DMBA DERVIVATIVES AND CHEMICAL CARCINOGENESIS

对于多环芳烃（PAH）的致癌性，统一的假设预测，7-羟甲基硫酸酯（SMBA）在7,12-二甲基苯[a] n外消旋烯（DMBA）的代谢激活、DNA结合和完全致癌性中起主要作用。然而，另一种假说预测，其他途径可能在DMBA致癌作用中发挥作用。因此，明确确定最终的亲电性和致癌性形式是一个相当有趣的问题。为了验证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)所选DMBA衍生物的制备和表征，2)DMBA及其衍生物/代谢物在体外大鼠肝脏匀浆中的代谢，以及在体内肝脏和乳腺中的代谢。代谢产物将使用HPLC和GC/MS进行鉴定和比较，并与一些参考模型代谢物进行比较，3)在完整的致癌模型中鉴定DMBA和模型代谢物7-甲酰基-12-甲基苯[a]蒽（7-FMBA）的最致癌形式，4)在体外和体内使用32p后标记法结合LC/MS/MS鉴定DMBA和7-FMBA相关DNA加合物的形成和鉴定。多环芳烃的7-羟甲基衍生物和其他羟基烷基衍生物，通过3'-磷酸腺苷-5'-磷酸磺酸依赖的硫转移酶活性，可以代谢激活初级和次级苯基醇衍生物，最终产生亲电诱变剂和致癌物。由于形成的芳烷基化剂可能是目前发现的多环芳烃最具致癌性的衍生物，亲电硫酸羟基烷基酯的形成似乎是将近因致癌物代谢激活为DNA损伤最终致癌物的主要途径。我们小组和其他人的工作已经产生了足够的证据，使许多研究人员相信亲电硫酸羟基烷基酯和密切相关的芳烷基化剂在引起DNA损伤、诱变和致癌方面起着重要作用。确定DMBA和7-FMBA的最终亲电性和致癌性形式可能最终导致预防目前被认为是由这类化学致癌物引起的某些人类癌症的方法。

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.