)[11] are major factors attributed to interindividual differences in the pharmacokinetics and response to CYP2C19 substrates.

CYP2C19*2 and *3 (loss-of-function alleles) are associated with diminished enzyme activity,[12][13] whereas CYP2C19*17 (gain-of-function allele) results in increased activity.[14] The Working Group of the Association for Molecular Pathology Clinical Practice Committee recommended these three variant alleles to be included in the minimal clinical pharmacogenomic testing panel, called tier 1. The extended panel of variant alleles, called tier 2, additionally includes the following CYP2C19 alleles: *4.001 (*4A), *4.002 (*4B), *5, *6, *7, *8, *9, *10, and *35, all of them associated with diminished enzyme activity. Although these tier 2 alleles are included in many platforms, they were not included in the tier 1 recommendations because of low minor allele frequency (which can increase false-positive occurrences), less well-characterized impact on CYP2C19 function, or a lack of reference materials. In partnership with the clinical testing community, the Centers for Disease Control and Prevention established the Genetic Testing Reference Material Program to meet the need for publicly available characterized reference materials. Its goal is to improve the supply of publicly available and well-characterized genomic DNA used as reference materials for proficiency testing, quality control, test development/validation, and research studies.[11]

The allele frequencies of CYP2C19*2 and *3 are significantly higher in Chinese populations than in European or African populations,[15] and are found at approximately 3–5% of European and 15–20% of Asian populations.[16][17] Among Arab population, the frequency of CYP2C19 genotypes including *1/*17, *1/*2, *2/*2, *3/*3, and *1/*3 were 20.2%, 16.7%, 6.1%, 5.45%, 0.7%, and 0.35%, respectively.[18] In a study of 2.29 million direct-to-consumer genetics research participants, the overall frequencies of *2, *3, and *17 were 15.2%, 0.3%, and 20.4%, respectively, but varied by ethnicity. The most common variant diplotypes were *1/*17 at 26% and *1/*2 at 19.4%. The less common *2/*17, *17/*17 and *2/*2 genotypes occurred at 6.0%, 4.4%, and 2.5%, respectively. Overall, 58.3% of participants had at least one increased-function or no-function CYP2C19 allele.[19]

CYP2C19 is involved in processing or metabolizing at least 10% of commonly prescribed drugs.[20] Variations to the enzyme can have a wide range of impacts to drug metabolism. In patients with an abnormal CYP2C19 variant certain benzodiazepines should be avoided, such as diazepam (Valium), lorazepam (Ativan), oxazepam (Serax), and temazepam (Restoril).[21] Other categories of drugs impacted by modified CYP2C19 include proton pump inhibitors, anticonvulsants, hypnotics, sedatives, antimalarial drugs, and antiretroviral drugs.[20]

On the basis of their ability to metabolize (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as ultrarapid metabolizers (UM), extensive metabolizers (EM) or poor metabolizers (PM).[17][22] In the case of proton pump inhibitors, PMs exhibit a drug exposure that is 3 to 13 times higher than that of EMs.[23] Loss-of-function alleles, CYP2C19*2 and CYP2C19*3 (and others, which are the subject of ongoing research) predict PMs,[17] and the gain-of-function CYP2C19*17 allele predicts UMs.[20]

Although the amount of CYP2C19 enzyme produced by the *17 allele is greater than of the *1 allele,[24] whether the carriers of the *17 allele experience any significant difference in response to drugs compared to the wild-type, is a topic of ongoing research, studies show varying results.[22][25] Some studies have found that the *17 variant's effect on the metabolism of omeprazole, pantoprazole, escitalopram, sertraline, voriconazole, tamoxifen and clopidogrel[22][26] is modest, particularly compared to the impact of loss-of-function alleles (*2, *3), therefore, in case of these medications, the EM designation is sometimes applied instead of the UM one.[22] For example, carriers of the *17 allele did not demonstrate different gastric pH comparing to *1 after taking the proton pump inhibitor omeprazole, a CYP2C19 substrate.[22] Other studies concluded that the *17 allele seems to be the factor responsible for lower response to some drugs, even at higher doses, for example, to escitalopram for symptom remission in major depressive disorder patients.[25] CYP2C19*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding; the highest risk was observed for CYP2C19*17 homozygous patients.[27][28] A study found that escitalopram serum concentration was 42% lower in patients homozygous for CYP2C19*17.[29] An important limitation of all these studies is the single-gene analysis, since most drugs that are metabolized by CYP2C19 are also metabolized by CYP2D6 and CYP3A4 enzymes. Besides that, other genes are involved in drug response, for example, escitalopram is transported by P-glycoprotein, encoded by the ABCB1 gene. In order for the studies on CYP2C19*17 to be conclusive, the differences in other genes that affect drug response have to be excluded.[25] The prevalence of the CYP2C19*17 variant is less than 5% in Asian populations and is approximately four times higher in European and African populations.[22]

