CYP2C19
Cytochrome P450 2C19
Gene Number: 1557
Location: 10q23.33
Key Functions: Drug metabolism, hepatic detoxification, CYP450 enzyme activity
The CYP2C19 gene, located on chromosome 10q23.33, encodes cytochrome P450 2C19, a heme-thiolate monooxygenase that plays a pivotal role in hepatic drug metabolism. As part of the cytochrome P450 superfamily, CYP2C19 catalyzes the oxidative biotransformation of numerous pharmaceuticals, xenobiotics, and endogenous substrates, contributing significantly to phase I detoxification in the liver.
Biochemically, CYP2C19 participates in the hydroxylation, demethylation, and oxidation of a broad range of therapeutic agents, including clopidogrel (Plavix), proton pump inhibitors (omeprazole, lansoprazole), certain antidepressants (citalopram, amitriptyline), antiepileptics (diazepam), and antifungals (voriconazole).
Its enzymatic activity directly determines plasma drug concentrations, influencing both efficacy and toxicity. For example, CYP2C19 is required to bioactivate clopidogrel into its active metabolite — a critical step for antiplatelet function — meaning individuals with reduced enzyme activity exhibit diminished therapeutic response and higher cardiovascular risk.
Genetically, CYP2C19 is highly polymorphic, with allelic variants defining distinct metabolizer phenotypes. The most studied loss-of-function alleles are CYP2C19*2 (rs4244285, splicing defect) and CYP2C19*3 (rs4986893, premature stop codon), which lead to inactive enzyme production. Carriers of these variants are classified as poor or intermediate metabolizers, depending on zygosity. Conversely, the CYP2C19*17 (rs12248560) variant enhances gene transcription, resulting in ultra-rapid metabolism. These genotype-driven differences profoundly impact therapeutic outcomes — poor metabolizers experience reduced efficacy of prodrugs like clopidogrel, while ultra-rapid metabolizers may have decreased plasma levels of active drugs such as proton pump inhibitors, shortening their duration of action.
Population studies reveal striking ethnic variability in CYP2C19 allele frequencies: loss-of-function variants occur in 15–20% of Asians, 2–5% of Europeans, and 4–7% of Africans, influencing global differences in drug response profiles. Such variability has driven the inclusion of CYP2C19 genotyping in pharmacogenomic guidelines by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and other regulatory bodies. These recommendations guide dose adjustments or drug substitutions, optimizing efficacy and minimizing adverse reactions.
In summary, CYP2C19 acts as a genetic gatekeeper of drug metabolism, balancing therapeutic precision and safety. Its polymorphic landscape exemplifies how molecular genetics intersects with clinical pharmacology, transforming medicine from a one-size-fits-all approach into a domain of personalized pharmacotherapy guided by the genome itself.
SNP ID | Your Genotype | Alternative Alleles | Interpretation |
|---|---|---|---|
rs4244285 | No matching variant or no valid DNA data | A | No interpretation available |
rs12248560 | No matching variant or no valid DNA data | T | No interpretation available |
rs4244285 (CYP2C19*2, splice defect)
GG – Normal function (extensive/normal metabolizer) (R).
AG – One loss-of-function allele; intermediate metabolizer. Reduced activation of clopidogrel, slower drug clearance (R).
AA – Two loss-of-function alleles; poor metabolizer. Greatly reduced CYP2C19 activity; impaired metabolism of clopidogrel, PPIs, certain antidepressants (R).
Functional effect: The A allele disrupts splicing, creating a nonfunctional enzyme. Carriers have reduced clearance of many substrates and impaired prodrug activation (e.g., clopidogrel), leading to increased adverse drug reactions or reduced efficacy depending on therapy (R).
rs12248560 (CYP2C19*17, promoter variant)
CC – Normal CYP2C19 activity; standard metabolism (R).
TC – One *17 allele; rapid metabolizer. Enhanced drug clearance, reduced response to standard PPI doses, increased bleeding risk with clopidogrel (R).
TT – Two *17 alleles; ultra-rapid metabolizer. Very high clearance of substrates, significantly reduced efficacy of some drugs (e.g., PPIs, SSRIs), increased risk of adverse effects with prodrugs (R).
Functional effect: The T allele increases promoter activity, upregulating CYP2C19 expression. This results in faster metabolism, which can either reduce efficacy (for drugs like PPIs or antidepressants) or increase activation of prodrugs like clopidogrel, raising bleeding risk [R].
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