MECHANISM OF BENZO?A?PYRENE CARCINOGENESIS

苯并芘致癌机制

• 批准号: 3252085
• 负责人: SUBODH KUMAR
• 金额: $ 20.13万
• 依托单位: BUFFALO STATE COLLEGE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3252085
• 关键词: DNA damage; Salmonella typhimurium; adduct; analog; benzopyrenediol epoxide; benzopyrenes; chemical carcinogenesis; chemical synthesis; chromatography; deoxyribonucleosides; environment related neoplasm /cancer; high performance liquid chromatography; laboratory mouse; laboratory rat; liver metabolism; mass spectrometry; microsomes; nuclear magnetic resonance spectroscopy; radiotracer; skin; toxin metabolism

Benzo[a]pyrene (BP), a widespread environmental carcinogen, has been widely used as a model compound for elucidating the mechanism by which polynuclear aromatic hydrocarbons (PAHs) induce carcinogenicity. It is well recognized that the bay-region diol epoxide metabolites, in particular (+)-anti-BPDE, with cellular DNA is critical for initiating the carcinogenic process induced by BP. However, a poor correlation between the level of (+)-BPDE- DNA adduct in a tissue and tissue susceptibility to BP-induced carcinogenesis does not fully support this concept. This lack of correlation suggest that, in addition to (+)-anti-BPDE-DNA adducts, the DNA adduct(s) of other reactive metabolite(s) of BP may also be of significant relevance in BP-induced carcinogenesis. For BP and other PAHs, the formation of phenolic bay-region diol epoxides (triol epoxides) is recently being recognized as an additional important metabolic reaction by which a hydrocarbon can be activated. Using the 32P-postlabeling technique, our preliminary studies have shown that one of the major DNA adducts formed by microsomal activation of synthetic 3-hydroxy-BP-7,8-diol (BP-triol), a major metabolite of 3-hydroxyBP and also a metabolic precursor of 3- hydroxy-BP-7,8-diol-9,10-epoxide (BPTE), co-chromatographs with anti-BPDE- dG. Therefore, it is likely that in vivo BP-DNA adducts previously believed to be derived from BPDE may in fact also be derived from BPTE. The major objective of the proposed research is to investigate whether any of the major DNA adducts of BP produced in vivo is derived from BPTE. The specific aims of the proposed research are: (i) To synthesize and characterize various deoxyribonucleoside 3'-monophosphate adducts of BPTE; (ii) To analyze and characterize DNA adducts of BP-triol formed after microsomal activation in the presence of DNA; (iii) To analyze and identify DNA adducts of BPDE-, BPTE- or BP-triol-derived DNA adducts; and (iv) To examine the relative persistence of BP-DNA adducts in mouse skin and mouse liver in vivo with particular emphasis on BPTE adducts.

苯并[a]芘（BP）是一种广泛存在的环境致癌物， 作为一种模型化合物，用于阐明多核 芳香烃（PAH）具有致癌性。 人们普遍认识到 湾区二醇环氧化物代谢物，特别是（+）-抗-BPDE， 对启动致癌过程至关重要 由BP引起。 然而，（+）-BPDE- 组织中的DNA加合物和组织对BP诱导的 致癌作用并不完全支持这一概念。 这种缺乏 相关性表明，除了（+）-抗BPDE-DNA加合物，DNA BP的其他反应性代谢产物的加合物也可能具有显著的 与BP诱发的致癌作用相关。 对于BP和其他PAH， 最近， 被认为是一种额外的重要代谢反应， 碳氢化合物可以被活化。 使用32 P后标记技术，我们的 初步的研究表明，一个主要的DNA加合物形成的， 合成3-羟基-BP-7，8-二醇（BP-三醇）的微粒体活化， 3-羟基BP的主要代谢物，也是3-羟基BP的代谢前体， 羟基-BP-7，8-二醇-9，10-环氧化物（BPTE），与抗BPDE- dG。 因此，很可能体内BP-DNA加合物先前 被认为源自BPDE的化合物实际上也可能源自BPTE。 拟议研究的主要目标是调查是否有任何 体内产生的BP的主要DNA加合物中有10%来自BPTE。 的 拟议研究的具体目标是：（一）综合和 表征BPTE的各种脱氧核糖核苷3 '-单磷酸加合物; (ii)为了分析和表征BP-三醇形成的DNA加合物， 在DNA存在下的微粒体活化;（iii）分析和鉴定 BPDE-、BPTE-或BP-三醇衍生的DNA加合物的DNA加合物;和（iv） 检查小鼠皮肤和小鼠皮肤中BP-DNA加合物的相对持久性， 体内肝脏，特别强调BPTE加合物。