# CARCINOGEN METABOLISM BY HOST INTESTINAL BACTERIA

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 1989 · $187,096

## Abstract

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.

## Key facts

- **NIH application ID:** 3172746
- **Project number:** 5R01CA034957-07
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **SAM.gov UEI:** JDLVAVGYJQ21
- **Principal Investigator:** PETER GOLDMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $187,096
- **Award type:** 5
- **Project period:** 1982-12-01 → 1989-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172746

## Citation

> US National Institutes of Health, RePORTER application 3172746, CARCINOGEN METABOLISM BY HOST INTESTINAL BACTERIA (5R01CA034957-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172746. Licensed CC0.

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