Formation of catechol estrogen glutathione conjugates and gamma-glutamyl transpeptidase-dependent nephrotoxicity of 17beta-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 17beta-estradiol. The basis for the species and tissue specificity is unclear. Detailed information on the disposition of 17beta-estradiol in this model is lacking. Because catechol estrogens have been implicated in this model of carcinogenesis, we investigated the metabolism and nephrotoxicity of 17beta-estradiol in golden Syrian hamsters, with emphasis on the formation of catechol estrogen thioethers. 17beta-Estradiol (50 micromol/kg, i.p.) is a mild nephrotoxicant, causing significant elevations in the urinary excretion of gamma-glutamyl transpeptidase (gamma-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 17beta-estradiol (50 micromol/kg, i.p.). 17beta-Estradiol-mediated nephrotoxicity is reduced by treating animals with acivicin, an inhibitor of gamma-GT, implying that toxicity is mediated by metabolites requiring metabolism by this enzyme. Following administration of 17beta-[14C]estradiol (100 micromol/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)-17beta-estradiol, 2-hydroxy-4-(glutathion-S-yl)-17beta-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)-17beta-estradiol, and 2-hydroxy-1-(glutathion-S-yl)-17beta-estradiol. At 5.4 micromol/kg of 17beta-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-17beta-estradiol and 2- and 4-hydroxyestrone. In summary, oxidation of catechol estrogens, followed by GSH conjugation, occurs in vivo and 17beta-estradiol is a mild nephrotoxicant in a manner dependent on the activity of gamma-GT.
Butterworth
M
M
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin 78712, USA.
Lau
S S
SS
Monks
T J
TJ
D000469:Alkaline Phosphatase / Q000652:urine; D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002292:Carcinoma, Renal Cell / Q000139:chemically induced* / Q000378:metabolism; D006224:Cricetinae; D004958:Estradiol / Q000493:pharmacokinetics / Q000633:toxicity*; D002393:Estrogens, Catechol / Q000096:biosynthesis* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000652:urine; D006029:Glycosuria / Q000139:chemically induced; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D008871:Microvilli / Q000187:drug effects / Q000473:pathology; D010084:Oxidation-Reduction; D013440:Sulfides / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000502:physiology* / Q000652:urine
D002393:Estrogens, Catechol; D013440:Sulfides; D004958:Estradiol; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D000469:Alkaline Phosphatase; D005978:Glutathione