ER stress in human hepatic cells treated with Efavirenz: Mitochondria again

作者：Apostolova Nadezda^*; Gomez Sucerquia Leysa J; Alegre Fernando; Funes Haryes A; Victor Victor M; Barrachina Maria D; Blas Garcia Ana; Esplugues Juan V

来源：Journal of Hepatology, 2013, 59(4): 780-789.

DOI：10.1016/j.jhep.2013.06.005

• ER stress
• Hepatotoxicity
• HIV
• Efavirenz
• Mitochondria
• Side effects

Background %26 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. %26lt;br%26gt;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. %26lt;br%26gt;Results: ER stress markers, including CHOP and GRP78 expression (both protein and mRNA), phosphorylation of eIF2a, 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 Rho degrees). 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. %26lt;br%26gt;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 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.

• 出版日期2013-10