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

Michael Butterworth, Serrine Lau, Terrence Monks

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36 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)561-567
Number of pages7
JournalCarcinogenesis
Volume18
Issue number3
DOIs
StatePublished - Mar 1997
Externally publishedYes

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Catechol Estrogens
gamma-Glutamyltransferase
Mesocricetus
Glutathione
Estradiol
Estrone
acivicin
Cricetinae
Carcinogenesis
Kidney
Species Specificity
Organ Specificity
Lipid Peroxides
Sulfides

ASJC Scopus subject areas

  • Cancer Research

Cite this

@article{35e9d18b64364beab4fd616cf39bed15,
title = "Formation of catechol estrogen glutathione conjugates and γ-glutamyl transpeptidase-dependent nephrotoxicity of 17β-estradiol in the golden Syrian hamster",
abstract = "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.",
author = "Michael Butterworth and Serrine Lau and Terrence Monks",
year = "1997",
month = "3",
doi = "10.1093/carcin/18.3.561",
language = "English (US)",
volume = "18",
pages = "561--567",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "3",

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TY - JOUR

T1 - Formation of catechol estrogen glutathione conjugates and γ-glutamyl transpeptidase-dependent nephrotoxicity of 17β-estradiol in the golden Syrian hamster

AU - Butterworth, Michael

AU - Lau, Serrine

AU - Monks, Terrence

PY - 1997/3

Y1 - 1997/3

N2 - 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.

AB - 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.

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U2 - 10.1093/carcin/18.3.561

DO - 10.1093/carcin/18.3.561

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