A metabolite of carcinogenic 2-acetylaminofluorene, 2-nitrosofluorene, induces redox cycling in mitochondria.
The present study was designed to confirm the recent proposal that 2-nitrosofluorene (2-NOF) as well as N-hydroxy-2-aminofluorene (N-OH-AF) induce a redox-cycle in rat liver mitochondria as part of the chronic toxic effects of the carcinogen 2-acetylaminofluorene (2-AAF). The formation of O2.- was demonstrated in submitochondrial particles by the formation of adrenochrome with NADH and succinate as respiratory substrates. 2-NOF was as effective as paraquat, a known redox-cycler, the lowest effective concentration being 0.4 nmol 2-NOF/mg protein. Experiments with isolated mitochondria showed that 2-NOF, in contrast to N-OH-AF, induces cyanide-resistant O2 consumption only in the presence of respiratory substrates, indicating that the reduction, but not the reoxidation, depends on a continuous flow of electrons through the respiratory chain of the mitochondrial membrane. Lipid peroxidation was estimated by the formation of thiobarbituric-acid-reactive substances. In comparison to the well-known prooxidant tert-butylhydroperoxide, 2-NOF was not significantly active. The results support the notion that 2-NOF induces oxidative stress by mitochondrial redox-cycling in vivo. Effects other than lipid peroxidation seem to be important for the chronic toxicity of 2-AAF.
Klöhn
P C
PC
Institute of Pharmacology and Toxicology, University of Würzburg, Germany.
Massalha
H
H
Neumann
H G
HG
D015073:2-Acetylaminofluorene / Q000378:metabolism* / Q000633:toxicity; D000418:Albumins / Q000494:pharmacology; D000818:Animals; D005449:Fluorenes / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D009603:Nitroso Compounds / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D051381:Rats; D017208:Rats, Wistar; D015219:Substrate Cycling / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
D000418:Albumins; D005449:Fluorenes; D009603:Nitroso Compounds; D013481:Superoxides; C012458:2-nitrosofluorene; C001368:N-hydroxy-2-aminofluorene; D015073:2-Acetylaminofluorene