Cytochrome P450 2C19

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Cytochrome P450 2C19 or Cytochrome P450 Family 2 Subfamily C Member 19 or CYP2C19 is a gene linked to drug metabolism. Variants in CYP2C19 or lack of the gene are extremely common, with one study finding that over 50% of people in the study had either no CYP2C19 gene or a variant of it.[1]

Function[edit | edit source]

Variants in CYP2C19 or the absence of the gene can significantly alter the drug metabolism of several medications, genotype‐based dosing guidelines available for these medications.[1]

Drug responses[edit | edit source]

CYP2C19 variants are known to affect the metabolism of the tricyclic antidepressants amitriptyline, clomipramine, doxepin and imipramine, the selective serotonin reuptake inhibitors (SSRIs) citalopram and sertraline, the antifungal drug voriconazole, and the antiplatelet agent clopidogrel which reduces blood clotting.[2]

An FDA warning was been added to clopidogrel in 2009 which started that genetic testing was available to determine if a patient could be a poor metabolizer, and that this would make the drug less effective.[3]

Variants[edit | edit source]

  • rs12248560 (CYP2C19*17) ultrarapid CYP2C19 metabolism and increases increases enzyme function, acting in the opposite way to rs4244285. In Europe, this variant affects between 1 in 3 and 1 in 9 people.[2]
  • rs4244285 (CYP2C19*2) is the most common variant in Caucasians, and results in aberrant splicing and loss of function, rs12248560 acts in the opposite way. This variant also affects around 1 in 5 people in the Romany (traveler) community in one study.[2] If combined with the CYP2C19*1 normal functioning variant drug effectiveness improves compared to having two copies of rs4244285.[3]
  • (CYP2C19*1) normal functioning[3]
  • rs17885098 (CYP2C19*1B) normal function[4]
  • rs3758581 (CYP2C19*1C, CYP2C19*3C, CYP2C19*4A, CYP2C19*4B and many others) 991A>G normal functioning, some others cause loss of function[4]
  • rs4986893 (CYP2C19*3, CYP2C19*3A, CYP2C19*3B, CYP2C19*3C 636 G>A) [5]
  • rs3758581 (CYP2C19*3A) loss of function[4]
  • rs17886522 (CYP2C19*3B or CYP2C19*20) loss of function[4]
  • rs3758581 (CYP2C19*3B or CYP2C19*20, CYP2C19*3C) loss of function[4]
  • rs144036596 (CYP2C19*3B or CYP2C19*20) loss of function[4]
  • rs4986893 (CYP2C19*3B or CYP2C19*20) loss of function[4]
  • rs397516695 (CYP2C19*3C) 407T>A[6][4]
  • rs17886522 (CYP2C19*3C) 1251A>C[7][4]
  • rs28399504 (CYP2C19*4) A>G[5]
  • rs unknown (CYP2C19*5) 1297 C>T [5]
  • rs unknown (CYP2C19*6)[5]

Conflicting data in different studies make it unclear which areas of European are most affected by these variants.[3]

Variant combinations[edit | edit source]

Likely effect Combination
Ultrarapid metabolizer: normal or increased activity (~5–30% of patients) Two increased activity alleles (*17) or one functional allele (*1) plus one increased-activity allele (*17), eg and rs12248560.
Extensive metabolizer: homozygous wild-type or normal activity (~35–50% of patients) Two functional (*1) alleles e.g.
Intermediate metabolizer: heterozygote or intermediate activity (~18–45% of patients)
Poor metabolizer: homozygous variant, mutant, low, or deficient activity (~2–15% of patients) [8]

CYP2D6[edit | edit source]

Common variants of cytochrome P450 2D6 (CYP2D6) also impact the effects of these drugs.

ME/CFS[edit | edit source]

No particular link to ME/CFS has been found for people with CYP2C19 gene variants. One study found CYP2C19 to be one of a number of genes associated with multiple chemical sensitivity, but other studies failed to find this.[1]

See also[edit | edit source]

Learn more[edit | edit source]

References[edit | edit source]

  1. 1.0 1.1 1.2 Ionova, Yelena; Ashenhurst, James; Zhan, Jianan; Nhan, Hoang; Kosinski, Cindy; Tamraz, Bani; Chubb, Alison (2020). "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. doi:10.1111/cts.12830. ISSN 1752-8062. PMC 7719394. PMID 32506666.
  2. 2.0 2.1 2.2 Petrović, Jelena; Pešić, Vesna; Lauschke, Volker M. (January 2020). "Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe". European Journal of Human Genetics. 28 (1): 88–94. doi:10.1038/s41431-019-0480-8. ISSN 1018-4813. PMC 6906321. PMID 31358955.
  3. 3.0 3.1 3.2 3.3 Center for Drug Evaluation and Research (June 28, 2019). "FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug". FDA.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 "CYP2C19". PharmVar Archive. Retrieved April 7, 2021.
  5. 5.0 5.1 5.2 5.3 "Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects". Blood. 108 (7): 2244–2247. October 1, 2006. doi:10.1182/blood-2006-04-013052. ISSN 0006-4971.
  6. "rs397516695 RefSNP Report - dbSNP - Short Genetic Variations". NCBI. Retrieved March 31, 2022.
  7. "rs17886522 RefSNP Report - dbSNP - Short Genetic Variations". NCBI. Retrieved March 31, 2022.
  8. Scott, S.A.; Sangkuhl, K.; Stein, C.M.; Hulot, J.-S.; Mega, J.L.; Roden, D.M.; Klein, T.E.; Sabatine, M.S.; Johnson, J.A. (2013). "Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update". Clinical Pharmacology & Therapeutics. 94 (3): 317–323. doi:10.1038/clpt.2013.105. ISSN 1532-6535. PMC 3748366. PMID 23698643.