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 化学品与肝微粒体和纯化的细胞色素P450和 环氧化物水解酶，iii）致突变性和致瘤性评价 的合成代谢物，iv）阐明的作用， 细胞色素P450系统和环氧化物水解酶在调节致突变性中的作用 这些代谢物，v）测定的速率和产品的 芳烃氧化物和二醇环氧化物与生物聚合物的反应和模型 化合物，和vi）寻找能够预防 反应性代谢物的致瘤性。 合成研究已经使 可用的光学纯的氧化芳烃以及顺式和反式二氢二醇 在环境致癌物喹啉的5，6位。 恶臭假单胞菌 (UV4)形成顺式-（5 R，6S）-二氢二醇，而肝微粒体形成高度 光学富集的（5 R，6S）-氧化物和（5 R，6S）-二氢二醇对代谢的影响 喹啉。 酸催化溶剂解研究取代 苯并[a]蒽5，6-氧化物以及理论计算（分子 力学的PCMODEL-PI和从头算的高斯86和88程序）， 碳正离子的稳定性表明空间因素的重要性 确定相对反应性。 这些数据将用于评估 微粒体环氧化物水解酶的解毒机制 毒性和致突变底物。 我们最近提出了一个经验主义的 核苷绝对构型圆二色谱预测规则 嘌呤碱的环外氨基在 湾区二醇环氧化物的苄环氧化物碳。 的应用 这一规则允许对两种配置的分配进行修正， 苯并[a]芘7，8-二醇9，10-环氧化物加合物以前被错误指定。 非致癌DE-1和致癌DE-2的溶剂分解研究 苯并[a]芘7，8-二醇9，10-环氧化物的非对映异构体表明存在差异 在中性pH下与生化亲核试剂反应机理中 （碳阳离子捕获对中性环氧化物的亲核攻击， 分别）。

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 and with purified cytochromes P450 and epoxide hydrolase, iii) evaluation of the mutagenicity and tumorigenicity of the synthetic metabolites, iv) elucidation of the roles of the cytochrome P450 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 arene oxide as well as cis and trans dihydrodiols at the 5,6-position of the environmental carcinogen quinoline. P. putida (UV4) forms the cis-(5R, 6S)-dihydrodiol while liver microsomes form highly optically enriched (5R, 6S)-oxide and (5R, 6S)-dihydrodiol on metabolism of quinoline. Acid-catalyzed solvolysis studies of substituted benz[a]anthracene 5,6-oxides as well as theoretical calculations (molecular mechanics by PCMODEL-PI and ab initio by GAUSSIAN 86 and 88 programs) of carbocation stability indicate the importance of steric factors in determining relative reactivity. These data are to be used in evaluation of the mechanism(s) by which microsomal epoxide hydrolase detoxifies such toxic and mutagenic substrates. We have recently proposed an empirical rule for prediction from CD spectra of absolute configuration of nucleoside adducts formed by reaction of the exocyclic amino groups of purine bases at the benzylic epoxide carbon of bay-region diol epoxides. Application of this rule has allowed correction of the assignment of configuration for two benzo[a]pyrene 7,8-diol 9,10-epoxide adducts previously misassigned. Solvolytic studies of the noncarcinogenic DE-1 and carcinogenic DE-2 diastereomers of benzo[a]pyrene 7,8-diol 9,10-epoxides suggest differences in their mechanism of reaction with biochemical nucleophiles at neutral pH (carbocation capture vs nucleophilic attack on neutral epoxide, respectively).