CYP2C19

Mammalian protein found in humans

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. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, 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. CYP2C19 has been annotated as (R) limonene 6 monooxygenase and (S) limonene 6 monooxygenase in UniProt.

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 Clinical Pharmacogenetics Implementation Consortium (CPIC) provides therapeutic guidelines that are widely utilized to suggest suitable treatment plans. These recommendations are particularly relevant for patients requiring antiplatelet medication and are based on the results of genotype testing. A key aspect of these CPIC guidelines is the translation of genotype to phenotype, a process that relies on the "star" nomenclature system maintained by the Pharmacogene Variation Consortium assigns labels to known polymorphisms that affect drug response. A label consists of a star (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) 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, whereas CYP2C19*17 (gain of function allele) results in increased activity. 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. and are found at approximately 3–5% of European and 15–20% of Asian populations. 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. 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. CYP2C19 is involved in processing or metabolizing at least 10% of commonly prescribed drugs. 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). Other categories of drugs impacted by modified CYP2C19 include proton pump inhibitors, anticonvulsants, hypnotics, sedatives, antimalarial drugs, and antiretroviral drugs. In the case of proton pump inhibitors, PMs exhibit a drug exposure that is 3 to 13 times higher than that of EMs. Loss of function alleles, CYP2C19*2 and CYP2C19*3 (and others, which are the subject of ongoing research) predict PMs, 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. Some studies have found that the *17 variant's effect on the metabolism of omeprazole, pantoprazole, escitalopram, sertraline, voriconazole, tamoxifen and clopidogrel 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. A study found that escitalopram serum concentration was 42% lower in patients homozygous for CYP2C19*17. 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. 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. A 2020 systematic review and meta analysis also confirmed that the CYP2C19*2 variant has a strong association with clopidogrel resistance.