title: Metabolic deglucuronidation and demethylation of estrogen conjugates as a source of parent estrogens and catecholestrogen metabolites in Syrian hamster kidney, a target organ of estrogen-induced tumorigenesis.
abstract: Estrogen-induced tumors in kidneys of male Syrian hamsters have been postulated to arise from cells which are damaged by free radicals and other reactive species generated during metabolic redox cycling of catecholestrogens and which at the same time are exposed to excessive growth stimulation mediated by estrogen receptors. In this study, we have determined the rates of metabolic deconjugation of estrogen glucuronides and of catecholestrogen methyl ethers by cellular fractions from male hamster kidney and liver to evaluate the contribution of this process to renal pools of parent estrogens and of catecholestrogen metabolites. Lysosomes from male hamster kidney catalyzed the deconjugation of estradiol- and estrone-3 beta-D-glucuronides at rates of 51.7 and 64.6 pmol/mg protein/min, respectively, which were 65 and 34% higher than corresponding deconjugation rates by liver lysosomes. Treatment of hamsters with estradiol implants for 9 days increased lysosomal glucuronidase activities for these estrogen glucuronides by 15 to 25% in kidney and doubled the activities in liver, but it did not alter their corresponding Km values. Microsomal glucuronidase activities in kidney and liver were approximately 10 to 20% of lysosomal activities. Rates of demethylation of 2- and 4-methoxyestradiol by kidney microsomes were comparable (with Vmax values of 24 and 30 pmol/mg protein/min, respectively), whereas the rate of demethylation of 2-methoxyestradiol by liver microsomes was approximately fivefold higher than that of 4-methoxyestradiol. The rates of renal demethylation of methoxyestrogens were comparable with previously published rates of renal aromatic hydroxylation of estradiol, whereas rates of hepatic demethylation were about one-fifth of the corresponding hydroxylation rates. It is concluded that metabolic deconjugation is an important source of primary estrogens and of catecholestrogen metabolites in hamster kidney, a target of estrogen-induced tumorigenesis. The increased renal estrogen glucuronidase activity during prolonged estradiol treatment may also facilitate the development of estrogen-induced tumors in this target organ.
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Zhu
authors.forename: E N
authors.initials: EN
authors.lastname: Evaristus
authors.forename: S K
authors.initials: SK
authors.lastname: Antoniak
authors.forename: S F
authors.initials: SF
authors.lastname: Sarabia
authors.forename: M J
authors.initials: MJ
authors.lastname: Ricci
authors.forename: J G
authors.initials: JG
authors.lastname: Liehr
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D002458:Cell Fractionation; D006224:Cricetinae; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D004966:Estrogens, Conjugated (USP) / Q000378:metabolism*; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007680:Kidney Neoplasms / Q000209:etiology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D008647:Mesocricetus; D008745:Methylation; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*
chemical_list: D004966:Estrogens, Conjugated (USP); C025482:estradiol-3-glucuronide; C015856:estrone-3-glucuronide; C045018:4-methoxyestradiol; D004970:Estrone; D004958:Estradiol; D000077584:2-Methoxyestradiol; D010089:Oxidoreductases, N-Demethylating; D005966:Glucuronidase