FORMATION OF CATECHOL ESTROGEN GLUTATHIONE CONJUGATES AND GAMMA-GLUTAMYL TRANSPEPTIDASE-DEPENDENT NEPHROTOXICITY OF 17-BETA-ESTRADIOL IN THE GOLDEN SYRIAN-HAMSTER

In an animal model of hormone-mediated carcinogenesis, male golden Syr ian hamsters develop renal carcinoma following prolonged exposure to 1 7 beta-estradiol, The basis for the species and tissue specificity is unclear, Detailed information on the disposition of 17 beta-estradiol in this model is lacking, Because catechol estrogens have been implica ted in this model of carcinogenesis, we investigated the metabolism an d nephrotoxicity of 17 beta-estradiol in golden Syrian hamsters, with emphasis on the formation of catechol estrogen thioethers, 17 beta-Est radiol (50 mu mol/kg, i.p.) is a mild nephrotoxicant, causing signific ant elevations in the urinary excretion of gamma-glutamyl transpeptida se (gamma-GT), alkaline phosphatase, glutathione S-transferase (GST) a nd glucose, Increases in renal protein carbonyls and lipid hydroperoxi des, which are markers of oxidative damage, also occur after administr ation of 17 beta-estradiol (50 mu mol/kg, i.p.), 17 beta-Estradiol-med iated nephrotoxicity is reduced by treating animals with acivicin, an inhibitor of gamma-GT, implying that toxicity is mediated by metabolit es requiring metabolism by this enzyme, Following administration of 17 beta-[C-14]estradiol (100 mu mol/kg) to hamsters, 9.7% of the dose is recovered in bile after 5 h, the majority (7.9%) representing aqueous metabolites, Seven catechol estrogen GSH conjugates were identified, 2-hydroxy-1,4-bis-(glutathion-S-yl)-17 beta-estradiol, 2-hydroxy-4-(gl utathion-S-yl)-17 a-estradiol,2-hydroxy-4-(glutathion-S-yl)-estrone, 4 -hydroxy-1-(glutathion-S-yl)-estrone, 2-hydroxy-1-(glutathion-S-yl)-es trone, 4-hydroxy-1-(glutathion-S-yl)-17 beta-estradiol, and 2-hydroxy- 1-(glutathion-S-yl)-17 beta-estradiol. At 5.4 mu mol/kg of 17 beta-est radiol, a dose-reflective of daily exposure levels in the hamster mode l of nephrocarcinogenicity, 12% of the dose is recovered within 5 h as a combination of GSH conjugates of 2- and 4-hydroxy-17 beta-estradiol and 2- and 4-hydroxyestrone. In summary, oxidation of catechol estrog ens, followed by GSH conjugation, occurs in vivo and 17 beta-estradiol is a mild nephrotoxicant in a manner dependent on the activity of gam ma-GT.