ACTIVATION OF POLYCYCLIC ENVIRONMENTAL MUTAGENS

这项研究的目的是深入了解化学致癌作用。 通过扩大细胞色素P-450代谢和核酸加合物的研究 在交替海湾区子集之外形成多环化合物 到目前为止，多核芳烃已被研究过。多环芳香族 待研究的化合物有环戊二烯(Cd)、菲、菲、 对乙酰基菲，对苯并菲。这些化合物的代谢物将是 分离、鉴定和鉴定致突变代谢物。 将建立一个模型P-450系统，在该系统中提出的恶烯络合物为 酶促氧转移中的中间体将稳定下来。 恶烯的表征及其与多环底物的反应将 有助于阐明P-450氧化的机制。从机械论 考虑因素和衬底的电子结构，a 将建立结构-反应性关系，然后通过 将预测的代谢图谱与实验观察的图谱进行比较。 活性代谢物，假定是从环氧化物的存在推断的环氧化物 将合成相应的二氢二醇，并与它们的加合物 鸟苷的特征。对于氧化物，突变被认为是一种 酸生成的碳正离子相对稳定性的作用 催化的环氧化物开环。这种结构-反应性关系可以是 通过比较酸的速率常数和产物分布来评估 氧化物的水解性和它们的致突变性。

The objective of this research is to gain insight into chemical carcinogenesis by extending studies on cytochrome P-450 metabolism and nucleic acid adduct formation to polycyclic compounds outside the subset of alternate, bay region polynuclear aromatics heretofore investigated. The polycyclic aromatic compounds to be studied are cyclopenta(cd)pyrene, cholanthrylene, acephenanthrylene, acenaphthylene. The metabolites of these compounds will be separated and characterized and the mutagenic metabolites identified. A model P-450 system will be constructed in which the oxene complex proposed as the intermediate in the enzymatic oxygen transfer will be stabilized. Characterization of the oxene and its reaction with polycyclic substrates will help to elucidate the mechanism of P-450 oxidations. From mechanistic considerations and the electronic structure of the substrates, a structure-reactivity relationship will be developed and then evaluated by comparing predicted metabolic profiles with profiles observed experimentally. The active metabolites, assumed to be the epoxides inferred from the presence of the corresponding dihydrodiols, will be synthesized and their adducts with guanosine characterized. For the oxides, mutagenicity is postulated to be a function of the relative stability of the carbonium ion resulting from acid catalyzed epoxide opening. This structure-reactivity relationship can be evaluated by comparing rate constants and product distributions of acid hydrolysis of the oxides with their mutagenic potency.