Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation

Abstract

We investigated the elimination routes for the 200 drugs that are sold most often by prescription count in the United States. The majority (78%) of the hepatically cleared drugs were found to be subject to oxidative metabolism via cytochromes P450 of the families 1, 2 and 3, with major contributions from CYP3A4/5 (37% of drugs) followed by CYP2C9 (17%), CYP2D6 (15%), CYP2C19 (10%), CYP1A2 (9%), CYP2C8 (6%), and CYP2B6 (4%). Clinically well-established polymorphic CYPs (i.e., CYP2C9, CYP2C19, and CYP2D6) were involved in the metabolism of approximately half of those drugs, including (in particular) NSAIDs metabolized mainly by CYP2C9, proton-pump inhibitors metabolized by CYP2C19, and beta blockers and several antipsychotics and antidepressants metabolized by CYP2D6. In this review, we provide an up-to-date summary of the functional polymorphisms and aspects of the functional genomics of the major human drug-metabolizing cytochrome P450s, as well as their clinical significance.

Functional characterization of eight human cytochrome P450 1A2 gene variants by recombinant protein expression

“…52 However, we have shown in this study that although the eight variants cause, seemingly on the whole, relatively minor activity changes (besides I386F and R456H), some variants can have profound effects on particular CYP1A2-mediated biotransformation, as was demonstrated for the bioactivation of NNK. As such, the results indicated that several of the studied allelic forms can have pharmokinetic and/or toxicokinetic consequences.…”

Frequency of Common Variants in Genes Involved in Lipid-Lowering Response to Statins in Chilean Subjects with Hypercholesterolemia

“…Comparing the frequency of the G allele (0.15) with those reported by other studies, we see a similarity with Brazilian population (0.13) (Cavalli et al), Asian (0.16) (Thompson et al) and Hispanic (0.09) (Ball et al, 1999), and the frequency of the mutant variant CYP3A4*1B was significantly higher than that observed in Europeans (0.05) (Sata et al, 2000) and American population, both white (0.04) and Black (0.54) (Ball et al) and lower in Africans (0.82) (Zanger et al, 2008) and Afro-American (0.67) (Sata et al). Gao et al (2008) demonstrated an association between the presence of G allele in hypercholesterolemic individuals who had a greater reduction of total cholesterol levels, when treated with atorvastatin 20 mg/day for 4 weeks in Asiatic population.…”

Effect of the CYP3A inhibitors, diltiazem and ketoconazole, on ticagrelor pharmacokinetics in healthy volunteers

“…CYP3A is abundant in the intestine and liver29, and is a key enzyme involved in the metabolism of many xenobiotics11,12. Extensive investigations have established that drugs can act as substrates, inhibitors, or inducers of CYP3A29.…”

“…Consequently, drug–drug interactions may occur which could result in altered exposure to a co-administered drug, thereby affecting efficacy and safety9,10. The most abundant drug-metabolizing enzyme in the liver is cytochrome P450 (CYP) 3A11,12, and clinically important interactions involving this enzyme are well documented12. Although ticagrelor is a direct-acting antiplatelet agent, it is metabolized to at least ten metabolites13.…”