It is proposed to continue current investigations of the reductive metabolism of such nitroheterocyclic drugs as metronidazole in the anaerobic flora in order to characterize the reactive intermediates that may be responsible for their carcinogenesis. Both animal and bacterial experiments are proposed. Thus, it will be determined whether the colon carcinogenicity of dimethylhydrazine is enhanced by metronidazole in germfree rats as others have found it to be in conventional rats. It will also be determined whether dimethylhydrazine's carcinogenicity is enhanced by such other nitroheterocyclic compounds in human use as misonidazole and nitrofurazone, these drugs differing from metronidazole in that they are reduced to the point of heterocyclic ring fragmentation not only in the flora but in the tissues of the germfree rat. Other studies will seek correlations between the metabolism of nitroimidazoles and their bactericidal and mutgenic activity. Thus, it is planned to determine the significance of previous observations that metronidazole's reduction by different anaerobes and by various chemical systems results in the formation of metabolites that are quantitatively different. At attempt will be made to relate these metabolic differences to differences in the mutagenicity of these systems for the Ames histidine auxotroph as a means of identifying key products of reduction from which one might infer the chemical structure of the mutagenic intermediate. In order to infer the critical characteristics of the reactive form of the nitroimidazoles, further comparisons will be made between misonidazole (a 2-nitroimidazole) and metronidazole (a 5-nitroimidazole). Misonidazole, although more rapidly reduced in bacterial cultures, is far less bactericidal but more mutagenic than metronidazole. Thus, it is planned to extend previous studies characterizing the reductive metabolism of misonidazole to seek one of its reduced metabolites whose accumulation may correlate with bactericidal activity in the way that metronidazole's bactericidal activity has been shown to correlate with the accumulation of acetamide. Similarly, reductive metabolites of misonidazole will be sought whose accumulation correlates with misonidazole's mutagenicity. Such comparisons between metronidazole and misonidazole should be helpful in inferring similarities and differnces in the structures of the reactive species of the two nitroimidazoles.
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