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Altered Drug and Steroid Metabolism by Mutations in Human NADPH Cytochrome P450 Reductase
Author(s) -
Pandey Amit,
Flück Christa
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb522
Subject(s) - cyp17a1 , drug metabolism , cytochrome p450 , cyp3a4 , menadione , reductase , biochemistry , chemistry , heme , aromatase , cytochrome b5 , enzyme , biology , genetics , cancer , breast cancer
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, ferricyanide, menadione, dichlorophenolindophenol etc either directly or as an electron donor to the actual catalyst. We had 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), 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. We have performed detailed enzymatic and biochemical characterization of the A287P variant of POR to study its effects on different substrates. We used purified preparations of wild type and A287P variant of human POR and performed testing with small molecule and protein substrates of POR under changing substrate, co‐factor and buffer conditions. Here we show that small molecule and protein substrates are affected in different ways by the A287P mutation. Similarly differential effects of common polymorphic variant of POR A503V have been evaluated with different drug metabolising P450s to understand the implications of POR variants on drug metabolism. In conclusion, variations in POR may lead to different activities of its redox partners that need to be evaluated individually.