Effects of nonvolatile agents on oxygen demand and energy status in isolated hepatocytes.
The role of hepatic energy deficits in the pathogenesis of anesthetic hepatotoxicity is suggested by the involvement of hypoxia in various animal models and by the ability of anesthetics to inhibit mitochondrial oxidations. We have been studying anesthetic effects on hepatocellular energy metabolism using suspensions of intact hepatocytes freshly isolated from phenobarbital-treated or untreated rats (+PB or -PB cells, respectively), an experimental system that is metabolically complete yet also biochemically homogeneous and accessible. In the present work, diazepam, lidocaine, thiopental, and enflurane, as well as the combination of thiopental and enflurane, were studied at concentrations similar to those achieved in vivo. Thiopental increased cellular oxygen consumption rate (VO2) in both +PB and -PB cells significantly, as did aminopyrine, a test substrate for PB-inducible cytochrome P450 activity. Diazepam increased VO2 only in +PB cells, as did enflurane, whereas lidocaine did not increase VO2 in either +PB or -PB cells. The combination of thiopental and enflurane significantly decreased VO2 in -PB cells but increased it in +PB cells. The higher VO2 in +PB cells compared to -PB cells, seen with all drugs tested (except lidocaine), was eliminated by prior addition of the P450 inhibitor metyrapone. Starting from steady states of oxygen metabolism, with VO2 offset by O2 supply from an overlying gas phase and PO2 stabilized at 24 mm Hg, aminopyrine significantly lowered extracellular PO2, increased lactate production, and decreased high energy phosphate levels within 10 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Anesthesiology, University of Nebraska Medical Center, Omaha 68105.
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Becker
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000632:Aminopyrine / Q000494:pharmacology*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D004737:Enflurane / Q000494:pharmacology; D007773:Lactates / Q000378:metabolism; D008012:Lidocaine / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects*; D010710:Phosphates / Q000378:metabolism; D051381:Rats; D013874:Thiopental / Q000494:pharmacology
D007773:Lactates; D010710:Phosphates; D000632:Aminopyrine; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; D004737:Enflurane; D008012:Lidocaine; D013874:Thiopental; D003975:Diazepam