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系统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。 海湾地区碳氢化合物致癌的一般理论 理论已经形成，它的预测正在用 几种碳氢化合物的合成潜在代谢物。当前的研究 已证明苯并吖啶的湾区3，4-二醇-1，2-环氧化物是一种 终极致癌物质。光学活性二氢二醇和二醇环氧化物 已经准备好用二苯并[c，h]吖啶衍生物来测试这一理论。 尽管6-氟苯并[a]芘在小鼠皮肤上的致瘤性很低，但 碳氢化合物被有效地代谢成海湾地区的二元醇环氧化物 苯并[a]芘。我们的细胞色素催化结合部位模型 通过研究光学活性的形成，对P-450c进行了探讨 萘和菲的1，2-氧化物。 1，2，3，4-四氢苯并[a]-菲(3R，4S)-环氧化物被鉴定为 目前已知的最好的微粒体环氧化物水解酶底物是 活性约为菲9，10-氧化物的8倍。一种新型的吡咯 能引起小鼠惊厥的羧嘧啶已从 热带植物大花文氏草。

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 system 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. A general theory of hydrocarbon-induced carcinogenesis, the bay-region theory, has been formulated and its predictions are being tested with synthetic potential metabolites of several hydrocarbons. Current studies have shown that a bay-region 3,4-diol-1,2-epoxide of benz[c]acridine is an ultimate carcinogen. Optically active dihydrodiols and diol epoxides have been prepared to test the theory with dibenz[c,h]acridine derivatives. Despite the low tumorigenicity of 6-fluorobenzo[a]pyrene on mouse skin, the hydrocarbon is metabolized to bay-region diol epoxides as efficiently as is benzo[a]pyrene. Our model for the catalytic binding site for cytochrome P-450c has been probed by studying the formation of optically active naphthalene and anthracene 1,2-oxides. 1,2,3,4-Tetrahydrobenz[a]-anthracene (3R,4S)-epoxide has been identified as the best presently known substrate for microsomal epoxide hydrolase and is about 8-fold more active than phenanthrene 9,10-oxide. A novel pyrrole carboxamidine which causes convulsions in mice has been isolated from the tropical plant Brunfelsia grandiflora.