Role of glutathione S-transferase Pi in cisplatin-induced nephrotoxicity.
One of the dose-limiting toxicities of cisplatin is nephrotoxicity. Renal toxicity is localized to quiescent proximal tubule cells, where the formation of DNA-adducts cannot account for the dose-limiting toxicity. Our earlier results have shown that a glutathione conjugate of cisplatin is metabolized to a nephrotoxicant via gamma-glutamyl transpeptidase (GGT) and a cysteine S-conjugate beta-lyase. The present study was designed to evaluate the potential role of glutathione S-transferase Pi (GSTP) in the initial steps of the bioactivation of cisplatin. Wild-type mice and mice deficient in both murine GSTP genes (GstP1/P2) were treated with cisplatin. Toxicity in both male and female mice was evaluated 5 days after treatment and renal damage was most severe in wild-type male mice. Wild-type males have approximately 10-fold higher levels of GSTP expression in the liver than females, suggesting that hepatic GSTP in the wild-type males contributed to the formation of the nephrotoxic platinum-glutathione conjugate. In GstP1/P2 null mice the gender difference in toxicity was eliminated. Our data show that GSTP expression is a determinant in cisplatin-induced nephrotoxicity and its levels contribute to sex-dependent differences.
Townsend
Danyelle M
DM
Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, 173 Ashley Avenue, P.O. Box 250505, Charleston, SC 29425, USA.
Tew
Kenneth D
KD
He
Lin
L
King
Jarrod B
JB
Hanigan
Marie H
MH
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D013437:Carbon-Sulfur Lyases / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012720:Severity of Illness Index; D012737:Sex Factors; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D000970:Antineoplastic Agents; D005723:gamma-Glutamyltransferase; D051549:Glutathione S-Transferase pi; C496557:Gstp1 protein, mouse; D013437:Carbon-Sulfur Lyases; C108902:cysteine-S-conjugate beta-lyase; D002945:Cisplatin