Toxicity of ifosfamide and its metabolite chloroacetaldehyde in cultured renal tubule cells |
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Authors: | James Springate Kenneth Chan Hong Lu Sherry Davies Mary Taub |
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Affiliation: | (1) Department of Biochemistry, School of Medicine and Biomedical Sciences, State University of New York, 14214 Buffalo;(2) Department of Pediatrics, School of Medicine and Biomedical Sciences, State University of New York, 14214 Buffalo;(3) Colleges of Pharmacy and Medicine, The Ohio State University, 43210 Ohio, Columbus;(4) Present address: Division of Nephrology, The Children’s Hospital, 219 Bryant Street, 14222 Buffalo, New York |
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Abstract: | Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde may contribute to this nephrotoxicity. The present study examined the effects of ifosfamide and chloroacetaldehyde on rabbit proximal renal tubule cells in primary culture. The ability of the uroprotectant medication sodium 2-mercaptoethanesulfonate (mesna) to prevent chloroacetaldehyde-induced renal cell injury was also assessed. Chloroacetaldehyde (12.5-150 microM) produced dose-dependent declines in neutral red dye uptake, ATP levels, glutathione content, and cell growth. Coadministration of mesna prevented chloroacetaldehyde toxicity while pretreatment of cells with the glutathione-depleting agent buthionine sulfoximine enhanced the toxicity of chloroacetaldehyde. Ifosfamide (1000-10,000 microM) toxicity was detected only at concentrations of 4000 microM or greater. Analysis of media collected from ifosfamide-treated cell cultures revealed the presence of several ifosfamide metabolites, demonstrating that renal proximal tubule cells are capable of biotransforming this chemotherapeutic agent. This primary renal cell culture system should prove useful in studying the cause and prevention of ifosfamide nephrotoxicity. |
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Keywords: | chloroacetaldehyde ifosfamide sodium 2-mercaptoethanesulfonate nephrotoxicity glutathione |
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