ENZYMATIC OXIDATION OF DRUGS TO TOXIC AND CARCINOGENIC METABOLITES

主要目标是阐明反应性的结构。 负责致癌、细胞毒性和 苯并[a]芘等多环芳香族化合物的致突变活性 碳氢化合物。所采取的方法包括：i)合成伯胺 氧化代谢物以及选定的次级氧化代谢物， 二)研究这些碳氢化合物与肝微粒体的代谢，如 以及纯化和重组的细胞色素P-450系统 不含环氧化物水解酶，iii)测试 细菌和哺乳动物细胞的合成代谢物，IV)阐明 细胞色素P-450半胱氨酸和环氧化物水解酶在细胞周期中的作用 增强或消除这些代谢物的诱变性，v) 这些化合物致癌活性的测定，vi) 所形成产品的形成速度和性质的测定 当反应性代谢物，如芳烃氧化物和二醇环氧化物与 生物聚合物和不太复杂的模型化合物，以及vii)寻找化合物 能够防止湾区二醇环氧化物的致瘤作用。 目前的化学研究包括解析和指定 苯并[c]-菲5，6-氧化物的绝对构型 九种多环烃的K区反式二氢二醇。一本小说 复杂烃类化合物的~1H和~(13)C核磁共振全归属方法 已经被开发出来了。代谢研究表明，苯并[c]菲 可能是一种微弱的致癌物，因为它不能很好地转化为湾区二醇环氧化物 7，12-二甲基苯并[a]菲被代谢成其(5S，6R)-氧化物 与理论预测一致。光学活性的肿瘤研究， 苯并[c]菲的湾区二醇环氧化物已确定 最强致癌代谢产物(4R，3S)-二醇-(2S，1R)-环氧化物 一种尚未描述的碳氢化合物。一种新的肝微体环氧化物水解酶 被一种机制选择性地失活并表现出特征 基于抑制剂。

The primary goal has been the elucidation of the structures of reactive metabolites which are responsible for the carcinogenic, cytotoxic, and mutagenic activity of benzo[a]pyrene and other polycyclic aromatic hydrocarbons. The approach taken consists of: i) synthesis of primary oxidative metabolites as well as selected secondary oxidative metabolites, ii) study of the metabolism of these hydrocarbons with liver microsomes, as well as with purified and reconstituted cytochrome P-450 systems with and without epoxide hydrolase, iii) tests for inherent mutagenicity of the synthetic metabolites toward bacterial and mammalian cells, iv) elucidation of the roles of the cytochrome P-450 cystem and epoxide hydrolase in potentiating or obliterating the mutagenicity of these metabolites, v) determination of the carcinogenic activity of these compounds, vi) determination of the rate of formation and nature of the products formed when reactive metabolites such as arene oxides and diol epoxides react with biopolymers and less complex model compounds, and vii) search for compounds capable of preventing the tumorigenic action of bay-region diol epoxides. Current chemical studies have included resolution and assignment of absolute configuration to benzo[c]-phenanthrene 5,6-oxide as well as the K-region trans dihydrodiols of nine polycyclic hydrocarbons. A novel method for complete 1H and 13C NMR assignment of complex hydrocarbons has been developed. Metabolism studies have shown that benzo[c]phenanthrene may be a weak carcinogen due to poor conversion to bay-region diol epoxides and that 7,12-dimethylbenz[a]anthracene is metabolized to its (5S,6R)-oxide in accord with theoretical predictions. Tumor studies on optically active, bay-region diol epoxides of benzo[c]phenanthrene have identified the (4R,3S)-diol-(2S,1R)-epoxide as the most potent carcinogenic metabolite of a hydrocarbon yet described. A new liver microsomal epoxide hydrolase has been characterized and shown to be selectively inactivated by a mechanism based inhibitor.