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The contribution of metronidazole and two metabolites to the mutagenic activity detected in urine of treated humans and mice.
Cancer Res 1977; 37(2):629-33CR

Abstract

The urine of two patients receiving therapeutic doses of the trichomonacide, metronidazole, was analyzed for mutagenic activity using the histidine auxotroph TA1535 of Salmonella typhimurium. The activity detected in the urine was significantly higher than could be accounted for by the presence of the administered drug. Chromatographic analysis of the urine indicated the presence of the metabolite 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole, which when tested in vitro with TA1535 was found to be ten times more active than metronidazole. An additional urinary metabolite, 1-acetic acid-2-methyl-5-nitroimadazole, was found to be inactive when similarly tested. The in vitro mutagenic activity of metronidazole and the two metabolites was unchanged by the addition of phenobarbital- or Aroclor-induced rat liver homogenate to the test system. In addition, metronidazole and the hydroxymethyl metabolite reverted S. typhimurium TA100 but not TA1537, TA1538, or TA98, and the acetic acid metabolite failed to revert any of the tester strains. In studies with mice, metronidazole was required in excess of the human dose in order for significant amounts of the hydroxymethyl metabolite to be detected in the urine. Urine from mice pretreated with the hepatotoxin, carbon tetrachloride, prior to the administration of metronidazole demonstrated approximately a 50% reduction in mutagenic activity, and the formation of the urinary metabolites was inhibited. These findings indicate the production of metabolites from the parent compound by the liver of the intact animal which could not be determined by use of the standard in vitro liver homogenate system.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

318924

Citation

Connor, T H., et al. "The Contribution of Metronidazole and Two Metabolites to the Mutagenic Activity Detected in Urine of Treated Humans and Mice." Cancer Research, vol. 37, no. 2, 1977, pp. 629-33.
Connor TH, Stoeckel M, Evrard J, et al. The contribution of metronidazole and two metabolites to the mutagenic activity detected in urine of treated humans and mice. Cancer Res. 1977;37(2):629-33.
Connor, T. H., Stoeckel, M., Evrard, J., & Legator, M. S. (1977). The contribution of metronidazole and two metabolites to the mutagenic activity detected in urine of treated humans and mice. Cancer Research, 37(2), pp. 629-33.
Connor TH, et al. The Contribution of Metronidazole and Two Metabolites to the Mutagenic Activity Detected in Urine of Treated Humans and Mice. Cancer Res. 1977;37(2):629-33. PubMed PMID: 318924.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The contribution of metronidazole and two metabolites to the mutagenic activity detected in urine of treated humans and mice. AU - Connor,T H, AU - Stoeckel,M, AU - Evrard,J, AU - Legator,M S, PY - 1977/2/1/pubmed PY - 1977/2/1/medline PY - 1977/2/1/entrez SP - 629 EP - 33 JF - Cancer research JO - Cancer Res. VL - 37 IS - 2 N2 - The urine of two patients receiving therapeutic doses of the trichomonacide, metronidazole, was analyzed for mutagenic activity using the histidine auxotroph TA1535 of Salmonella typhimurium. The activity detected in the urine was significantly higher than could be accounted for by the presence of the administered drug. Chromatographic analysis of the urine indicated the presence of the metabolite 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole, which when tested in vitro with TA1535 was found to be ten times more active than metronidazole. An additional urinary metabolite, 1-acetic acid-2-methyl-5-nitroimadazole, was found to be inactive when similarly tested. The in vitro mutagenic activity of metronidazole and the two metabolites was unchanged by the addition of phenobarbital- or Aroclor-induced rat liver homogenate to the test system. In addition, metronidazole and the hydroxymethyl metabolite reverted S. typhimurium TA100 but not TA1537, TA1538, or TA98, and the acetic acid metabolite failed to revert any of the tester strains. In studies with mice, metronidazole was required in excess of the human dose in order for significant amounts of the hydroxymethyl metabolite to be detected in the urine. Urine from mice pretreated with the hepatotoxin, carbon tetrachloride, prior to the administration of metronidazole demonstrated approximately a 50% reduction in mutagenic activity, and the formation of the urinary metabolites was inhibited. These findings indicate the production of metabolites from the parent compound by the liver of the intact animal which could not be determined by use of the standard in vitro liver homogenate system. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/318924/The_contribution_of_metronidazole_and_two_metabolites_to_the_mutagenic_activity_detected_in_urine_of_treated_humans_and_mice L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=318924 DB - PRIME DP - Unbound Medicine ER -