MECHANISM OF BENZO?A?PYRENE CARCINOGENESIS

苯并芘致癌机制

• 批准号: 3252087
• 负责人: SUBODH KUMAR
• 金额: $ 20.69万
• 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/3252087
• 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质，已被广泛应用。 作为模型化合物用来阐明多核的机制 芳香烃(PAHs)具有致癌作用。它是公认的 湾区二醇环氧化物代谢物，特别是(+)-抗BPDE， 是启动致癌过程的关键 由BP诱导。然而，(+)-BPDE水平之间的相关性很差- 组织中的DNA加合物与组织对BP的敏感性 致癌并不完全支持这一概念。这种缺乏 相关性表明，除了(+)-抗BPDE-DNA加合物外，DNA BP的其他反应性代谢物(S)的加合物(S)也可能具有重要意义 与BP致癌的相关性。对于BP和其他多环芳烃来说， 酚湾区二醇环氧化物(三醇环氧化物)的形成是近年来的研究热点 被认为是另一种重要的代谢反应，通过它 碳氢化合物可以被激活。使用32P-后标记技术，我们的 初步研究表明，主要的DNA加合物之一是由 人工合成的3-羟基-BP-7，8-二醇(BP-Triol)，a 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共层析- DG。因此，很可能在体内BP-DNA加合物先前 被认为来源于BPDE的化合物实际上也可能来源于BPTE。 拟议研究的主要目标是调查是否有 在体内产生的主要DNA加合物中，有一部分来自BPTE。这个 拟议研究的具体目标是：(1)综合和 表征BPTE的各种脱氧核糖核苷3‘-单磷酸加合物； (Ii)分析和表征后形成的BP-三醇的DNA加合物 在DNA存在的情况下微粒体的激活；(Iii)分析和鉴定 BPDE、BPTE或BP-三醇衍生的DNA加合物的DNA加合物；及(Iv) 检测BP-DNA加合物在小鼠皮肤和小鼠体内的相对持久性 活体肝脏，特别强调BPTE加合物。