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.
Footnotes
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This work was supported by Grant R01CA57530 (M.H.H.) from the National Cancer Institute, National Institutes of Health. This work was presented in abstract form: Townsend DM and Hanigan MH (2000) In vivo metabolism of cisplatin to a nephrotoxin by gamma-glutamyl transpeptidase and beta-lyase. Proc Am Assoc Cancer Res 41:266.
Abbreviations
- GGT
- γ-glutamyl transpeptidase
- acivicin
- α-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid
- AOAA
- aminooxyacetic acid
- BUN
- blood urea nitrogen
- PLP
- pyridoxal 5′-phosphate
- Received September 5, 2001.
- Accepted October 10, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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