CARCINOGEN METABOLISM BY HOST INTESTINAL BACTERIA

建议继续目前对还原的研究。 甲硝唑等硝基杂环药物在人体内的代谢 厌氧菌群，以表征活性中间体 可能是它们致癌的原因。无论是动物还是细菌 提出了实验方案。因此，将确定冒号是否 甲硝唑增强二甲基肼的致癌性 像其他人一样，无菌大鼠在常规大鼠中也存在这种情况。会的 也要确定二甲基肼的致癌性是否增强 人类使用的其他硝基杂环化合物，如咪唑和 呋喃西林，这些药物不同于甲硝唑，因为它们是 还原到杂环环碎裂的程度不仅在 但在无菌大鼠的组织中。其他研究将寻求 硝基咪唑类化合物的代谢与其代谢的相关性 杀菌和致突变活性。因此，计划确定 以前观察到甲硝唑减量的意义 不同的厌氧菌和不同的化学系统导致了 形成数量上不同的代谢物。在尝试中 会把这些新陈代谢的差异与 这些系统对Ames组氨酸营养缺陷体的致突变性 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。为了推断出 硝基咪唑类反应型的临界特性， 将进一步比较米索硝唑(2-硝基咪唑) 和甲硝唑(一种5-硝基咪唑)。咪唑类药物，尽管更多 在细菌培养中迅速减少，杀菌作用要小得多，但更多 比甲硝唑更具致突变性。因此，计划将之前的 米索硝唑还原代谢特性的研究 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， 将寻找米索硝唑的还原代谢物，其累积 与米索硝唑的致突变性有关。这样的比较在 甲硝唑和米索硝唑有助于推断相似之处 以及两者的活性物种结构的差异 硝基咪唑类药物。

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.