Abstract
CYP3A ranks among the most abundant cytochrome P450 enzymes in the liver, playing a dominant role in metabolic elimination of clinically used drugs. A main member in CYP3A family, CYP3A4 expression and activity vary considerably among individuals, attributable to genetic and non-genetic factors, affecting drug dosage and efficacy. However, the extent of genetic influence has remained unclear. This review assesses current knowledge on the genetic factors influencing CYP3A4 activity. Coding region CYP3A4 polymorphisms are rare and account for only a small portion of inter-person variability in CYP3A metabolism. Except for the promoter allele CYP3A4*1B with ambiguous effect on expression, common CYP3A4 regulatory polymorphisms were thought to be lacking. Recent studies have identified a relatively common regulatory polymorphism, designated CYP3A4*22 with robust effects on hepatic CYP3A4 expression. Combining CYP3A4*22 with CYP3A5 alleles *1, *3 and *7 has promise as a biomarker predicting overall CYP3A activity. Also contributing to variable expression, the role of polymorphisms in transcription factors and microRNAs is discussed.
Highlights
Inter-individual variability in drug absorption, distribution, metabolism and elimination (ADME), arising from both genetic and non-genetic factors, is a main cause of therapeutic failure or undesirable adverse effects
As pharmacogenomic biomarkers begin to play a prominent role in personalized medicine, predictive tests for CYP3A activity, in particular that of CYP3A4 and CYP3A5 could have substantial clinical utility
Because the impact of polymorphisms in CYP3A5 and CYP3A7 on drug metabolism depends on the concomitant expression status of CYP3A4, variants in CYP3A4 or in genes regulating CYP3A4 expression must be considered in developing a genetic biomarker panel for predicting CYP3A activity
Summary
Inter-individual variability in drug absorption, distribution, metabolism and elimination (ADME), arising from both genetic and non-genetic factors, is a main cause of therapeutic failure or undesirable adverse effects. Because the impact of polymorphisms in CYP3A5 and CYP3A7 on drug metabolism depends on the concomitant expression status of CYP3A4, variants in CYP3A4 or in genes regulating CYP3A4 expression must be considered in developing a genetic biomarker panel for predicting CYP3A activity. Overlaid onto such a genetic allele panel must be an assessment of relative substrate selectivity for each dug and isozymes; in some instances, a drug could be predominantly metabolized by CYP3A5 or CYP3A7 so that CYP3A4 activity has less impact. Because of the eminent role of CYP3A4 in drug metabolism, we discuss in detail all proposed functional variants; even if they are rare, as new genotyping and sequencing methodologies enable rare variants with clear evidence for effect on expressed protein activity to be incorporated into predictive biomarker panels
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