title: Lack of mitochondrial toxicity of darunavir, raltegravir and rilpivirine in neurons and hepatocytes: a comparison with efavirenz.
abstract: OBJECTIVE
  Growing evidence associates the non-nucleoside reverse transcriptase inhibitor efavirenz with several adverse events. Newer antiretrovirals, such as the integrase inhibitor raltegravir, the non-nucleoside reverse transcriptase inhibitor rilpivirine and the protease inhibitor darunavir, claim to have a better toxicological profile than efavirenz while producing similar levels of efficacy and virological suppression. The objective of this study was to determine the in vitro toxicological profile of these three new antiretrovirals by evaluating their effects on the mitochondrial and cellular parameters altered by efavirenz in hepatocytes and neurons.
  
  
  METHODS
  Hep3B cells and primary rat neurons were treated with clinically relevant concentrations of efavirenz, darunavir, rilpivirine or raltegravir. Parameters of mitochondrial function, cytotoxicity and oxidative and endoplasmic reticulum stress were assessed using standard cell biology techniques.
  
  
  RESULTS
  None of the new compounds altered the mitochondrial function of hepatic cells or neurons, while efavirenz decreased mitochondrial membrane potential and enhanced superoxide production in both cell types, effects that are known to significantly compromise the functioning of mitochondria, cell viability and, ultimately, cell number. Of the four drugs assayed, efavirenz was the only one to alter the protein expression of LC3-II, an indicator of autophagy, and CHOP, a marker of endoplasmic reticulum stress and the unfolded protein response.
  
  
  CONCLUSIONS
  Darunavir, rilpivirine and raltegravir do not induce toxic effects on Hep3B cells and primary rat neurons, which suggests a safer hepatic and neurological profile than that of efavirenz.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain ana.blas@uv.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Blas-García
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Polo
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Alegre
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
authors.forename: Haryes A
authors.initials: HA
authors.lastname: Funes
authors.affiliation: Hospital Clínic-IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Martínez
authors.affiliation: Facultad de Ciencias de la Salud, Universidad Jaime I, Castellón de la Plana, Spain CIBERehd, Valencia, Spain.
authors.forename: Nadezda
authors.initials: N
authors.lastname: Apostolova
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain CIBERehd, Valencia, Spain.
authors.forename: Juan V
authors.initials: JV
authors.lastname: Esplugues
mesh_terms: D000480:Alkynes; D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity; D048588:Benzoxazines / Q000633:toxicity*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003521:Cyclopropanes; D000069454:Darunavir; D024882:Drug Resistance, Viral / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D011760:Pyrrolidinones / Q000633:toxicity*; D000068898:Raltegravir Potassium; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity; D000068696:Rilpivirine; D013449:Sulfonamides / Q000633:toxicity*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009570:Nitriles; D011743:Pyrimidines; D011760:Pyrrolidinones; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D000068898:Raltegravir Potassium; D000068696:Rilpivirine; C098320:efavirenz; D000069454:Darunavir
keywords: CNS; HIV; adverse effects; hepatotoxicity; mitochondria