Impairment of respiration and oxidative phosphorylation by redox cyclers 2-nitrosofluorene and menadione.
The present study was designed to investigate the effects of 2-nitrosofluorene (NOF), a metabolite of carcinogenic 2-acetylaminofluorene, on mitochondrial respiration and oxidative phosphorylation. NOF reacts with the NADH:ubiquinone oxidoreductase (complex I) and consumes oxygen in a rotenone-insensitive manner. Unlike menadione, which is able to bypass the rotenone-block and to restore ATP-formation, NOF-induced electron flow was almost completely uncoupled. In normal respiration both redox-cyclers decreased the respiratory control and P/O ratios at low concentrations (2-20 nmol/mg) in NADH-dependent oxidation. With succinate as substrate, only NOF was significantly active. In contrast to NOF, the hydroxamic acid N-hydroxy-2-acetylaminofluorene (N-OH-AAF) impaired mitochondrial energy conversion only at much higher concentrations (80 nmol/mg). At concentrations > 10 nmol/mg, NOF inhibited electron flow through the respiratory chain in NADH- and succinate-dependent oxidation, as determined by dinitrophenolate-uncoupled respiration. The small protective effect of L-cysteine indicates that covalent binding of the nitroso-compound to SH-groups may not explain sufficiently the inhibitory effect of NOF. The results support the notion that redox cyclers impair oxidative phosphorylation by establishing alternative pathways for electron transport in the respiratory chain.
Klöhn
P C
PC
Department of Toxicology, University of Würzburg, Germany.
Neumann
H G
HG
D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004396:Coloring Agents / Q000494:pharmacology; D006881:Hydroxyacetylaminofluorene / Q000633:toxicity; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009603:Nitroso Compounds / Q000633:toxicity*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000633:toxicity; D012680:Sensitivity and Specificity; D013386:Succinates / Q000378:metabolism / Q000494:pharmacology; D019802:Succinic Acid; D014812:Vitamin K / Q000633:toxicity*
D002273:Carcinogens; D004396:Coloring Agents; D009603:Nitroso Compounds; D013386:Succinates; D012402:Rotenone; D009243:NAD; D014812:Vitamin K; C012458:2-nitrosofluorene; D006881:Hydroxyacetylaminofluorene; D019802:Succinic Acid; D019297:2,4-Dinitrophenol