Protein and Gene Structure and Regulation of NADPH-Cytochrome P450 Oxidoreductase

Abstract

The enzyme NADPH-cytochrome P450 oxidoreductase (NADPH: ferrihemoprotein oxidoreductase, E.C. 1.6.2.4, hereafter referred to as reductase) is a component of the microsomal mixed function oxidase system, functioning in the endoplasmic reticulum (Williams and Kamin 1962; Phillips and Langdon 1962) and nuclear membrane (Kasper 1971) to catalyze electron transfer from NADPH to cytochrome P450 (Lu and Coon 1968). This 78-kDa flavin mononucleotide (FMN)- and flavin adenine dinucleotide (FAD)-containing (Iyanagi and Mason 1973) flavoprotein can also reduce other microsomal proteins, such as cytochrome b ₅ (Enoch and Strittmatter 1979), heme oxygenase (Schacter et al. 1972), and fatty acid elongase (Ilan et al. 1981), as well as nonphysiologic electron acceptors such as cytochrome c, ferricyanide, menadione, and dichlorophenolindophenol (Williams and Kamin 1962). Reductase-catalyzed redox cycling of antitumor anthracycline compounds is a factor in the antitumor activity and toxicity of these compounds (Bachur et al. 1978, 1979), while electron transfer to mitomycin C produces the active form of this antitumor compound (Keyes et al. 1984). in conjunction with EDTA-Fe²⁺, cytochrome P450 or O₂ ⁻, the reductase can initiate microsomal lipid peroxidation (Pederson et al. 1973; reviewed by Sevanian et al. 1990).