title: The Effects of Fentanyl on Hepatic Mitochondrial Function.
abstract: Remifentanil interferes with hepatic mitochondrial function. The aim of the present study was to evaluate whether hepatic mitochondrial function is affected by fentanyl, a more widely used opioid than remifentanil.
  
  
  
  Human hepatoma HepG2 cells were exposed to fentanyl or pretreated with naloxone (an opioid receptor antagonist) or 5-hydroxydecanoate (5-HD, an inhibitor of mitochondrial adenosine triphosphate (ATP)-sensitive potassium [mitoKATP] channels), followed by incubation with fentanyl. Mitochondrial function and metabolism were then analyzed.
  
  
  
  Fentanyl marginally reduced maximal mitochondrial complex-specific respiration rates using exogenous substrates (decrease in medians: 11%-18%; P = 0.003-0.001) but did not affect basal cellular respiration rates (P = 0.834). The effect on stimulated respiration was prevented by preincubation with naloxone or 5-HD. Fentanyl reduced cellular ATP content in a dose-dependent manner (P < 0.001), an effect that was not significantly prevented by 5-HD and not explained by increased total ATPase concentration. However, in vitro ATPase activity of recombinant human permeability glycoprotein (an ATP-dependent drug efflux transporter) was significantly stimulated by fentanyl (P = 0.004).
  
  
  
  Our data suggest that fentanyl reduces stimulated mitochondrial respiration of cultured human hepatocytes by a mechanism that is blocked by a mitoKATP channel antagonist. Increased energy requirements for fentanyl efflux transport may offer an explanation for the substantial decrease in cellular ATP concentration.
authors.affiliation: From the *Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; and †Department of Clinical Research, Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Siamak
authors.initials: S
authors.lastname: Djafarzadeh
authors.forename: Madhusudanarao
authors.initials: M
authors.lastname: Vuda
authors.forename: Victor
authors.initials: V
authors.lastname: Jeger
authors.forename: Jukka
authors.initials: J
authors.lastname: Takala
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Jakob
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000819:agonists / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005283:Fentanyl / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D006880:Hydroxy Acids / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000701:Analgesics, Opioid; D003652:Decanoic Acids; D045222:Electron Transport Chain Complex Proteins; D006880:Hydroxy Acids; D009292:Narcotic Antagonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D009270:Naloxone; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D005283:Fentanyl