The alleles CYP2C19*2[30] and *3 may reduce the efficacy of clopidogrel (Plavix), an antiplatelet medication. The basis for this reduced effect of clopidogrel in patients who have a gene of reduced activity may seem somewhat paradoxical, but can be understood as follows. Clopidogrel is administered as a "prodrug", a drug that is inactive when taken, and then depends on the action of an enzyme in the body to be activated. In patients with a gene of reduced activity, clopidogrel may not be metabolized to its biologically active form and therefore not achieve pharmacological effect in the body. The relative risk of major cardiac events among patients treated with clopidogrel is 1.53 to 3.69 times higher for carriers of CYP2C19*2 and CYP2C19*3 compared with non-carriers.[31] A 2020 systematic review and meta-analysis also confirmed that the CYP2C19*2 variant has a strong association with clopidogrel resistance.[30] In 2021 a higher risk of stroke at 90 days was found with clopidogrel than ticagrelor, which does not require metabolic conversion, among Han Chinese CYP2C19 loss-of-function carriers with minor ischemic stroke or TIA.[32]

Ligands

The following is a table of selected substrates, inducers, and inhibitors of CYP2C19. Where classes of agents are listed, there may be exceptions within the class.

Inhibitors of CYP2C19 can be classified by their potency, such as:

  • Strong being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance of substrates.[33]
  • Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or 50–80% decrease in clearance of substrates.[33]
  • Weak 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 of substrates.[33]
Selected inducers, inhibitors, and substrates of CYP2C19
Substrates Inhibitors Inducers
Strong
Moderate
Weak
Unspecified potency
Unspecified potency

