Targets of chloroacetaldehyde-induced nephrotoxicity.
Chloroacetaldehyde, one of the main products of hepatic ifosfamide metabolism, contributes to its nephrotoxicity. However, the pathophysiology of this toxicity is not fully understood. The present work examined the time and dose effects of clinically relevant concentrations of chloroacetaldehyde (25-75microM) on precision-cut rat renal cortical slices metabolizing a physiological concentration of lactate. Chloroacetaldehyde toxicity was demonstrated by the decrease in total glutathione and cellular ATP levels. The drop of cellular ATP was linked to the inhibition of oxidative phosphorylation at the level of complex I of the mitochondrial respiratory chain. The large decrease in glucose synthesis from lactate was explained by the inhibition of some gluconeogenic enzymes, mainly glyceraldehyde 3-phosphate dehydrogenase. The decrease in lactate utilization was demonstrated not only by a defect of gluconeogenesis but also by the decrease in [(14)CO(2)] formation from [U-(14)C]-lactate. All the effects of chloroacetaldehyde were concentration and time-dependent. Finally, the chloroacetaldehyde-induced inhibition of glyceraldehyde 3-phosphate dehydrogenase, which is also a glycolytic enzyme, suggests that, under conditions close to those found during ifosfamide therapy, the inhibition of glycolytic pathway by chloroacetaldehyde might be responsible, at least in part, for the therapeutic efficacy of ifosfamide.
Knouzy
Burhan
B
Université Lyon1, Faculté de médecine Laennec, Lyon Cedex 08, France.
Dubourg
Laurence
L
Baverel
Gabriel
G
Michoudet
Christian
C
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D004791:Enzyme Inhibitors / Q000633:toxicity; D004798:Enzymes / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology*; D007700:Kinetics; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism
D004791:Enzyme Inhibitors; D004798:Enzymes; D013438:Sulfhydryl Compounds; D019344:Lactic Acid; D000255:Adenosine Triphosphate; C004656:chloroacetaldehyde; D005978:Glutathione; D000079:Acetaldehyde