ENZYMATIC OXIDATION OF DRUGS TO TOXIC AND CARCINOGENIC METABOLITES

主要目标是阐明 反应性代谢物是致癌物质， 多环芳烃的细胞毒性和致突变活性 芳香烃. 所采取的方法包括： 初级和次级氧化代谢物，ii）研究 肝微粒体的碳氢化合物代谢，以及 用纯化和重建的细胞色素P-450系统， 不含环氧化物水解酶，iii）测试 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增强或 消除这些代谢物的致突变性，v） 确定这些化合物的致癌活性，vi） 反应速率和产物性质的测定 由芳烃氧化物和二醇环氧化物在与 生物聚合物和模型化合物，以及vii）寻找能够 防止活性代谢物的致瘤作用。 目前的化学研究包括氧杂环庚三烯的新合成 其在由以下物质制备苯并环芳烃氧化物的过程中形成 二溴乙酸盐前体。 在选定的情况下，可从PMO预测 计算，芳烃氧化物经历了容易的光重排 相同的氧杂卓。 pH依赖的溶剂分解反应的研究 前茂I 3，4-氧化物已经建立了前所未有的变化， 碳阳离子中间体形成的速率决定步骤 (low pH）以通过溶剂（高pH）捕获碳阳离子。 检测核苷酸催化的 苯并（a）芘7，8-二醇9，10-环氧化物确立了 核苷酸和烃之间的堆积相互作用 在这种通用酸（磷酸盐）催化的过程中。 苯并菲立体选择性代谢为1，2-苯并菲 氧化物对映体被证明是依赖于细胞色素P- 使用了450份制剂。 肿瘤研究证实， 将6-氟取代基引入高度致瘤性的 苯并（a）芘7，8-二醇9，10-环氧消除致癌物质 活性，可能是由于构象变化。

The primary goal has been the elucidation of the structures of reactive metabolites which are responsible for the carcinogenic, cytotoxic and mutagenic activity of polycyclic aromatic hydrocarbons. The approach taken consists of: i) synthesis of primary and secondary oxidative metabolites, ii) study of the metabolism of the hydrocarbons with liver microsomes, as well as with purified and reconstituted cytochrome P-450 systems with and without epoxide hydrolase, iii) tests for mutagenicity of the synthetic metabolites, 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 reaction rates and nature of the products formed by arene oxides and diol epoxides upon reaction with biopolymers and model compounds, and vii) search for agents capable of preventing the tumorigenic action of active metabolites. Current chemical studies have included a new synthesis of oxepins which form during the preparation of benzo-ring arene oxides from dibromoacetate precursors. In selected cases, predictable from PMO calculations, the arene oxides undergo facile photorearrangements to the same oxepins. Studies of the pH dependent solvolysis of precocene I 3,4-oxide have established an unprecedented change in rate determining step from formation of a carbocation intermediate (low pH) to capture of the carbocation by solvent (high pH). Examination of the nucleotide - catalyzed hydrolysis of benzo(a)pyrene 7,8-diol 9,10-epoxide established the importance of stacking interactions between the nucleotide and the hydrocarbon in this general-acid (phosphate) catalyzed process. Stereoselective metabolism of triphenylene to triphenylene 1,2- oxide enantiomers was shown to be dependent on the cytochrome P- 450 preparation utilized. Tumor studies established that introduction of a 6-fluoro substituent into the highly tumorigenic benzo(a)pyrene 7,8-diol 9,10-epoxide eliminates carcinogenic activity, possibly due to a conformational change.