See also

  • Cytochrome P450 oxidase

References

  1. ↑ "Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily". Biochemistry 30 (13): 3247–3255. April 1991. doi:10.1021/bi00227a012. PMID 2009263. 
  2. ↑ "A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24". Genomics 28 (2): 328–332. July 1995. doi:10.1006/geno.1995.1149. PMID 8530044. 
  3. ↑ "CYP2C19 gene". https://ghr.nlm.nih.gov/gene/CYP2C19. 
  4. ↑ "Cytochrome P450 2C19 (CYP2C19) Genotype". June 2013. http://www.mayomedicallaboratories.com/articles/features/cyp2c19/index.html. 
  5. ↑ "Developmental expression of human hepatic CYP2C9 and CYP2C19". The Journal of Pharmacology and Experimental Therapeutics 308 (3): 965–974. March 2004. doi:10.1124/jpet.103.060137. PMID 14634042. 
  6. ↑ "Entrez Gene: CYP2C19 cytochrome P450, family 2, subfamily C, polypeptide 19". National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/gene/1557. "This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize many xenobiotics, including the anticonvulsive drug mephenytoin, omeprazole, diazepam and some barbiturates. Polymorphism within this gene is associated with variable ability to metabolize mephenytoin, known as the poor metabolizer and extensive metabolizer phenotypes. The gene is located within a cluster of cytochrome P450 genes on chromosome 10q24."  This article incorporates text from this source, which is in the public domain.
  7. ↑ "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews 66 (4): 1106–1140. October 2014. doi:10.1124/pr.113.007781. PMID 25244930. 
  8. ↑ 8.0 8.1 "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling". Prostaglandins & Other Lipid Mediators 113–115: 2–12. October 2014. doi:10.1016/j.prostaglandins.2014.09.001. PMID 25240260. 
  9. ↑ "Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway". Journal of Lipid Research 55 (6): 1150–1164. June 2014. doi:10.1194/jlr.M047357. PMID 24634501. 
  10. ↑ "Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1851 (4): 356–365. April 2015. doi:10.1016/j.bbalip.2014.07.020. PMID 25093613. 
  11. ↑ 11.0 11.1 "Recommendations for Clinical CYP2C19 Genotyping Allele Selection: A Report of the Association for Molecular Pathology". The Journal of Molecular Diagnostics 20 (3): 269–276. May 2018. doi:10.1016/j.jmoldx.2018.01.011. PMID 29474986. 
  12. ↑ "Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin". The Journal of Pharmacology and Experimental Therapeutics 286 (3): 1490–1495. September 1998. PMID 9732415. 
  13. ↑ "Genetic variations and haplotypes of CYP2C19 in a Japanese population". Drug Metabolism and Pharmacokinetics 20 (4): 300–307. August 2005. doi:10.2133/dmpk.20.300. PMID 16141610. 
  14. ↑ "A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants". Clinical Pharmacology and Therapeutics 79 (1): 103–113. January 2006. doi:10.1016/j.clpt.2005.10.002. PMID 16413245. 
  15. ↑ "The CYP2C19 enzyme polymorphism". Pharmacology 61 (3): 174–183. September 2000. doi:10.1159/000028398. PMID 10971203. 
  16. ↑ "Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19". Clinical Pharmacokinetics 29 (3): 192–209. September 1995. doi:10.2165/00003088-199529030-00005. PMID 8521680. 
  17. ↑ 17.0 17.1 17.2 "Clinical significance of the cytochrome P450 2C19 genetic polymorphism". Clinical Pharmacokinetics 41 (12): 913–958. 2002. doi:10.2165/00003088-200241120-00002. PMID 12222994. 
  18. ↑ "The CYP2C19 genotypes and its effect on clopidogrel as an anti-platelet drug among the Arab population". Indian Journal of Pharmacology 53 (1): 85–87. 2021. doi:10.4103/ijp.IJP_690_20. PMID 33976007. 
  19. ↑ "CYP2C19 allele frequencies in over 2.2 million direct-to-consumer genetics research participants and the potential implication for prescriptions in a large health system". Clinical and Translational Science 13 (6): 1298–1306. June 2020. doi:10.1111/cts.12830. PMID 32506666. 
  20. ↑ 20.0 20.1 20.2 "CYP2C19 gene" (in en). https://ghr.nlm.nih.gov/gene/CYP2C19. 
  21. ↑ "American Association of Clinical Chemistry Annual Meeting 2014: Utility of Genetic Testing in Practical Pain Management". 2014. http://www.autogenomics.com/?q=node/224. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 22.8 "Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17". British Journal of Clinical Pharmacology 69 (3): 222–230. March 2010. doi:10.1111/j.1365-2125.2009.03578.x. PMID 20233192. 
  23. ↑ "CYP2C19 polymorphism and proton pump inhibitors". Basic & Clinical Pharmacology & Toxicology 95 (1): 2–8. July 2004. doi:10.1111/j.1600-0773.2004.pto950102.x. PMID 15245569. 
  24. ↑ Psychiatric Pharmacogenomics. Oup USA. 2010. p. 62. ISBN 978-0195367294. 
  25. ↑ 25.0 25.1 25.2 "CYP2C19 polymorphisms and outcomes of Escitalopram treatment in Brazilians with major depression". Heliyon 6 (5): e04015. May 2020. doi:10.1016/j.heliyon.2020.e04015. PMID 32509985. Bibcode: 2020Heliy...604015B. 
