Formation of catechol estrogen glutathione conjugates and γ-glutamyl transpeptidase-dependent nephrotoxicity of 17β-estradiol in the golden Syrian hamster

In an animal model of hormone-mediated carcinogenesis, male golden Syrian hamsters develop renal carcinoma following prolonged exposure to 17β-estradiol. The basis for the species and tissue specificity is unclear. Detailed information on the disposition of 17β-estradiol in this model is lacking. Because catechol estrogens have been implicated in this model of carcinogenesis, we investigated the metabolism and nephrotoxicity of 17β-estradiol in golden Syrian hamsters, with emphasis on the formation of catechol estrogen thioethers. 17β-Estradiol (50 μmol/kg, i.p.) is a mild nephrotoxicant, causing significant elevations in the urinary excretion of γ-glutamyl transpeptidase (γ-GT), alkaline phosphatase, glutathione S-transferase (GST) and glucose. Increases in renal protein carbonyls and lipid hydroperoxides, which are markers of oxidative damage, also occur after administration of 17β-estradiol (50 μmol/kg, i.p.). 17β-Estradiol-mediated nephrotoxicity is reduced by treating animals with acivicin, an inhibitor of γ-GT, implying that toxicity is mediated by metabolites requiring metabolism by this enzyme. Following administration of 17β-[¹⁴C]estradiol (100 μmol/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)-17β-estradiol, 2-hydroxy-4-(glutathion-S-yl)-17β-estradiol, 2-hydroxy-4-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-estrone, 2-hydroxy-1-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-17β-estradiol, and 2-hydroxy-1-(glutathion-S-yl)-17β-estradiol. At 5.4 μmol/kg of 17β-estradiol, a dose-reflective of daily exposure levels in the hamster model of nephrocarcinogenicity, 12% of the dose is recovered within 5 h as a combination of GSH conjugates of 2- and 4-hydroxy-17β-estradiol and 2- and 4-hydroxyestrone. In summary, oxidation of catechol estrogens, followed by GSH conjugation, occurs in vivo and 17β-estradiol is a mild nephrotoxicant in a manner dependent on the activity of γ-GT.