title: Mitochondrial (dys)function - a factor underlying the variability of efavirenz-induced hepatotoxicity?
abstract: OBJECTIVE
  The non-nucleoside analogue reverse transcriptase inhibitor efavirenz is associated with hepatic toxicity and metabolic disturbances. Although the mechanisms involved are not clear, recent evidence has pinpointed a specific mitochondrial action of efavirenz accompanied by the induction of an endoplasmic reticulum (ER) stress/unfolded protein response in human hepatic cells. The aim of this study was to further investigate the involvement of this organelle by evaluating efavirenz's effects in cells lacking functional mitochondria (rho°) and comparing them with those of the typical mitotoxic agent rotenone, a standard complex I inhibitor, and the ER stress inducer thapsigargin.
  
  
  METHODS
  Hep3B rho(+) and rho° cells were treated with clinically relevant concentrations of efavirenz, then mitochondrial function and cytotoxicity were studied using standard cell biology techniques.
  
  
  RESULTS
  Efavirenz-treated rho° cells exhibited a substantial reduction in parameters indicative of mitochondrial interference, such as increased superoxide production, mitochondrial mass/morphology alterations and enhanced expression of LONP, a highly conserved mitochondrial protease. In line with these results, the cytotoxic effect (cell number, chromatin condensation, cell cycle alterations and induction of apoptosis) of efavirenz was less pronounced in Hep3B respiration-depleted cells than in wild-type cells. The effect of efavirenz was both similar and different from those of two distinct mitochondrial stressors, thapsigargin and rotenone.
  
  
  CONCLUSIONS
  Cells lacking normal mitochondria (rho°) are less vulnerable to efavirenz. Our results provide further evidence that the hepatic damage induced by efavirenz involves acute interference with mitochondria and extend our knowledge of the response of mitochondria/ER to a stress stimulus.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universitat de Valencia, Valencia, Spain; FISABIO-Hospital Universitario Dr Peset, Valencia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Polo
authors.forename: F
authors.initials: F
authors.lastname: Alegre
authors.forename: H A
authors.initials: HA
authors.lastname: Funes
authors.forename: A
authors.initials: A
authors.lastname: Blas-Garcia
authors.forename: V M
authors.initials: VM
authors.lastname: Victor
authors.forename: J V
authors.initials: JV
authors.lastname: Esplugues
authors.forename: N
authors.initials: N
authors.lastname: Apostolova
mesh_terms: D000480:Alkynes; D048588:Benzoxazines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D003521:Cyclopropanes; D004272:DNA, Mitochondrial / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz