RELATIVE IMPORTANCE OF BACTERIAL AND MAMMALIAN NITROREDUCTASES FOR NIRIDAZOLE MUTAGENESIS

Abstract

Niridazole is a nitrothiazole anthelminithic agent used to treat schistosomiasis [in humans]. Its antibacterial activity requires the presence of the nitro group; a synthetic desnitro analog was completely inactive. Niridazole was mutagenic for Salmonella typhimurium tester strains TA 1538, TA 98, and TA 100, suggesting that it was bofh a frameshift 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. Since bacterial killing limited the dose of niridazole to 0.33 .mu.g/plate in standard tester strains (1/2O Km for the mammalian liver enzymes), further studies were performed using niridazole-resistant, histidine-dependent mutants derived from strains TA 98 and TA iOO. These mutants were nitroreductase deficient and resisted the mutagenic effects of niridazole, in the presence or absence of S-9, up to concentrations of 10 .mu.g/plate. Even at niridazole concentrations of up to 100 .mu.g/plate, rat liver S-9 was ineffective in enhancing the mutagenicity of niridazole. The mutagenicity of niridazole is dependent on its aromatic nitro group and a specific bacterial nitroreductase. [Niridazole is also thought to be a carcinogen].