- 作者：Nadezda Apostolova ; Leysa J. Gomez-Sucerquia ; Fern ; o Alegre ; Haryes A. Funes ; Victor M. Victor ; Maria D. Barrachina ; Ana Blas-Garcia ; Juan V. Esplugues
- 关键词：ER ; endoplasmic reticulum ; UPR ; unfolded protein response ; PI ; protease inhibitor ; HIV1 ; human immunodeficiency virus 1 ; HCV ; hepatitis C virus ; EFV ; efavirenz ; cART ; combined antiretroviral therapy ; ¦¤¦·m ; mitochondrial membrane potential ; ROS ; reactive
- 刊名：Journal of Hepatology
- 出版年：2013
- 出版时间：October, 2013
- 年：2013
- 卷：59
- 期：4
- 页码：780-789
- 全文大小：2460 K
Background & Aims
ER stress is associated with a growing number of liver diseases, including drug-induced hepatotoxicity. The non-nucleoside analogue reverse transcriptase inhibitor Efavirenz, a cornerstone of the multidrug strategy employed to treat HIV1 infection, has been related to the development of various adverse events, including metabolic disturbances and hepatic toxicity, the mechanisms of which remain elusive. Recent evidence has pinpointed a specific mitochondrial effect of Efavirenz in human hepatic cells. This study assesses the induction of ER stress by Efavirenz in the same model and the implication of mitochondria in this process.Methods
Primary human hepatocytes and Hep3B were treated with clinically relevant concentrations of Efavirenz and parameters of ER stress were studied using standard cell biology techniques.
Results
ER stress markers, including CHOP and GRP78 expression (both protein and mRNA), phosphorylation of eIF2¦Á, and presence of the spliced form of XBP1 were upregulated. Efavirenz also enhanced cytosolic Ca2+ content and induced morphological changes in the ER suggestive of ER stress. This response was greatly attenuated in cells with altered mitochondrial function (Rho¡ã). The effects of Efavirenz on the ER, and particularly in regard to the mitochondrial involvement, differed from those elicited by a standard pharmacological ER stressor.
Conclusions
This newly discovered mechanism of cellular insult involving ER stress and UPR response may help comprehend the hepatic toxicity that has been associated with the widespread and life-long use of Efavirenz. In addition, the specificity of the actions of Efavirenz observed expands our knowledge of the mechanisms that trigger ER stress and shed some light on the mitochondria/ER interplay in drug-induced hepatic challenge.