Abstract
Human CYP3A enzymes (including CYP3A4 and CYP4A5) metabolize about 40% of all drugs and numerous other environmental and endogenous substances. CYP3A activity is highly variable within and between humans. As a consequence, therapy with standard doses often results in too low or too high blood and tissue concentrations resulting in therapeutic failure or dose-related adverse reactions. It is an unanswered question how much of the big interindividual variation in CYP3A activity is caused by genetic or by environmental factors. This question can be answered by the twin study approach. Using midazolam as CYP3A probe drug, we studied 43 monozygotic and 14 dizygotic twins and measured midazolam and its metabolite 1-OH-midazolam. In addition, endogenous biomarkers of CYP3A activity, 4ß-OH-cholesterol and 6ß-OH-cortisol, were analyzed. Additive genetic effects accounted for only 15% of the variation in midazolam AUC, whereas 48% was attributed to common environmental factors. In contrast, 73, 56, and 31% of 1-OH-midazolam, 4ß-OH-cholesterol and 6ß-OH-cortisol variation was due to genetic effects. There was a low phenotypic correlation between the four CYP3A biomarkers. Only between midazolam and its 1-OH-metabolite, and between midazolam and 6ß-OH-cortisol we found significant bivariate genetic correlations. Midazolam AUC differed depending on the CYP3A4∗22 variant (p = 0.001) whereas plasma 4ß-OH-cholesterol was significantly lower in homozygous carriers of CYP3A5∗3 (p = 0.02). Apparently, non-genomic factors played a dominant role in the inter-individual variation of the CYP3A probe drug midazolam. A small intra-individual pharmacokinetic variation after repeated administration of midazolam was rated earlier as indication of high heritability of CYP3A activity, but according to present data that could also largely be due to constant environmental factors and/or heritability of liver blood flow. The higher heritabilities of 4ß-OH-cholesterol and of 1-OH-midazolam may deserve further research on the underlying factors beyond CYP3A genes.Clinical Trial Registration: ClinicalTrials.gov: NCT01845194 and EUDRA-CT: 2008-006223-31.
Highlights
The cytochrome P450 (CYP) enzymes 3A4 and 3A5 play a key role in the biotransformation of about 40% of currently used drugs (Evans and Relling, 1999)
In a population not exposed to known inducers or inhibitors, heritability of CYP3A activity was found to be relatively small, when using midazolam as biomarker
The estimates of CYP3A heritability varied depending on the biomarker used, which could partially be explained by the specific features of each probe substance, but it clearly indicates that the one and only correct in vivo biomarker of CYP3A activity does not exist
Summary
The cytochrome P450 (CYP) enzymes 3A4 and 3A5 play a key role in the biotransformation of about 40% of currently used drugs (Evans and Relling, 1999). CYP3A enzymes catalyze the biotransformation of numerous exogenous and endogenous substances, notably cholesterol, bile acids, and many steroid hormones (Patki et al, 2003; Bodin et al, 2005; Klein and Zanger, 2013). The homologous isozyme CYP3A5 has partially overlapping substrate specificity with CYP3A4 but may significantly contribute to CYP3A metabolic activity with some drugs like tacrolimus. About 10–15% of persons with European ancestry express CYP3A5 and that can be analyzed by genotyping. Only a small fraction of the variation in CYP3A4 expression and activity can far be explained by defined genotypes
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