Quinone and nitrofurantoin redox cycling by recombinant cytochrome b5 reductase

Toxicology and Applied Pharmacology
John T SzilagyiJeffrey D Laskin

Abstract

NADH cytochrome b5 reductase mediates electron transfer from NADH to cytochrome b5 utilizing flavin adenine dinucleotide as a redox cofactor. Reduced cytochrome b5 is an important cofactor in many metabolic reactions including cytochrome P450-mediated xenobiotic metabolism, steroid biosynthesis and fatty acid metabolism, hemoglobin reduction, and methionine and plasmalogen synthesis. Using recombinant human enzyme, we discovered that cytochrome b5 reductase mediates redox cycling of a variety of quinones generating superoxide anion, hydrogen peroxide, and, in the presence of transition metals, hydroxyl radicals. Redox cycling activity was oxygen-dependent and preferentially utilized NADH as a co-substrate; NADH was 5-10 times more active than NADPH in supporting redox cycling. Redox cycling activity was greatest for 9,10-phenanthrenequinone and 1,2-naphthoquinone, followed by 1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone (menadione), nitrofurantoin and 2-hydroxyestradiol. Using menadione as the substrate, quinone redox cycling was found to inhibit reduction of cytochrome b5 by cytochrome b5 reductase, as measured by heme spectral changes in cytochrome b5. Under anaerobic conditions where redox cycling is inhibited, menadio...Continue Reading

Citations

May 16, 2020·Oxidative Medicine and Cellular Longevity·Rumiana BakalovaTatsuya Higashi
Dec 12, 2019·Biochimica Et Biophysica Acta. Bioenergetics·Gabriel N ValérioAlejandro K Samhan-Arias
May 23, 2021·Cell Biology and Toxicology·Lukas S WijayaStefan Schildknecht

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