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： 初级和次级代谢物，ii）研究 碳氢化合物与肝微粒体，以及与纯化 和重组细胞色素P-450系统， 环氧化物水解酶，iii）合成的 iv）阐明细胞色素P-450的作用 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）测定 这些化合物的致癌活性，vi）测定 芳烃的反应速率和产物性质 氧化物和二醇环氧化物与生物聚合物反应， 模型化合物，和vii）寻找能够预防 活性代谢物的致瘤作用。 当前化学 研究包括合成和分配绝对 衍生自以下的光学活性5，6-氧化物的构型 蒽、7，12-二甲基苯并蒽和 苯并（c）菲及其绝对值的归属 主要1，2-二氢二醇代谢物的构型 苯并菲。 主要的3，4- 苯并（c）菲通过细胞色素形成的5，6-氧化物 P-450C已经确定。 NMR方法测定 芳烃氧化物对映体组成以及形成 用手性方法预测它们的绝对构型 已开发了镧系元素位移试剂。 非对映异构体6- 氟苯并（a）芘7，8-二醇9，10-环氧化物，其不同之处在于 从非氟化类似物的构象，已被 合成的，和一个显着的影响，构象，其速率 溶剂分解的原理。 特异性抑制机制 细胞色素P450c的2-溴-4'-硝基苯乙酮已被 阐明。 脱氧鸟苷和脱氧腺苷加合物 由4个光学活性的DNA烷基化形成 苯并（c）菲3，4-二醇1，2-环氧化物已经被 已经鉴定了其中几种加合物 在用本发明的化合物处理培养的啮齿动物胚胎细胞后， 母烃

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 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 the synthesis and assignment of absolute configuration of the optically active 5,6-oxides derived from chrysene, 7,12-dimethylbenz(a)anthracene and benzo(c)phenanthrene as well as assignment of absolute configuration of the predominant 1,2-dihydrodiol metabolite from triphenylene. The absolute configurations of the principal 3,4- and 5,6-oxides formed from benzo(c)phenanthrene by cytochrome P-450c have been determined. An NMR method for determining the enantiomeric composition of arene oxides as well as for predicting their absolute configuration by the use of chiral lanthanide shift reagents has been developed. Diastereomeric 6- fluorobenzo(a)pyrene 7,8-diol 9,10-epoxides, which differ in conformation from the unfluorinated analogues, have been synthesized, and a marked effect of conformation of their rates of solvolysis demonstrated. The mechanism of specific inhibition of cytochrome P450c by 2-bromo-4'-nitroacetophenone has been elucidated. The deoxyguanosine and deoxyadenosine adducts formed by alkylation of DNA by 4 optically active benzo(c)phenanthrene 3,4-diol 1,2-epoxides have been characterized and several of these adducts have been identified upon treatment of rodent embryonic cells in culture with the parent hydrocarbon.