Inhibition of γ-Glutamyl Transpeptidase or CysteineS-Conjugate β-Lyase Activity Blocks the Nephrotoxicity of Cisplatin in Mice
- 1 January 2002
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 300 (1), 142-148
- https://doi.org/10.1124/jpet.300.1.142
Abstract
Cisplatin is nephrotoxic. The mechanism underlying this organ-specific toxicity is unknown. We hypothesize that cisplatin is metabolized via a γ-glutamyl transpeptidase (GGT) and cysteineS-conjugate β-lyase-dependent pathway that has been shown to activate several haloalkenes to nephrotoxins. To test this hypothesis, we inhibited GGT and cysteine S-conjugate β-lyase in C57BL/6 mice and analyzed the effect of the inhibitors on the nephrotoxicity of cisplatin. GGT was inhibited by pretreating the mice with acivicin. Cysteine S-conjugate β-lyase was inhibited by aminooxyacetic acid (AOAA). Male C57BL/6 mice were treated with 15 mg/kg cisplatin (i.p.) and sacrificed on day 5. Half the mice treated with cisplatin alone died before sacrifice. The cisplatin-treated mice sacrificed at 5 days had significantly elevated levels of blood urea nitrogen (BUN). Histologic analysis revealed severe damage to the renal proximal tubules. Pretreatment with acivicin or AOAA protected the mice from the nephrotoxicity of cisplatin. None of the pretreated animals died before sacrifice. BUN levels and quantitative histologic analysis of the kidneys confirmed the protective effect of acivicin and AOAA. Platinum levels in the kidneys were not altered by acivicin or AOAA, indicating that neither affected the uptake of cisplatin into the kidney. Likewise, cisplatin-induced weight loss was not altered by acivicin or AOAA, suggesting that weight loss and nephrotoxicity are via distinct mechanisms. These data support the hypothesis that the nephrotoxicity of cisplatin is due to the metabolism of a platinum-glutathione conjugate by GGT and cysteineS-conjugate β-lyase to a potent nephrotoxin.Keywords
This publication has 34 references indexed in Scilit:
- The Molecular Evolution of Pyridoxal‐5′‐Phosphate‐Dependent EnzymesAdvances in enzymology and related areas of molecular biology, 2000
- Expression of γ-glutamyl transpeptidase in stage III and IV ovarian surface epithelial carcinomas does not alter response to primary cisplatin-based chemotherapyAmerican Journal of Obstetrics and Gynecology, 1998
- GLUTATHIONE-DEPENDENT BIOACTIVATION OF HALOALKENESAnnual Review of Pharmacology and Toxicology, 1998
- Immunohistochemical detection of gamma-glutamyl transpeptidase in normal human tissue.Journal of Histochemistry & Cytochemistry, 1996
- Biotransformation and Membrane Transport in NephrotoxicityCritical Reviews in Toxicology, 1996
- Nephrotoxicity mechanism of cis-platinum (II) diamine dichloride in miceToxicology Letters, 1994
- Bioactivation of nephrotoxins and renal carcinogens by glutathione S-conjugate formationToxicology Letters, 1993
- Biotransformation of the hexachlorobutadiene metabolites 1-(glutathion-S-yl)-pentachlorobutadiene and 1-(cystein-S-yl)-pentachlorobutadiene in the isolated perfused rat liverXenobiotica, 1992
- The in vivo disposition of 2-bromo-[14C]hydroquinone and the effect of γ-glutamyl transpeptidase inhibitionToxicology and Applied Pharmacology, 1990
- Role of γ-glutamyltranspeptidase and β-lyase in the nephrotoxicity of hexachloro-1,3-butadiene and methyl mercury in miceToxicology Letters, 1990