Desipramine Ameliorates Cr(VI)-Induced Hepatocellular Apoptosis via the Inhibition of Ceramide Channel Formation and Mitochondrial PTP Opening
Desipramine Ameliorates Cr(VI)-Induced Hepatocellular Apoptosis via the Inhibition of Ceramide Channel Formation and Mitochondrial PTP Opening
复制标题
地昔帕明通过抑制神经酰胺通道形成和线粒体 PTP 打开来改善 Cr(VI) 诱导的肝细胞凋亡
DOI：
10.1159/000369657
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发表时间：
2014-01-01
影响因子：
--
通讯作者：
Zhong, Caigao
中科院分区：
文献类型：
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作者：
Luo, Lei;Xie, Ying;Zhong, Caigao
背景：六价铬是一种常见的环境污染物。铬(VI)暴露可导致肝脏严重损伤，但减轻铬(VI)肝毒性的预防措施有待进一步研究。酸性鞘磷脂酶(ASMase)负责神经酰胺的产生，通过神经鞘蛋白的水解酶。本研究旨在探讨天冬氨酸氨基转移酶(ASMase)抑制剂地昔帕明(DES)对铬(VI)肝毒性的影响。方法：将L-02肝细胞与不同浓度的六价铬共同孵育24小时，测定ASMase活性和神经酰胺含量。此外，该研究还研究了DES在ASMase活性和神经酰胺水平中所起的作用。最后，检测DES对线粒体通透性转换孔(PTP)和PTP开放成分的mRNA和蛋白表达的影响。结果：铬(VI)可使L-02肝细胞ASMase活性和神经酰胺含量升高。结果表明，与铬(VI)组相比，DES和Cr(VI)联合处理组的细胞凋亡率、ASMase活性和神经酰胺含量均降低。此外，DES还通过干预线粒体PTP各组分的mRNA和蛋白表达，抑制了铬(VI)诱导的线粒体PTP开放。结论：DES对六价铬诱导的肝细胞凋亡具有保护作用，其机制可能与抑制神经酰胺通道的形成和线粒体PTP的开放有关。版权所有(C)2014年S.Karger AG，巴塞尔
Background: Hexavalent chromium (Cr(VI)) is a common environmental pollutant. Cr(VI) exposure can lead to severe damage in the liver, but the preventive measures to diminish Cr(VI)induced hepatotoxicity need further study. Acid sphingomyelinase (ASMase) is responsible for the production of ceramide via the hydrolysis of sphingomyelin. The present study was designed to investigate effects of desipramine (DES), as an ASMase inhibitor, on Cr(VI)-induced hepatotoxicity. Methods: L-02 hepatocytes were incubated with different concentrations of Cr(VI) for 24h, and ASMase activities and ceramide levels were measured. Moreover, the study investigated the role of DES played in ASMase activities and ceramide levels. Finally, effects of DES on mRNA and protein expressions of the components of mitochondrial permeability transition pore (PTP) and PTP opening were detected. Results: The ASMase activities and ceramide contents increased in L-02 hepatocytes treated with Cr(VI). The results demonstrated that apoptosis rates, ASMase activities and ceramide content decreased in groups treated with the combination of DES and Cr(VI) compared to Cr(VI) groups. Furthermore, DES inhibited Cr(VI)-induced mitochondrial PTP opening by intervening the mRNA and protein expressions of the components of mitochondrial PTP. Conclusions: DES may exert protective effects on Cr(VI)-induced hepatocellular apoptosis probably by inhibiting ceramide channel formation and mitochondrial PTP opening. Copyright (C) 2014 S. Karger AG, Basel