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 药物、多环芳烃和其他物质的活性 环境化学品。所采取的方法包括：i)合成 初级和次级氧化代谢物，II)代谢的研究 与肝微粒体有关的化学物质，以及与纯化和 含和不含环氧化物水解酶的重组细胞色素P-450体系 三)评价合成物的致突变性和致瘤性 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， 五)测定芳烃氧化物和芳烃的反应速率和产物 二醇环氧化物与生物聚合物和模型化合物，以及vi)搜索 能够防止反应性代谢物致瘤性的试剂。 合成研究现已使纯光湾区成为可能。 苯并[g]大黄烯的11，12-二醇-13，14-环氧化物的检测 诱变和致瘤活动。分子的比较溶剂学研究 二苯并[a，j]菲的湾区3，4-二醇-1，2-环氧化物 氮杂类似物，其中7位或7位的氮取代了CH 14表明，14位氮的影响很小(2到5倍 减速)对酸催化的或 与pH无关的(中性到碱性)区域，而氮在第7位 显著减少(23倍)酸催化反应。一本小说 观察到了阳离子酸催化的反应机理。 后一种情况。旋光性分子的共价键研究 湾区-3，4-二醇-1，2-二苯并[a，j]菲的环氧化物对小牛的影响 胸腺DNA体外鉴定出一种新的胞嘧啶加合物 除了预期的16个腺嘌呤和鸟嘌呤加合物。 细菌和中国仓鼠V79细胞的致突变性研究 结果表明，二苯并[a，h]吖啶的10，11-二醇8，9-环氧化物的活性更强 诱变剂比3，4-二醇1，2-环氧化物更符合它们在 化学反应。

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.