The Toxicity of Aromatic Nitrocompounds to Bovine Leukemia Virus-Transformed Fibroblasts: The Role of Single-Electron Reduction

Biochim Biophys Acta. 1995 Aug 31;1268(2):159-64. doi: 10.1016/0167-4889(95)00064-y.

Abstract

Bovine leukemia virus-transformed lamb embryo fibroblasts (line FLK) possess activity of DT-diaphorase of ca. 260 U/mg protein and similar levels of other NADP(H)-oxidizing enzymes: NADH:oxidase, 359 U/mg; NADPH:oxidase, 43 U/mg; NADH:cytochrome-c reductase, 141 U/mg; NADPH:cytochrome-c reductase, 43 U/mg. In general, the toxicity of aromatic nitrocompounds towards FLK cells increases on increase of single-electron reduction potentials (E1(1)) of nitrocompounds or the log of their reduction rate constants by single-electron-transferring enzymes, microsomal NADPH:cytochrome P-450 reductase (EC 1.6.2.4) and mitochondrial NADH:ubiquinone reductase (EC 1.6.99.3). No correlation between the toxicity and reduction rate of nitrocompounds by rat liver DT-diaphorase (EC 1.6.99.2) was observed. The toxicity is not significantly affected by dicumarol, an inhibitor of DT-diaphorase. Nitrocompounds examined were poor substrates for DT-diaphorase, being 10(4) times less active than menadione. Their poor reactivity is most probably determined by their preferential binding to a NADPH binding site, but not to menadione binding site of diaphorase. These data indicate that at comparable activities of DT-diaphorase and single-electron-transferring NAD(P)H dehydrogenases in the cell, the toxicity of nitrocompounds will be determined mainly by their single-electron reduction reactions.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Transformed / drug effects
  • Cell Survival / drug effects
  • Leukemia Virus, Bovine
  • NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors*
  • NADPH Dehydrogenase / antagonists & inhibitors*
  • Nitro Compounds / pharmacology*
  • Oxidation-Reduction
  • Quinones / pharmacology
  • Sheep
  • Vitamin K / antagonists & inhibitors

Substances

  • Nitro Compounds
  • Quinones
  • Vitamin K
  • NAD(P)H Dehydrogenase (Quinone)
  • NADPH Dehydrogenase