Blaich G, Pfaff E, Metzler M
Institute of Pharmacology and Toxicology, University of Würzburg, Federal Republic of Germany.
Biochem Pharmacol. 1987 Oct 1;36(19):3135-40. doi: 10.1016/0006-2952(87)90623-x.
Under certain modulating conditions the liver of the male Syrian golden hamster is a target organ for the carcinogenic effect of the synthetic estrogen diethylstilbestrol (DES). As a basis for mechanistic studies aimed at elucidating the role of metabolic activation in the process of DES-induced neoplasia, the metabolism of 14C-DES was investigated in freshly isolated hamster hepatocytes. These oxidative metabolites of DES, viz. Z,Z-dienestrol,3'-hydroxy-DES and 1-hydroxy-E-DES, were formed in 14.2, 9.1, and 0.3% yield, respectively, when hepatocytes were incubated with 50 nmol DES/mg cellular protein for 60 min. Glucuronides (4.0%) and sulfates (2.8%) of DES and of the oxidative metabolites were also found, and non-extractable binding of radioactivity to cellular protein was observed indicating the formation of reactive intermediates. The capability of hamster hepatocytes to oxidize and conjugate DES should allow the investigation of the effects of modulators on the metabolic activation of DES in this cellular system in order to help clarify the mechanisms of DES-induced hepatocarcinogenesis.
在某些调节条件下，雄性叙利亚金仓鼠的肝脏是合成雌激素己烯雌酚（DES）致癌作用的靶器官。作为旨在阐明代谢活化在DES诱导肿瘤形成过程中作用的机制研究基础，对新鲜分离的仓鼠肝细胞中14C-DES的代谢进行了研究。当肝细胞与50 nmol DES/mg细胞蛋白孵育60分钟时，DES的这些氧化代谢产物，即Z,Z-己二烯雌酚、3'-羟基-DES和1-羟基-E-DES的生成量分别为14.2%、9.1%和0.3%。还发现了DES及其氧化代谢产物的葡萄糖醛酸苷（4.0%）和硫酸盐（2.8%），并且观察到放射性与细胞蛋白的不可提取结合，表明形成了反应性中间体。仓鼠肝细胞氧化和结合DES的能力应有助于研究调节剂对该细胞系统中DES代谢活化的影响，从而有助于阐明DES诱导肝癌发生的机制。
