Received for publication May 15, 2006.
Revised October 17, 2006.
Accepted for publication October 18, 2006.

Genetic variation of human cytochrome P450 reductase as a potential biomarker for mitomycin C-induced cytotoxicity

Abstract

The importance of genetic variation on clinical response to various drugs is now well recognized. Identification of genetic biomarkers that can predict efficacy and toxicity of chemotherapeutic drugs in cancer patients holds a great promise in treatment improvement and cost reduction. Mitomycin C (MMC) is a common anticancer drug used for the treatment of numerous types of tumors. Metabolism-mediated activation, by either one-electron or two-electron reduction, plays a critical role in the chemotherapeutic action of MMC. Cytochrome P450 reductase (POR) is a major enzyme responsible for MMC activation through the one-electron reductive pathway, which leads to the production of semiquinone anion radicals and subsequent DNA damage in the cells. Recently, a total of 6 naturally occurring human POR variants with single amino acid changes (Y181D, A287P, R457H, V492E, C569Y, and V608F) have been identified. Although the catalytic efficiency of these variants in reduction of cytochrome c was reported to be altered, their capability in activating MMC, a direct substrate of POR, has not been examined. In the present study, we demonstrated that except for the C569Y variant, MMC-induced toxicity assayed as cell viability and proliferative capability was significantly decreased in the Flp-In CHO cells stably expressing all the other POR variants in comparison with the cells expressing wild-type human POR. Cells expressing the V608F and Y181D variants had a complete loss in the capability to activate MMC. Our finding suggests that these functional POR genetic variations may serve as a potential biomarker to predict the chemotherapeutic response to MMC.

Key words: genetic polymorphism, NADPH cytochrome P450 reductase, pharmacogenomics, toxicity