Clinical Information

The cytochrome P450 (CYP) 3A4 enzyme is responsible for the metabolism of approximately 50% of drugs that undergo hepatic metabolism and first-pass metabolism in intestinal epithelial cells, including lipid-lowering drugs. The CYP3A4 enzyme activity is highly variable. Interindividual differences in enzyme expression may be due to several factors including: variable homeostatic control mechanisms, disease states that alter homeostasis, up- or down-regulation by environmental stimuli, and genetic variation.(1) A CYP3A4 intron 6 variant, CYP3A4*22 (c.522-191C->T), affects hepatic expression of CYP3A4 and response to statin drugs. The CYP3A4*22 allele is associated with reduced CYP3A4 activity, which may result in a better response to lipid-lowering drugs, such as simvastatin, atorvastatin, or lovastatin. However, reduced CYP3A4 activity may also be associated with statin-induced myopathy, especially for simvastatin. Studies show that in livers with the wild-type genotype (homozygous C or CC) the CYP3A4 mRNA level and enzyme activity were 1.7- and 2.5-fold greater than in heterozygous CYP3A4*22 (CT) and homozygous CYP3A4*22 (TT) carriers, respectively. In 235 patients taking stable doses of drugs for lipid control, carriers of the T allele required significantly lower statin doses for optimal lipid control than did non-T carriers.(2) These results indicate that CYP3A4*22 markedly affects expression of CYP3A4 and could serve as a biomarker for CYP3A4 metabolizer phenotype. The reported allele frequency of CYP3A4*22 in Caucasians was 5% to 8%. The allele frequency is 4.3% in African Americans and in Chinese.