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Antimutagenic Effects of 2(3)-tert-Butyl-4-hydroxyanisole and of Antimicrobial Agents¹

Departments of Pathobiology [R. P. B., S-Y. L. O., E. B.] and Pharmacology and Experimental Therapeutics [E. B.], Johns Hopkins Medical Institutions, Baltimore, Maryland 21205

Administration of the antioxidants 2(3)-tert-butyl-4-hydroxyanisole (BHA) and ethoxyquin (1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline) with the diet resulted in a marked decrease in the levels of mutagens present in mice treated with benzo(a)pyrene. This was reflected in the results of the host-mediated assay and determinations of the mutagenic activities of the urine, with the use of the sensitive tester strains TA100 and TA98 of Salmonella typhimurium his^– developed by Ames and coworkers. Treatment with BHA was effective also in reducing the mutagenic activities in vivo of hycanthone, three other antischistosomal compounds, metronidazole, diazepam, and mebendazole. These effects were accompanied by increases in the thiol levels of some tissues. The production of mutagenic metabolites of two other antischistosomal drugs, 4-isothiocyano-4'-nitrodiphenylamine and oxamniquine, was not reduced by BHA treatment. However, such reductions in mutagenicity could be achieved by the administration of enteric antibacterial agents, implicating the role of intestinal microorganisms in the mutagenic activation of certain chemical agents. Combined treatment of mice with BHA and enteric antimicrobial agents reduced the levels of mutagens derived from metronidazole by more than 90%, and the combined treatments were more effective than was either treatment alone.

¹ Supported by grants and contracts from NIH (GM-16492 and CA-18251) and the Agency of International Development. A preliminary report has been presented at the 62nd Annual Meeting of the American Society of Pharmacology and Experimental Therapeutics, April 9 to 14, 1978, Atlantic City, N. J. (5).

² To whom requests for reprints should be addressed.

Received 4/26/78. Accepted 8/24/78.