P450 oxidoreductase: genetic polymorphisms and implications for drug metabolism and toxicity

Abstract

Background: Cytochrome P450 oxidoreductase (POR) is the only electron donor for all microsomal cytochrome P450 monooxygenases (CYP), some of which are phase I drug-metabolizing enzymes, responsible for oxidation of more than 80% of drugs. Objectives: To provide a more thorough understanding of the genetic factors influencing drug metabolism, we address the role of genetic polymorphisms in the POR gene, and their implications for drug metabolism and cytotoxicity. Methods: The scope of this review is intended to cover polymorphisms currently identified in the POR gene, assess their functional significance on POR activity, and address their impact on CYP-mediated drug metabolism. POR is also responsible for directly metabolizing several anticancer prodrugs via a 1-electron reduction reaction, so the effect of POR polymorphisms on the direct bioactivation of drugs is also considered. Results/conclusion: POR is a polymorphic enzyme that can affect CYP-mediated drug metabolism as well as direct bioactivation of prodrugs. Genetic polymorphisms in the POR gene may help to explain altered drug-metabolizing phenotypes.

Keywords::

• cytochrome P450 oxidoreductase
• drug metabolism
• genetic polymorphism
• pharmacogenetics
• POR
• toxicity

Acknowledgements

The authors thank CD Klaassen, TL Pazdernik, GA Reed and MA Montello for their critical reading of this manuscript.

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