title: Ifosfamide toxicity in cultured proximal renal tubule cells.
abstract: Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that ifosfamide metabolites, particularly chloroacetaldehyde, produced within the kidney contribute to nephrotoxicity. The present study examined the effects of ifosfamide and its metabolites, chloroacetaldehyde and acrolein, on rabbit proximal renal tubule cells in primary culture, using a transwell culture system that allows separate access to apical and basolateral cell surfaces. The ability of the uroprotectant medications sodium 2-mercaptoethanesulfonate (mesna) and amifostine to prevent chloroacetaldehyde-and acrolein-induced renal cell injury was also assessed. Ifosfamide (2,000-4,000 microM) did not affect transcellular inulin diffusion but caused a modest but significant impairment in organic ion transport; this impairment was greater when ifosfamide was added to the basolateral compartment of the transwell. Chloroacetaldehyde and acrolein (6.25-100 microM) produced dose-dependent impairments in transcellular inulin diffusion and organic ion transport. Chloroacetaldehyde was a more potent toxin than acrolein. Co-administration of mesna or amifostine prevented metabolite toxicity. Amifostine was only protective when added to the apical compartment of transwells. These results show that ifosfamide is taken up by renal tubule cells preferentially through their basolateral surfaces, and supports the hypothesis that chloroacetaldehyde is primarily responsible for ifosfamide-induced nephrotoxicity. The protective effect of mesna and amifostine in vitro contrasts with clinical experience showing that these medications do not eliminate ifosfamide nephrotoxicity in vivo.
authors.affiliation: Department of Pediatrics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, and Division of Nephrology, Women's & Children's Hospital, Buffalo, NY 14214, USA. jspringate@upa.chob.edu
authors.forename: James
authors.initials: J
authors.lastname: Springate
authors.forename: Mary
authors.initials: M
authors.lastname: Taub
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000633:toxicity; D000171:Acrolein / Q000494:pharmacology; D004999:Amifostine / Q000494:pharmacology; D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007069:Ifosfamide / Q000633:toxicity*; D007444:Inulin / Q000493:pharmacokinetics; D017136:Ion Transport / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D015080:Mesna / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology; D011817:Rabbits; D019789:Tetraethylammonium / Q000493:pharmacokinetics; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics
chemical_list: D020011:Protective Agents; D019789:Tetraethylammonium; D000171:Acrolein; D007444:Inulin; C004656:chloroacetaldehyde; D000079:Acetaldehyde; D004999:Amifostine; D015080:Mesna; D007069:Ifosfamide; D010130:p-Aminohippuric Acid