Pharmacogenomics of CYP2C9: Functional and Clinical Considerations

Abstract

CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare 'variants of uncertain significance', which are increasingly detected as more exome and genome sequencing of diverse populations is conducted.

Keywords: CYP2C9; cytochrome P450; pharmacogenomics; polymorphism; warfarin.

Figure 1

CYP2C9 structure showing substrate recognition sites (SRS) according to Gotoh [28]. The SRS are denoted by arrows: SRS1 (red), SRS2 (green), SRS3 (blue), SRS4 (yellow), SRS5 (orange) and SRS6 (magenta). The secondary structure elements of the rest of the protein are shown in white. The haem molecule is shown in ball and sticks with C, O, N, and Fe atoms in cyan, red, blue, and orange, respectively (from [29]). Reproduced with permission from Nair, P.C.; McKinnon, R.A.; Miners, J.O. Cytochrome P450 structure–function: insights from molecular dynamics simulations. Drug Metab. Rev. 2016, 48, 434–452; published by Taylor and Francis, 2016.