Nitroreductive metabolic activation of some carcinogenic nitro heterocyclic food contaminants in rat mammary tissue cellular fractions

Several nitrofurans and nitroimidazoles have been widely used in veterinary medicine. Some of these compounds are breast carcinogens in rodents and their mechanism of action is hypothesized to be related to reactive metabolites generated by nitroreduction and/or via oxygen-dependent redox cycling. The present work describes the nitroreductive metabolism of nitrofurazone, nitrofurantoin, furazolidone, and metronidazole by the cytosolic and microsomal fractions of mammary tissue from female Sprague-Dawley rats. The data obtained were compared with those obtained with nifurtimox and benznidazole, two well-known rodent carcinogen/mutagens nitroheterocycles. The nitroreductase activity of pure milk xanthine-oxidoreductase (XOR) was evaluated for screening purposes. All the nitrofurans were nitroreduced either by the pure XOR or the cytosolic fraction in the presence of hypoxanthine, and these activities were inhibited by allopurinol. Furthermore, they were nitroreduced by the microsomal fraction in the presence of NADPH, except for the nitrofurazone, suggesting the participation of cytochrome P450 reductase. Nitrofurans metabolism was significantly more intense than that of NFX. No equivalent nitroreductase activity was observed in either subcellular fraction using nitroimidazolic compounds as substrates. These results suggest that the nitroreductive metabolism of nitrofurans and the subsequent redox cycling might be involved in the associated mammary tissue carcinogenic effects. (C) 2008 Elsevier Ltd. All rights reserved.