title: The purine analogues abacavir and didanosine increase acetaminophen-induced hepatotoxicity by enhancing mitochondrial dysfunction.
abstract: BACKGROUND
  NRTIs are essential components of HIV therapy with well-documented, long-term mitochondrial toxicity in hepatic cells, but whose acute effects on mitochondria are unclear. As acetaminophen-induced hepatotoxicity also involves mitochondrial interference, we hypothesized that it would be exacerbated in the context of ART.
  
  
  METHODS
  We evaluated the acute effects of clinically relevant concentrations of the most widely used NRTIs, alone or combined with acetaminophen, on mitochondrial function and cellular viability.
  
  
  RESULTS
  The purine analogues abacavir and didanosine produced an immediate and concentration-dependent inhibition of oxygen consumption and complex I and III activity. This inhibition was accompanied by an undermining of mitochondrial function, with increased production of reactive oxygen species and reduction of mitochondrial membrane potential and intracellular ATP levels. However, this interference did not compromise cell survival. Co-administration with concentrations of acetaminophen below those considered hepatotoxic exacerbated the deleterious effects of both compounds on mitochondrial function and compromised cellular viability, showing a clear correlation with diminished glutathione levels.
  
  
  CONCLUSIONS
  The simultaneous presence of purine analogues and low concentrations of acetaminophen significantly potentiates mitochondrial dysfunction, increasing the risk of liver injury. This new mechanism is relevant given the liver's susceptibility to mitochondrial dysfunction-related toxicity and the tendency of the HIV infection to increase oxidative stress.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain FISABIO-Hospital Universitario Doctor Peset, Valencia, Spain CIBERehd, 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martí-Rodrigo
authors.affiliation: FISABIO-Hospital Universitario Doctor Peset, Valencia, Spain CIBERehd, Valencia, Spain.
authors.forename: Víctor M
authors.initials: VM
authors.lastname: Víctor
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain FISABIO-Hospital Universitario Doctor 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 Doctor 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: Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain CIBERehd, Valencia, Spain Facultad de Ciencias de la Salud, Universidad Jaime I, Castellón de la Plana, 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 Doctor Peset, Valencia, Spain CIBERehd, Valencia, Spain.
authors.forename: Juan V
authors.initials: JV
authors.lastname: Esplugues
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D019380:Anti-HIV Agents / Q000633:toxicity*; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D016049:Didanosine / Q000633:toxicity*; D015224:Dideoxynucleosides / Q000633:toxicity*; D045222:Electron Transport Chain Complex Proteins / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008930:Mitochondria, Liver / Q000187:drug effects*; D028361:Mitochondrial Diseases / Q000139:chemically induced*; D010101:Oxygen Consumption / Q000187:drug effects; D026361:Reactive Nitrogen Species / Q000378:metabolism; D000099227:Abacavir
chemical_list: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D019380:Anti-HIV Agents; D016049:Didanosine; D015224:Dideoxynucleosides; D045222:Electron Transport Chain Complex Proteins; D005978:Glutathione; D026361:Reactive Nitrogen Species; D000099227:Abacavir