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Relative Importance of Bacterial and Mammalian Nitroreductases for Niridazole Mutagenesis

Divisions of Pediatric Pharmacology and Infectious Disease, Department of Pediatrics, Rainbow Babies and Children's Hospital [J. L. B., A. F., L. W. M., W. T. S.], and the Genetics Center [J. L. B.] and Department of Pharmacology [J. L. B., E. F., L. T. W.], Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

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 µg/plate in standard tester strains (1/20 K_m 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 µg/plate. In addition, even at niridazole concentrations of up to 100 µg/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.

¹ Present address: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pa. 19104.

² Recipient of grants from WHO and the Rockefeller Foundation.

³ Recipient of Grant 5R01-CA23692 and Research Career Development Award 1KO-4-CA-00443 from the National Cancer Institute.

Received 3/ 2/80. Accepted 8/22/80.