DMBA DERVIVATIVES AND CHEMICAL CARCINOGENESIS

DMBA 衍生物与化学致癌作用

• 批准号: 6175308
• 负责人: James W Flesher
• 金额: $ 24.38万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6175308
• 关键词: adduct; analog; benzanthracenes; chemical carcinogen; chemical carcinogenesis; chemical synthesis; drug design /synthesis /production; drug metabolism; electrochemistry; enzyme activity; laboratory rat; liver metabolism; mammary gland; sulfotransferase; tissue /cell culture

The unified hypothesis, for the carcinogenic properties of polycyclic aromatic hydrocarbons (PAH), predicts that the 7- hydroxymethyl sulfate ester, SMBA, plays a major role in the metabolic activation, DNA binding, and complete carcinogenicity of 7,12-dimethylbenz[a]a nth racene (DMBA). However, alternative hypotheses predict that other pathways may play a role in DMBA carcinogenesis. It is therefore a matter of considerable interest to identify clearly the ultimate electrophilic and carcinogenic forms. To test the validity and generality of the hypothesis for the carcinogenic properties of DMBA and model metabolites, we plan to carry out: 1) The preparation and characterization of selected DMBA derivatives, 2) The metabolism of DMBA and selected derivatives/metabolites in rat-liver homogenates, in vitro, and in liver and mammary gland, in vivo. The products of metabolism will be identified and compared using HPLC and GC/MS, with a number of reference model metabolites, 3) The identification of the most carcinogenic forms of DMBA and of the model metabolite 7-formyl-12-methyl benz[a]anthracene (7-FMBA) in a complete carcinogenesis model, 4) The formation and identification of DMBA and 7-FMBA related DNA adducts, in vitro and in vivo using the 32P-postlabeling method together with LC/MS/MS. Sulfation of the 7-hydroxymethyl derivative and other hydroxyalkyl derivatives of PAH, by 3'-phosphoadenosine-5'-phosphosulfate-dependent sulfotransferase activity, can metabolically activate primary and secondary benzylic alcohol derivatives to ultimate electrophilic mutagens and carcinogens. Since the aralkylating agents formed may be the most carcinogenic derivatives of PAH yet identified, electrophilic hydroxyalkyl sulfate ester formation appears to be a major pathway for the metabolic activation of proximate carcinogens to DNA damaging ultimate carcinogens. Work done by our group and by others has resulted in enough evidence to convince many researchers that electrophilic hydroxyalkyl sulfate esters, and closely related aralkylating agents, play a major role in causing DNA damage, mutagenesis, and carcinogenesis. Identification of the ultimate electrophilic and carcinogenic forms of DMBA and 7-FMBA may eventually lead to methods for the prevention of some of the human cancer that is currently considered to be caused by this class of chemical carcinogens.

针对多环芳烃 (PAH) 的致癌特性，统一假说预测 7-羟甲基硫酸酯 (SMBA) 在 7,12-二甲基苯并[a]a nth 外消旋体 (DMBA) 的代谢激活、DNA 结合和完全致癌性中起主要作用。 然而，另一种假设预测其他途径可能在 DMBA 致癌过程中发挥作用。 因此，明确确定最终的亲电子形式和致癌形式是一个非常令人感兴趣的问题。 为了测试 DMBA 和模型代谢物致癌特性假设的有效性和普遍性，我们计划进行：1）选定的 DMBA 衍生物的制备和表征，2）DMBA 和选定的衍生物/代谢物在大鼠肝匀浆中的体外代谢以及肝脏和乳腺中的体内代谢。将使用 HPLC 和 GC/MS 鉴定代谢产物，并与许多参考模型代谢物进行比较，3) 在完整的致癌模型中鉴定 DMBA 的最强致癌形式和模型代谢物 7-甲酰基-12-甲基苯并[a]蒽 (7-FMBA)，4) DMBA 和 7-FMBA 相关 DNA 加合物的形成和鉴定， 使用 32P 后标记方法和 LC/MS/MS 进行体外和体内分析。 PAH 的 7-羟甲基衍生物和其他羟烷基衍生物通过 3'-磷酸腺苷-5'-磷酸硫酸盐依赖性磺基转移酶活性进行硫酸化，可以代谢激活伯醇和仲苄醇衍生物，最终形成亲电诱变剂和致癌剂。 由于所形成的芳烷基化剂可能是迄今为止已确定的最具致癌性的 PAH 衍生物，因此亲电子羟烷基硫酸酯的形成似乎是将邻近致癌物代谢活化为破坏 DNA 的最终致癌物的主要途径。 我们小组和其他人所做的工作已经产生了足够的证据，使许多研究人员相信亲电子羟烷基硫酸酯和密切相关的芳烷基化剂在引起 DNA 损伤、诱变和致癌方面发挥着重要作用。对 DMBA 和 7-FMBA 最终亲电子和致癌形式的鉴定可能最终会找到预防某些目前被认为是由此类化学致癌物引起的人类癌症的方法。