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.

建议继续对还原性进行当前的调查甲硝唑在厌氧菌群以表征反应性中间体可能负责其癌变。动物和细菌提出了实验。因此，将确定是否结肠甲硝唑在与其他人一起发现它是在常规大鼠中。会还可以确定二甲基氢嗪的致癌性是否得到增强通过这样的其他硝基化合物化合物，在人类使用中，例如misonidazole和硝基呋喃酮，这些药物与甲硝唑不同，因为它们是降低到杂环环的点不仅在植物群但在无毛大鼠的组织中。其他研究将寻求硝基咪唑的代谢及其它们的相关性杀菌性和毒素活性。因此，计划确定先前观察的意义，即甲硝唑减少了不同的厌氧菌和各种化学系统导致定量不同的代谢产物的形成。尝试将提出将这些代谢差异与差异联系起来的这些系统的诱变性是ames组氨酸合子营养的一种手段确定还原的关键产品，从中可以推断出诱变中间体的化学结构。为了推断硝基咪唑的反应性形式的临界特征， Misonidazole（2-硝基咪唑）将进行进一步的比较和甲硝唑（5-硝基咪唑）。 Misonidazole，尽管更多细菌培养物的迅速降低，杀菌性差得多，但更多诱变比甲硝唑。因此，计划扩展以前曲目的研究表征了Misonidazole的还原性代谢其减少的代谢产物的积累可能与甲硝唑的杀菌活性的杀菌活性已显示与乙酰胺的积累相关。相似地，将寻求减少Misonidazole的还原代谢物的积累与Misonidazole的诱变相关。这种比较之间的比较甲硝唑和米替唑唑应有助于推断相似之处和两者的反应性物种的结构不同氮咪唑。