CARCINOGEN METABOLISM BY HOST INTESTINAL BACTERIA

肠道宿主细菌对致癌物的代谢

基本信息

批准号：
3172746
负责人：
PETER GOLDMAN
金额：
$ 18.71万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
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

项目摘要

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.

建议继续目前的还原研究甲硝唑等硝基杂环类药物的代谢厌氧菌群，以表征反应中间体可能是其致癌的原因。动物和细菌都有提出了实验。因此，将确定结肠是否甲硝唑可增强二甲肼的致癌性无菌大鼠与其他人在传统大鼠中发现的情况一样。它将还需确定二甲肼的致癌性是否增强人类使用的其他硝基杂环化合物，如米索硝唑和呋喃西林，这些药物与甲硝唑不同，不仅在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及其相关性杀菌和诱变活性。因此，计划确定先前观察到甲硝唑减少的意义不同的厌氧菌和不同的化学系统导致形成数量上不同的代谢物。尝试时将把这些代谢差异与这些系统对艾姆斯组氨酸营养缺陷型的致突变性是一种手段确定关键的减排产品，从中可以推断出诱变中间体的化学结构。为了推断硝基咪唑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）。米索硝唑虽然多在细菌培养物中迅速减少，杀菌作用远较弱，但更多致突变性高于甲硝唑。因此，计划延长之前的表征米索硝唑还原代谢的研究，以寻求一种其减少的代谢物的积累可能与甲硝唑的杀菌活性与甲硝唑的杀菌活性相同已被证明与乙酰胺的积累相关。相似地，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相关。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活性物质结构的差异硝基咪唑类。