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

Qinglian Zhai; Maaike van der Lee; Teun van Gelder; Jesse J Swen

doi:10.3389/fphar.2022.912618

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

Front Pharmacol. 2022 Jun 16:13:912618. doi: 10.3389/fphar.2022.912618. eCollection 2022.

Authors

Qinglian Zhai¹, Maaike van der Lee¹, Teun van Gelder¹, Jesse J Swen¹

Affiliation

¹ Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, Netherlands.

Abstract

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.

Keywords: CYP3A locus; CYP3A4; CYP3A5; enzyme activity; genetic variants; missing heritability; pharmacogenomics.

Publication types

Review