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）代谢研究 化学物质与肝微粒体和纯化的细胞色素P450 和环氧化物水解酶，iii）评价致突变性， 合成代谢物的致瘤性，iv）阐明 细胞色素P450系统和环氧化物水解酶在调节 这些代谢物的致突变性，v）测定这些代谢物的致突变率， 芳烃氧化物和二醇环氧化物与生物聚合物的反应产物 和模型化合物，以及vi）寻找能够预防 反应性代谢物的致瘤性。 过去的大部分努力 2000年的研究主要集中在致癌的海湾地区二醇的DNA加合物上 环氧化物代谢物。 已经制定了一项战略， 含有N6- 2 ′-脱氧腺苷和N2- 2 ′-脱氧鸟苷的寡核苷酸 二醇环氧化物的加合物，其中嘌呤的环外氨基 碱通过环氧化物的顺式或反式打开键合到烃上 在苄基位置。 制备所需的N-取代嘌呤， 由烃氨基三醇和适当封端的氟类似物 基地。 选择封闭基团，使得标准 亚磷酰胺化学可用于自动化DNA合成仪。 预期这种加合的DNA寡聚体在生物医学中具有巨大的价值。 致突变和致癌机制的研究。 突变 次黄嘌呤（鸟嘌呤）磷酸核糖转移酶编码区 用PCR方法检测了中国仓鼠V-79细胞HPRT基因的表达。 西诺金（+）-7R，8 S-二羟基-9S，10 R-环氧-7，8，9，10-四氢苯并[a]- 芘 虽然这种致癌物质已知会引起点突变， 鸟嘌呤，在非常低的非细胞毒性剂量下的研究表明， 腺嘌呤也发生了相当数量的突变，这表明， 有少量的A-T热点被突变所掩盖 当使用更高的非环境剂量时，G-C碱基对。

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. Most of the effort in the past year has concentrated on DNA adducts of carcinogenic bay-region diol epoxide metabolites. A strategy has been developed for synthesis of oligonucleotides containing N6-2'-deoxyadenosine and N2-2'-deoxyguanosine adducts of diol epoxides where the exocyclic amino groups of the purine bases are bonded to the hydrocarbon by cis or trans opening of the epoxide at the benzylic position. The required N-substituted purines are prepared from hydrocarbon aminotriols and appropriately blocked fluorine analogs of the bases. The blocking groups were selected such that standard phosphoramidite chemistry can be used on an automated DNA synthesizer. Such adducted DNA oligomers are expected to be of immense value in the study of mechanisms of mutagenesis and carcinogenesis. Mutations in the coding region of the hypoxanthine (guanine) phosphoribosyltransferase (HPRT) gene of Chinese hamster V-79 cells were examined with the car- cinogen (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]- pyrene. Although this carcinogen is known for causing point mutations at guanine, studies at very low, noncytotoxic doses have indicated that comparable numbers of mutations also occur at adenine, suggestive that there is a small number of A-T hot spots which are obscured by mutations at G-C base pairs when higher, nonenvironmental doses are used.