2-hydroxy-4-glutathion-S-yl-17β-estradiol and 2-hydroxy-1-glutathion-S-yl-17β-estradiol produce oxidative stress and renal toxicity in an animal model of 17β-estradiol-mediated nephrocarcinogenicity

• Published in: Carcinogenesis (New York) Vol. 19; no. 1; pp. 133 - 139
• Main Authors: BUTTERWORTH, M, LAU, S. S, MONKS, T. J
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 1998
• Subjects: Animal tumors. Experimental tumors; Biological and medical sciences; Experimental renal and urinary tract tumors; Medical sciences; Tumors; Kidney disease; Oxidative stress; Urinary system disease; Enzyme; Metabolite; Toxicity; Transferases; Rodentia; Estrogen; 17β-Estradiol; Pyrocatechol; Malignant tumor; Aminoacyltransferases; Carcinogenesis; Kidney; γ-Glutamyltransferase; Vertebrata; Mammalia; Animal; Sex steroid hormone; Mechanism of action; Hamster; Glutathione
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/19.1.133

Chronic exposure of male Syrian hamsters to a variety of estrogens has been linked with a high incidence of renal carcinoma. The basis of this species and tissue specificity remains to be resolved. We have recently shown that (i) 17 beta -estradiol is nephrotoxic in the hamster in a manner dependent upon the activity of gamma -glutamyl transpeptidase and (ii) 17 beta -estradiol is metabolized to a variety of catechol estrogen glutathione conjugates. We report that the catechol estrogen glutathione conjugates exhibit redox properties similar to those of the catechol estrogens, and maintain the ability to generate superoxide radicals. Administration of 2-hydroxy-4-glutathion-S-yl-17 beta -estradiol or 2-hydroxy-1-glutathion-S-yl-17 beta -estradiol (0.27-5.0 mu mol/kg) to Syrian hamsters, produces mild nephrotoxicity. Repeated daily administration of 2-hydroxy-4-glutathion-S-yl-17 beta -estradiol causes a sustained elevation in urinary markers of renal damage and in the concentration of renal protein carbonyls and lipid hydroperoxides. Catechol estrogen oxidation and conjugation of glutathione in the liver, followed by the selective uptake of the redox active conjugates in tissues rich in gamma -glutamyl transpeptidase may contribute to 17 beta -estradiol-induced renal tumors in the hamster.