Cisplatin nephrotoxicity is mediated by gamma glutamyltranspeptidase, not via a C-S lyase governed biotransformation pathway

• Published in: Toxicology (Amsterdam) 2008-07, Vol.249 (2), p.184-193
• Main Authors: Wainford, Richard D., Weaver, Richard J., Stewart, Keith N., Brown, Paul, Hawksworth, Gabrielle M.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - metabolism; Antineoplastic Agents - toxicity; Biological and medical sciences; Biotransformation; Body Weight - drug effects; Cell Separation; Cisplatin; Cisplatin - metabolism; Cisplatin - toxicity; Enzyme Inhibitors - pharmacology; gamma-Glutamyltransferase - antagonists & inhibitors; gamma-Glutamyltransferase - physiology; Human proximal tubular cell cultures; Humans; In vivo; Kidney Diseases - chemically induced; Kidney Diseases - pathology; Kidney Diseases - physiopathology; Kidney Function Tests; Kidney Tubular Necrosis, Acute - chemically induced; Kidney Tubular Necrosis, Acute - pathology; Lyases - antagonists & inhibitors; Lyases - physiology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nephrotoxicity; Rat proximal tubular cell cultures; Rats; Rats, Sprague-Dawley; Species Specificity; Toxicology
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2008.05.006

Cisplatin exhibits dose-limiting nephrotoxicity in rodents and man. This study investigates the mechanism of cisplatin nephrotoxicity in vivo and in an in vitro model system. Nephrotoxicity was induced in rats (6 mg/kg cisplatin i.p.) and mice (10 mg/kg cisplatin i.p.). Cisplatin administration significantly elevated blood urea nitrogen (BUN) and serum creatinine in male Sprague Dawley rats day 5 post-treatment (BUN Δ + 28 ± 5 μmol/ml; serum creatinine Δ + 108 ± 4 nmol/ml, P < 0.05) and in male C57BL6 mice day 4 post-treatment (BUN Δ + 21 ± 4 μmol/ml; serum creatinine Δ + 81 ± 5 nmol/ml, P < 0.05). Nephrotoxicity was confirmed by histological analysis that revealed significant damage to the proximal tubules of cisplatin- versus saline vehicle-treated animals. Inhibition of gamma glutamyltranspeptidase prevented cisplatin nephrotoxicity in Sprague Dawley rats (day 5 BUN Δ + 1 ± 2 μmol/ml; serum creatinine Δ + 8 ± 4 nmol/ml) and C57BL6 mice (day 4 BUN Δ + 1 ± 0.8 μmol/ml; serum creatinine Δ − 1 ± 2 nmol/ml), but not cellular toxicity in rat proximal tubular (RPT) or human proximal tubular (HPT) cultures. Inhibition of aminopeptidase N (AP-N) or renal dipeptidase (RDP) in male Sprague Dawley rats, or in RPT and HPT cell cultures, did not reduce cisplatin toxicity. In contrast to published findings inhibition of C-S lyase did not prevent the nephrotoxicity of cisplatin in vivo or cellular toxicity in vitro. These data demonstrate that the biotransformation enzymes AP-N, RDP and C-S lyase are not implicated in the metabolism of cisplatin to a nephrotoxic metabolite as has been previously hypothesised. Instead, our data demonstrate that gamma glutamyltranspeptidase is a key enzyme involved in mediating cisplatin nephrotoxicity, which potentially acts to cleave cisplatin–GSH conjugates to a toxic metabolite.