Work

Polymorphisms of CYP2C8 Alter First-Electron Transfer Kinetics and Increase Catalytic Uncoupling

Year: 2019

Type: article

Abstract: Cytochrome P450 2C8 (CYP2C8) epoxygenase is responsible for the metabolism of over 60 clinically relevant drugs, notably the anticancer drug Taxol (paclitaxel, PAC). Specifically, there are naturally occurring polymorphisms, CYP2C8*2 and CYP2C8*3, that display altered PAC hydroxylation rates despite these mutations not being located in the active site. Herein, we demonstrate that these polymorphisms result in a greater uncoupling of PAC metabolism by increasing the amount of hydrogen peroxide formed per PAC turnover. Anaerobic stopped-flow measurements determined that these polymorphisms have altered first electron transfer kinetics, compared to CYP2C8*1 (wildtype), that suggest electron transfer from cytochrome P450 reductase (CPR) is disfavored. Therefore, these data demonstrate that these polymorphisms affect the catalytic cycle of CYP2C8 and suggest that redox interactions with CPR are disrupted.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms20184626

Authors: William R. Arnold, Susan Zelasko, Daryl D. Meling, Kimberly Sam, Aditi Das

Institution: University of Illinois Urbana-Champaign

Language: English

Topic: Pharmacogenetics and Drug Metabolism

Subfield: Pharmacology

Field: Pharmacology, Toxicology and Pharmaceutics

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $1,824

Funders: American Heart Association, National Institutes of Health, University of Illinois at Urbana-Champaign, National Institute of General Medical Sciences