CARCINOGEN METABOLISM BY HOST INTESTINAL BACTERIA

肠道宿主细菌对致癌物的代谢

• 批准号: 3172744
• 负责人: PETER GOLDMAN
• 金额: $ 18万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-12-01 至 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3172744
• 关键词: acetamides; anaerobic bacteria; antibacterial agents; antiprotozoal agents; chemical carcinogen; chemical structure function; cocarcinogen; drug carcinogenesis; drug metabolism; drug related neoplasm /cancer; enteric bacteria; germ free condition; heterocyclic compounds; imidazole; infection related neoplasm /cancer; methylhydrazines; metronidazole; mutagen testing; mutagens; nitro compounds; nitrosamines; reduction; tissue /cell culture; toxin metabolism

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.

建议继续目前对还原性的调查， 代谢等硝基杂环药物甲硝唑在 厌氧植物群，以表征活性中间体， 可能是它们致癌的原因 动物和细菌 实验提出。 因此，将确定结肠是否 二甲肼的致癌性被甲硝唑增强， 无菌大鼠，就像其他人在传统大鼠中发现的那样。 它将 还要确定二甲基肼的致癌性是否增强 由人用的其他硝基杂环化合物如米索硝唑和 呋喃西林，这些药物不同于甲硝唑，因为它们是 减少到杂环断裂的点，不仅在 植物群，但在无菌大鼠的组织中。 其他研究将寻求 硝基咪唑类药物代谢与其代谢产物的相关性 杀菌和致突变活性。 因此，计划确定 以前的观察结果，甲硝唑的减少， 不同的厌氧菌和各种化学系统的结果， 形成数量上不同的代谢物。 企图 将使这些代谢差异与不同的 这些系统对艾姆斯组氨酸营养缺陷型的致突变性 确定减少的关键产品，从中可以推断出 诱变中间体的化学结构。 为了推断出 硝基咪唑的反应形式的关键特征， 将进一步比较米索硝唑（2-硝基咪唑） 和甲硝唑（5-硝基咪唑）。 米索硝唑，尽管更多 在细菌培养物中迅速减少，杀菌作用要小得多， 比甲硝唑更有致突变性 因此，计划延长以前的 表征米索硝唑还原代谢的研究， 其还原代谢物的积累可能与 甲硝唑的杀菌活性 已被证明与乙酰胺的积累有关。 同样地， 将寻找米索硝唑的还原代谢物，其积累 与米索硝唑的致突变性有关 这样的比较， 甲硝唑和米索硝唑应该有助于推断相似性 以及两者反应物种结构的差异 硝基咪唑。