The Contribution of Metronidazole and Two Metabolites to the Mutagenic Activity Detected in Urine of Treated Humans and Mice1

tract. Metronidazole has also been suggested as an antial cohol drug, and several reports have been presented on this possible use. In addition, this drug has recently been under investigation for use in treating anaerobic bacterial infec tions (11). The carcinogenic and mutagenic potential of this widely used drug has been the subject of several recent reports. After p.o. administration to mice, the compound was found to induce a variety of neoplasms, especially lung tumors (8). Voogd et a!. (12) reported the compound to be mutagenic when tested against 3 species of bacteria including histi dine auxotrophs of Salmonella typhimurium strains hisG46 and TA1530. In addition, McCann et al. (5) reported metro nidazole to be mutagenic with another strain of S. typhimu rium TA100. Aasenkmanz and Speck (7), using TA100 and a nitnomeductase minus mutant of TA100, have shown that reduction of metmonidazole by either the bacterial nitnone ductase or by matliver preparations under anaerobic condi tions is necessary fan the conversion of the compound to a mutagenic form (6). Legator et al. (4) showed that, after treatment with therapeutic doses of metronidazole, muta genic activity could be demonstrated in the urine of human subjects using S. typhimurium as the indicator organism. Recently, Speck et al. (9), using TA100, evaluated metabo bites separated by chromatography from urine of treated human subjects and found mutagenic activity at spots with AF values similar to those of the hydroxymethyl metabolite and the acetic acid metabolite, as well as an additional spot previously not reported. In the present study, the relative mutagenicity of metmoni dazole and 2 major metabolites known to occur in the urine was determined using S. typhimurium TA1535, TA1537, TA1538, TA100, and TA98, and the contribution of these compounds to the overall mutagenic activity found in the urine of treated human subjects and mice was investigated. In order to determine whether the liver is implicated in the conversion of metmonidazoleto the urinary metabolites, the influence of the hepatotoxic agent, carbon tetnachbonide, an the metabolism of the drug was studied.