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

Br J Pharmacol. 2010 Aug;160(8):2069-84. doi: 10.1111/j.1476-5381.2010.00866.x.


Background and purpose: Efavirenz (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 approach: In vitro studies were performed to address the effect of clinically relevant concentrations of EFV (10, 25 and 50 microM) on human hepatic cells.

Key results: Cellular 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 implications: Clinically 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes
  • Anti-HIV Agents / toxicity*
  • Antioxidants / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Benzoxazines / toxicity*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Chromans / pharmacology
  • Chromatin Assembly and Disassembly / drug effects
  • Cyclopropanes
  • Dose-Response Relationship, Drug
  • Female
  • Glutathione / metabolism
  • HeLa Cells
  • Humans
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / pathology
  • Oxidative Stress / drug effects*
  • Phosphatidylserines / metabolism
  • Superoxides / metabolism
  • Time Factors


  • Alkynes
  • Anti-HIV Agents
  • Antioxidants
  • Apoptosis Regulatory Proteins
  • Benzoxazines
  • Chromans
  • Cyclopropanes
  • Phosphatidylserines
  • Superoxides
  • Glutathione
  • efavirenz
  • 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid