Mechanisms of the ifosfamide-induced inhibition of endocytosis in the rat proximal kidney tubule.
The Fanconi syndrome is a common side effect of the chemotherapeutic agent ifosfamide. Current evidences suggest that chloroacetaldehyde (CAA), one of the main metabolites of ifosfamide activation, contributes to its nephrotoxicity. However, the pathophysiology of CAA-induced Fanconi syndrome is not fully understood. The present work examined the adverse effects of CAA on precision-cut rat renal cortical slices, which allowed studying the toxic effect of CAA on proximal endocytosis. We demonstrated that clinically relevant concentrations of CAA (< or =200 microM) are able to inhibit the uptake of horseradish peroxidase, a marker of proximal tubular cell endocytosis in renal tubular proximal cells. CAA > or =75 microM has adverse effects, both on viability parameters and on energy metabolism, as shown by the great decrease in total glutathione and ATP levels. In addition, the V-ATPase, which plays a crucial role in intracellular vesicle trafficking, was inhibited by 100 microM of CAA. By contrast, the slight decrease in Na-K-ATPase activity observed for CAA> or = 125 microM (maximum inhibition: 33%) could not totally explain the inhibition of the reabsorption processes. In conclusion, the addition of the two main adverse effects of CAA (decrease in ATP levels and inhibition of the V-ATPase) could explain the inhibition of endocytosis and the Fanconi syndrome observed during ifosfamide treatments.
Yaseen
Zeinab
Z
INSERM U 820-Métabolomique et maladies métaboliques, Faculté Laennec, 7-11 rue Paradin, Lyon cedex 08, France.
Michoudet
Christian
C
Baverel
Gabriel
G
Dubourg
Laurence
L
D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006735:Horseradish Peroxidase; D007069:Ifosfamide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; C004656:chloroacetaldehyde; D006735:Horseradish Peroxidase; D000251:Adenosine Triphosphatases; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione; D000079:Acetaldehyde; D007069:Ifosfamide