Ifosfamide metabolite chloroacetaldehyde causes renal dysfunction in vivo.
Renal injury is a common side-effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that the ifosfamide metabolite chloroacetaldehyde may be responsible for this nephrotoxicity. The present study examined the effect of increasing amounts of intrarenally infused chloroacetaldehyde on kidney function, glutathione content and malondialdehyde formation. The ability of the uroprotectant medication sodium 2-mercaptoethanesulfonate (mesna) to prevent chloroacetaldehyde-induced renal injury was also assessed. Intrarenal chloroacetaldehyde infusion caused dose-dependent declines in glomerular filtration rate and p-aminohippuric acid clearance and increases in urine flow rate, sodium, glucose and protein excretion. These abnormalities were associated with progressive kidney glutathione depletion and malondialdehyde accumulation. Mesna infusion did not affect renal function but did cause a significant fall in kidney glutathione content. Simultaneous administration of chloroacetaldehyde and mesna only partially corrected renal functional abnormalities and prevented malondialdehyde accumulation but not glutathione depletion. These results show that the ifosfamide metabolite chloroacetaldehyde causes kidney dysfunction, glutathione depletion and lipid peroxidation in vivo. Mesna provides limited protection against chloroacetaldehyde nephrotoxicity, potentially explaining its inability to completely prevent ifosfamide-related renal injury in clinical practice.
Springate
J E
JE
Department of Pediatrics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, USA.
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D006029:Glycosuria / Q000652:urine; D007069:Ifosfamide / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D015227:Lipid Peroxidation; D008297:Male; D015080:Mesna / Q000627:therapeutic use; D011507:Proteinuria / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000652:urine
D018906:Antineoplastic Agents, Alkylating; D012964:Sodium; C004656:chloroacetaldehyde; D005978:Glutathione; D000079:Acetaldehyde; D015080:Mesna; D007069:Ifosfamide