  26. ↑ "Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention". Clinical Pharmacology and Therapeutics 109 (3): 705–715. March 2021. doi:10.1002/cpt.2039. PMID 32897581. 
  27. ↑ "Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement". Circulation 121 (4): 512–518. February 2010. doi:10.1161/CIRCULATIONAHA.109.885194. PMID 20083681. 
  28. ↑ "The gain-of-function variant allele CYP2C19*17: a double-edged sword between thrombosis and bleeding in clopidogrel-treated patients". Journal of Thrombosis and Haemostasis 10 (2): 199–206. February 2012. doi:10.1111/j.1538-7836.2011.04570.x. PMID 22123356. 
  29. ↑ "Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients". Clinical Pharmacology and Therapeutics 83 (2): 322–327. February 2008. doi:10.1038/sj.clpt.6100291. PMID 17625515. 
  30. ↑ 30.0 30.1 "Cyp2C19*2 Polymorphism Related to Clopidogrel Resistance in Patients With Coronary Heart Disease, Especially in the Asian Population: A Systematic Review and Meta-Analysis". Frontiers in Genetics 11: 576046. 2020. doi:10.3389/fgene.2020.576046. PMID 33414804. 
  31. ↑ "Effects of CYP2C19 genotype on outcomes of clopidogrel treatment". The New England Journal of Medicine 363 (18): 1704–1714. October 2010. doi:10.1056/NEJMoa1008410. PMID 20979470. https://www.pure.ed.ac.uk/ws/files/8152528/Pare_G_2010.pdf. 
  32. ↑ "Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA". The New England Journal of Medicine 385 (27): 2520–2530. December 2021. doi:10.1056/NEJMoa2111749. PMID 34708996. https://nottingham-repository.worktribe.com/output/6345566. 
  33. ↑ 33.0 33.1 33.2 Center for Drug Evaluation and Research. "Drug Interactions & Labeling – Drug Development and Drug Interactions: Table of Substrates, Inhibitors, and Inducers". https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#classInhibit. 
  34. ↑ 34.00 34.01 34.02 34.03 34.04 34.05 34.06 34.07 34.08 34.09 34.10 34.11 34.12 34.13 34.14 34.15 34.16 34.17 34.18 34.19 34.20 34.21 34.22 34.23 34.24 34.25 34.26 34.27 34.28 34.29 34.30 34.31 34.32 34.33 34.34 34.35 34.36 34.37 34.38 34.39 "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. 2007. http://medicine.iupui.edu/flockhart/table.htm. 
  35. ↑ 35.00 35.01 35.02 35.03 35.04 35.05 35.06 35.07 35.08 35.09 35.10 35.11 35.12 35.13 35.14 35.15 35.16 35.17 35.18 35.19 35.20 "Fakta för förskrivare: Interaktion mellan läkemedel" (in sv). http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352. 
  36. ↑ "Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes". Drug Metabolism and Disposition 42 (11): 1971–1977. November 2014. doi:10.1124/dmd.114.060285. PMID 25187485. 
  37. ↑ Alkattan A, Alsalameen E. "Polymorphisms of genes related to phase-I metabolic enzymes affecting the clinical efficacy and safety of clopidogrel treatment". Expert Opin Drug Metab Toxicol. 2021 May 15:1–11. doi:10.1080/17425255.2021.1925249. Epub ahead of print. PMID 33931001.
  38. ↑ "Metabolism of (+)- and (–)–limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes". Drug Metabolism and Disposition 30 (5): 602–607. May 2002. doi:10.1124/dmd.30.5.602. PMID 11950794. 
  39. ↑ "Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects". British Journal of Clinical Pharmacology 64 (1): 67–74. July 2007. doi:10.1111/j.1365-2125.2007.02846.x. PMID 17298483. 
  40. ↑ "Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide". British Journal of Pharmacology 153 (7): 1579–1586. April 2008. doi:10.1038/sj.bjp.0707685. PMID 18204476. 
  41. ↑ 41.0 41.1 41.2 41.3 41.4 "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. 
  42. ↑ "Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes". Antimicrobial Agents and Chemotherapy 47 (11): 3464–3469. November 2003. doi:10.1128/AAC.47.11.3464-3469.2003. PMID 14576103. 
  43. ↑ "Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4". Clinical Pharmacology and Therapeutics 95 (6): 653–662. June 2014. doi:10.1038/clpt.2014.50. PMID 24569517. 
  44. ↑ 44.0 44.1 "Combination Therapy and Drug Interactions". Antiepileptic drugs (5th ed.). Hagerstwon, MD: Lippincott Williams & Wilkins. 2002. p. 100. ISBN 0781723213. OCLC 848759609. https://books.google.com/books?id=HAOY0qG-vAYC&pg=PA100. 
  45. ↑ "Effect of proton pump inhibitors on the serum concentrations of the selective serotonin reuptake inhibitors citalopram, escitalopram, and sertraline". Therapeutic Drug Monitoring 37 (1): 90–97. February 2015. doi:10.1097/FTD.0000000000000101. PMID 24887634. 
  46. ↑ "Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes". European Journal of Clinical Pharmacology 57 (11): 799–804. January 2002. doi:10.1007/s00228-001-0396-3. PMID 11868802. 
  47. ↑ "Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects". Clinical Pharmacology and Therapeutics 73 (3): 264–271. March 2003. doi:10.1067/mcp.2003.14. PMID 12621391. 

External links



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