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

International Journal of Molecular Sciences

Daryl D. Meling¹  Susan Zelasko¹  William R. Arnold¹  Kimberly Sam¹  Aditi Das¹ 

[1] Department of Biochemistry, University of Illinois Urbana-Champaign, 3813 Veterinary Medicine Basic Sciences Building, 2001 South Lincoln Avenue, Urbana, IL 61802, USA;

关键词: CYP2C8;    polymorphisms;    reactive oxygen species;    paclitaxel;    cytochrome P450 reductase;    electron transfer;   

DOI  :  10.3390/ijms20184626

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown