ENZYMATIC OXIDATION OF DRUGS TO TOXIC AND CARCINOGENIC METABOLITES

主要目标是阐明反应性的结构， 致癌、细胞毒性和致突变的代谢物 多环芳烃和其他化学品的活性 环境化学品。所采取的方法包括： 初级和次级氧化代谢物，ii）研究 化学物质与肝微粒体，以及与纯化和 有和没有环氧化物水解酶的重构细胞色素P-450系统， iii）评价合成的化合物的致突变性和致肿瘤性， 代谢物，iv）阐明的作用。细胞色素P-450系统 和环氧化物水解酶调节这些代谢物的致突变性， v）测定芳烃氧化物的反应速率和产物， 二醇环氧化物与生物聚合物和模型化合物，和vi）寻找 能够防止反应性代谢物的致瘤性的试剂。 合成研究现已使光学纯海湾地区 苯并[g]芘的11，12-二醇-13，14-环氧化物 致突变和致肿瘤活性。的比较溶剂分解研究 二苯并[ a，j ]蒽的海湾区3，4-二醇-1，2-环氧化物 氮杂-类似物，其中氮已取代7位的CH，或 14位上的氮的影响很小（2 - 5倍 减速）对酸催化或酸催化中的溶剂分解反应性的影响。 pH-非依赖性（中性至碱性）区域，而7位为氮 显着降低（23倍）的酸催化反应。一种新型 在该反应中观察到了双阳离子酸催化的反应机理 后一种情况。光学活性物质的共价键合检查 二苯并[ a，j ]蒽的月桂基-3，4-二醇1，2-环氧化物 体外胸腺DNA的研究证实了一种新的胞嘧啶加合物 除了预期的腺嘌呤和鸟嘌呤的16个加合物之外。 在细菌和中国仓鼠V79细胞中进行的致突变性研究 表明二苯并[a，h]吖啶的10，11-二醇8，9-环氧化物更有效 诱变剂比3，4-二醇1，2-环氧化物在雅阁符合它们的差异， 化学反应性

The primary goal has been the elucidation of the structures of reactive metabolites responsible for the carcinogenic, cytotoxic and mutagenic activity of drugs, polycyclic aromatic hydrocarbons, and other environmental chemicals. The approach taken consists of: i) synthesis of primary and secondary oxidative metabolites, ii) study of the metabolism of the chemicals with liver microsomes, as well as with purified and reconstituted cytochrome P-450 systems with and without epoxide hydrolase, iii) evaluation of the mutagenicity and tumorigenicity of the synthetic metabolites, iv) elucidation of the roles of the. cytochrome P-450 system and epoxide hydrolase in modulating the mutagenicity of these metabolites, v) determination of the rates and products of reactions of arene oxides and diol epoxides with biopolymers and model compounds, and vi) search for agents capable of preventing the tumorigenicity of reactive metabolites. Synthetic studies have now made available optically pure bay-region 11,12-diol-13,14-epoxides of benzo[g]chrysene for testing of their mutagenic and tumorigenic activities. Comparative solvolytic studies of the bay-region 3,4-diol-1,2-epoxides of dibenz [ a, j ] anthracene with aza-analogs in which nitrogen has been substituted for CH at positions 7 or 14 have shown that nitrogen at position 14 has little effect (2 to 5-fold deceleration) on solvolytic reactivity in either the acid catalyzed or ph-independent (neutral to basic) regions whereas nitrogen at position 7 markedly decreases (23-fold) the acid-catalyzed reaction. A novel dicationic acidcatalyzed reaction mechanism has been observed in this latter case. Examination of the covalent bonding of the optically active bay-region-3,4-diol 1,2-epoxides of dibenz [ a, j ] anthracene to calf thymus DNA in vitro has allowed identification of a novel cytosine adduct in addition to the anticipated 16 adducts at adenine and guanine. Mutagenicity studies in bacteria and in Chinese hamster V79 cells have shown the 10,11-diol 8,9-epoxides of dibenz[a,h]acridine are more potent mutagens than the 3,4-diol 1,2-epoxides in accord with their differences in chemical reactivity.