ENZYMATIC OXIDATION OF DRUGS TO TOXIC AND CARCINOGENIC METABOLITES

其主要目标是阐明其结构 导致致癌物质的活性代谢物， 多环芳香族化合物的细胞毒性和致突变活性 碳氢化合物。所采取的方法包括：i)合成 初级和次级代谢物，II)代谢研究 含肝微粒子的碳氢化合物，以及与纯化的碳氢化合物 和重组的细胞色素P-450系统 环氧化物水解酶，III)合成产物的致突变性试验 代谢物，IV)细胞色素P-450作用的阐明 体系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 芳烃生成产物的反应速率和性质 氧化物和二元醇环氧化物与生物聚合物和 模型化合物，以及vii)寻找能够防止 活性代谢物的致癌作用。现代化学 研究包括绝对化合物的合成和归属。 具有光学活性的5，6-氧化物的构型 大黄烯、7，12-二甲基苯并(A)菲和 苯并(C)菲及其绝对归属 主要1，2-二氢二醇代谢产物的构型 三苯基。主体3，4-的绝对构型 和5，6-氧化物，由苯并(C)菲通过细胞色素生成 P-450c已被测定。一种核磁共振波谱测定方法 芳烃氧化物的对映体组成以及对映体 利用手性预测它们的绝对构型 研制了一种新型的稀土变换试剂。非对映异构体6- 氟苯并(A)芘7，8-二醇9，10-环氧化物，它们在 来自非氟类似物的构象，已经被 合成，并对其速率的构象有显著的影响 所展示的溶积作用。特异性抑制的机制 2-溴-4‘-硝基苯乙酮对细胞色素P450c的作用 已澄清。脱氧鸟苷和脱氧腺苷加合物 由4个光学活性的DNA烷基化而成 苯并(C)菲3，4-二醇1，2-环氧化物已被 并鉴定了其中的几个加合物。 在处理啮齿动物胚胎细胞的培养中 母体碳氢化合物。

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.