Targets of chloroacetaldehyde-induced nephrotoxicity

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• 作者：Burhan Knouzy ; Laurence Dubourg ; Gabriel Baverel ; Christian Michoudet
• 关键词：Ifosfamide ; Chloroacetaldehyde ; Kidney ; Toxicity ; Precision-cut slices
• 刊名：Toxicology in Vitro
• 出版年：2010
• 出版时间：February 2010
• 年：2010
• 卷：24
• 期：1
• 页码：99-107
• 全文大小：380 K

文摘

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 (25–75 μM) 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 [¹⁴CO₂] formation from [U-¹⁴C]-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.