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Enhanced oxidative stress and increased mitochondrial mass during Efavirenz-induced apoptosis in human hepatic cells

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Enhanced oxidative stress and increased mitochondrial mass during Efavirenz-induced apoptosis in human hepatic cells

dc.contributor.author	Apostolova, Nadezda	es_ES
dc.contributor.author	Gómez Sucerquia, Leysa Jackeline	es_ES
dc.contributor.author	Moran, A	es_ES
dc.contributor.author	Alvarez, A	es_ES
dc.contributor.author	Blas García, Ana	es_ES
dc.contributor.author	Esplugues Mota, Juan Vicente	es_ES
dc.date.accessioned	2015-06-29T10:34:11Z
dc.date.available	2015-06-29T10:34:11Z
dc.date.issued	2010	es_ES
dc.identifier.citation	British Journal of Pharmacology Vol. 160 Issue 8: pp. 2069-2084	es_ES
dc.identifier.uri	http://hdl.handle.net/10550/44813
dc.description.abstract	BACKGROUND AND PURPOSEEfavirenz (EFV) is widely used in the treatment of HIV-1 infection. Though highly efficient, there is growing concern about EFV-related side effects, the molecular basis of which remains elusive.EXPERIMENTAL APPROACHIn vitro studies were performed to address the effect of clinically relevant concentrations of EFV (10, 25 and 50 µM) on human hepatic cells.KEY RESULTSCellular proliferation and viability were reduced in a concentration-dependent manner. Analyses of the cell cycle and several cell death parameters (chromatin condensation, phosphatidylserine exteriorization, mitochondrial proapoptotic protein translocation and caspase activation) revealed that EFV triggered apoptosis via the intrinsic pathway. In addition, EFV directly affected mitochondrial function in a reversible manner, inducing a decrease in mitochondrial membrane potential and an increase in mitochondrial superoxide production, followed by a reduction in cellular glutathione content. The rapidity of these actions rules out any involvement of mitochondrial DNA replication, which, until now, was thought to be the main mechanism of mitochondrial toxicity of antiretroviral drugs. Importantly, we also observed an increase in mitochondrial mass, manifested as an elevated cardiolipin content and enhanced expression of mitochondrial proteins, which was not paralleled by an increase in the mtDNA/nuclear DNA copy number ratio. The toxic effect of EFV was partially reversed by antioxidant pretreatment, which suggests ROS generation is involved in this effect.CONCLUSION AND IMPLICATIONSClinically relevant concentrations of EFV were shown to be mitotoxic in human hepatic cells in vitro, which may be pertinent to the understanding of the hepatotoxicity associated with this drug.	es_ES
dc.subject	reactive oxygen species	es_ES
dc.subject	antiretroviral drugs	es_ES
dc.subject	hepatotoxicity	es_ES
dc.subject	cell death	es_ES
dc.subject	side effects	es_ES
dc.subject	Efavirenz	es_ES
dc.subject	mitochondria	es_ES
dc.title	Enhanced oxidative stress and increased mitochondrial mass during Efavirenz-induced apoptosis in human hepatic cells	es_ES
dc.type	journal article	es_ES
dc.identifier.doi	10.1111/j.1476-5381.2010.00866.x	es_ES
dc.identifier.idgrec	073684	es_ES