Mechanisms of the ifosfamide-induced inhibition of endocytosis in the rat proximal kidney tubule

Abstract

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.

Drug-induced acid-base disorders

“…Another suspected pathway in rat proximal tubules is endocytosis inhibition resulting from CAA-induced decrease in ATP levels [117].…”

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

“…7 Several mechanisms for ifosfamide-induced nephrotoxicity have been reported including oxidative stress, depletion of glutathione and inhibition of endocytosis in renal tubular proximal cells. 8 Ifosfamide (IF) is metabolized by hepatic CYP3A4 and 2B6. IF mustard, which is produced by ring hydroxylation pathway, is the pharmacological active metabolite, whereas chloroacetaldehyde, which is produced from chlorethyl side oxidation, is largely believed to be responsible for the nephrotoxic effects of IF.…”

Progression of cyclophosphamide-induced acute renal metabolic damage in carnitine-depleted rat model

“…While both CP and IFO have severe urotoxic side-effects, only ifosfamide is thought to be nephrotoxic, causing tubular damage and resulting in Fanconi syndrome [4][5][6][7]. However, recent studies have demonstrated that CP has nephrotoxicity besides its urotoxicity, which both in turn limit its clinical utility [8][9][10][11][12].…”