Human kidney tubules detoxify chloroacetaldehyde, a presumed nephrotoxic metabolite of ifosfamide.
The nephrotoxic effects of the antineoplastic drug ifosfamide have been attributed to its hepatic metabolite chloroacetaldehyde. The effects of chloroacetaldehyde on isolated human kidney cortex tubules metabolizing lactate (a physiologic substrate in human kidneys) were investigated. At concentrations of > or =0.5 mM, chloroacetaldehyde was toxic to the human kidney tubules, as demonstrated by a dramatic decrease in cellular ATP levels and a large increase in lactate dehydrogenase release; chloroacetaldehyde also stimulated pyruvate accumulation and inhibited lactate removal and glucose synthesis. These effects, which were associated with incomplete disappearance of chloroacetaldehyde and extensive depletion of the cellular CoA, acetyl-CoA, and glutathione contents, were prevented by the addition of thiol-protecting drugs (mesna and amifostine). Human kidney tubules were demonstrated to metabolize chloroacetaldehyde at high rates, presumably via aldehyde dehydrogenase, which is very active in human kidneys. Carbon-13 nuclear magnetic resonance spectroscopy measurements indicated that human kidney tubules converted [2-(13)C]chloroacetaldehyde to [2-(13)C]chloroacetate, the further metabolism of which was very limited. At equimolar concentrations, chloroacetate was much less toxic than chloroacetaldehyde, indicating that chloroacetate synthesis from chloroacetaldehyde by human kidney tubules represents a detoxification mechanism that could play a role in vivo in preventing or limiting the nephrotoxic effects observed during ifosfamide therapy.
Dubourg
Laurence
L
Laboratory of Metabolic and Renal Physiopathology, Institut National de la Santé et de la Recherche Médicale Unit 499, Faculty of Medicine R. T. H. Laënnec, Lyon, France.
Michoudet
Christian
C
Laboratory of Metabolic and Renal Physiopathology, Institut National de la Santé et de la Recherche Médicale Unit 499, Faculty of Medicine R. T. H. Laënnec, Lyon, France.
Cochat
Pierre
P
Laboratory of Metabolic and Renal Physiopathology, Institut National de la Santé et de la Recherche Médicale Unit 499, Faculty of Medicine R. T. H. Laënnec, Lyon, France.
Baverel
Gabriel
G
Laboratory of Metabolic and Renal Physiopathology, Institut National de la Santé et de la Recherche Médicale Unit 499, Faculty of Medicine R. T. H. Laënnec, Lyon, France.
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000506:poisoning*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism*; D006801:Humans; D007069:Ifosfamide / Q000378:metabolism*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects*; D007672:Kidney Cortex / Q000201:enzymology; D007684:Kidney Tubules / Q000378:metabolism / Q000502:physiology*; D019344:Lactic Acid / Q000378:metabolism; D009994:Osmolar Concentration; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D018906:Antineoplastic Agents, Alkylating; D013438:Sulfhydryl Compounds; D019344:Lactic Acid; C004656:chloroacetaldehyde; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D007069:Ifosfamide