Why We Need to Take a Closer Look at Genetic Contributions to CYP3A Activity

Cytochrome P450 3A (CYP3A) subfamily enzymes are involved in the metabolism of 40% of drugs in clinical use. Twin studies have indicated that 66% of the variability in CYP3A4 activity is hereditary. Yet, the complexity of the CYP3A locus and the lack of distinct drug metabolizer phenotypes has limited the identification and clinical application of CYP3A genetic variants compared to other Cytochrome P450 enzymes. In recent years evidence has emerged indicating that a substantial part of the missing heritability is caused by low frequency genetic variation. In this review, we outline the current pharmacogenomics knowledge of CYP3A activity and discuss potential future directions to improve our genetic knowledge and ability to explain CYP3A variability.

Automated summary

CYP3A enzymes play a crucial role in the metabolism of drugs used in clinical practice. Genetic factors have been shown to contribute significantly to the variability in CYP3A4 activity. However, the complex nature of the CYP3A locus has hindered the identification and clinical application of genetic variants compared to other Cytochrome P450 enzymes. Recent evidence suggests that low frequency genetic variations account for a substantial portion of the missing heritability. This review provides an overview of the current pharmacogenomics knowledge of CYP3A activity and discusses potential future directions for improving our understanding of CYP3A variability.