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


OBJECTIVE
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.


CONCLUSIONS
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.
Hart
Steven N
SN
University of Kansas Medical Center, Department of Pharmacology, Toxicology, and Therapeutics, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA.
Zhong
Xiao-Bo
XB
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics* / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics
D004364:Pharmaceutical Preparations; D011355:Prodrugs; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase