Relative importance of bacterial and mammalian nitroreductases for niridazole mutagenesis.
Niridazole is a nitrothiazole anthelmintic agent used to treat schistosomiasis. Its antibacterial activity was found to require the presence of the nitro group; a synthetic desnitro analog was completely inactive. Niridazole was mutagenic for Salmonella tester strains TA1538, TA98, and TA100, suggesting that it was both a frame-shift- and a base substitution-type mutagen. It was effective under both aerobic and anaerobic conditions, while similar testing of the desnitro niridazole produced consistently negative results. Addition of rat liver S-9 fraction under either aerobic or anaerobic conditions did not enhance mutagenicity. However, since bacterial killing limited the dose of niridazole to 0.33 microgram/plate in standard tester strains (1/20 Km for the mammalian liver enzymes), further studies were performed using niridazole-resistant, histidine-dependent mutants derived from strains TA98 and TA100. These mutants were found to be nitroreductase deficient and to resist the mutagenic effects of niridazole, in the presence or absence of S-9, up to concentrations of 10 microgram/plate. In addition, even at niridazole concentrations of up to 100 microgram/plate, rat liver S-9 was ineffective in enhancing the mutagenicity of niridazole. These results suggest that the mutagenicity of niridazole is dependent on its aromatic nitro group and a specific bacterial nitroreductase.
D000332:Aerobiosis; D000900:Anti-Bacterial Agents; D001711:Biotransformation; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens; D009560:Niridazole / Q000378:metabolism; D009574:Nitro Compounds / Q000378:metabolism; D009601:Nitroreductases; D010088:Oxidoreductases / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D009153:Mutagens; D009574:Nitro Compounds; D010088:Oxidoreductases; D009601:Nitroreductases; D009560:Niridazole