Drug residue formation from ronidazole, a 5-nitroimidazole. I. Characterization of in vitro protein alkylation

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Abstract

The metabolic activation of [14C]ronidazole by rat liver enzymes to metabolite(s) bound to macromolecules was investigated. The alkylation of protein by [14C]ronidazole metabolite(s) was catalyzed most efficiently by rat liver microsomes, in the absence of oxygen utilizing NADPH as a source of reducing equivalents. Based on a comparison of total ronidazole metabolized versus the amount bound to microsomal protein, approximately one molecule alkylates microsomal protein for every 20 molecules of ronidazole metabolized. Protein alkylation was strongly inhibited by sulfhydryl-containing compounds such as cysteine and glutathione whereas methionine had no effect. Based on HPLC analysis of ronidazole, cysteine was found not to inhibit microsomal metabolism of ronidazole ruling out a decrease in the rate of production of the reactive metabolite(s) as the mechanism of cysteine inhibition.

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Cited by (30)

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    It is still not fully understood whether the nitroradical anion state or a further reduced state, e.g. the nitrosoimidazole state, is the actual agent (Moreno and Docampo, 1985). There is certain evidence that the latter could be the case (West et al., 1982; Wislocki et al., 1984). In G. lamblia, several factors have been suggested to reduce 5-nitroimidazoles, including ferredoxin, which in turn receives electrons from pyruvate:ferredoxin oxidoreductase (Townson et al., 1996), nitroreductase 1 (Nillius et al., 2011), and thioredoxin reductase (Leitsch et al., 2011).

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    Metronidazole is a prodrug that requires reduction of the nitro group to generate the cytotoxic nitroradical anion that undergoes further reduction resulting in the generation of nitrosoimidazole (12, 13). This active form can then react with sulfhydryl groups (14) and DNA (15) while being further reduced to an amine via a hydroxylamine intermediate. Here, we report for the first time multiple novel roles of two GOGAT β subunit-like proteins in E. histolytica.

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