Regulation of metabolism by mutations and polymorphisms in NADPH cytochrome P450 reductase

Seminar by:

Prof. Amit Pandey
Pediatric Endocrinology Unit, Department of Pediatrics, University
Children’s Hospital Bern and Department of Clinical Research, University of
Bern, Switzerland

Cytochrome P450 oxidoreductase (POR) is required for the metabolic reactions catalyzed by cytochrome P450s in the endoplasmic reticulum. It also participates in metabolism of several other molecules like mitomycin C, doxorubicin, ferricyanide, menadione, dichlorophenolindophenol and nitro blue tetrazolium etc, either directly or as an electron donor to the actual catalyst. We had previously described mutations in POR from patients with disruption in sex steroid metabolism and established that alterations in POR lead to reduced activities of steroid metabolizing enzymes CYP17A1 (Flück et al. Nature Genetics 36:228 2004) and CYP19A1 (Pandey et al. Mol. Endocrinol. 21:2579 2007) and more recently, also of heme oxygenase and CYP3A4 (Pandey & Flück, Pharmacology & Therapeutics 138:229 2013). In the patients classified as “European” or “Caucasian” most common POR mutation is A287P. We have observed variable effects of A287P variant on activities of different redox partners of POR. The CYP3A4 and 17OH-hydroxylase and 17,20 lyase activities of CYP17A1 are reduced but CYP19A1, CYP21A2 remain unaffected. In this study we have performed detailed enzymatic and biochemical characterization of the A287P variant of POR to study its effects on different substrates. Similarly differential effects of common polymorphic variant of POR A503V have been evaluated with different drug metabolizing P450s to understand the implications of POR variants on drug metabolism. Variations in POR may lead to different activities of its redox partners that need to be evaluated individually.

Arranged by Nikos Hatzakis and Tomas Laursen 

http://www.pandeylab.org/