Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs.
To characterize the early events in liver injury produced by halothane, experiments were performed in genetically susceptible guinea pigs 19 hours after halothane exposure. Serum bile acid concentrations were fourfold increased in halothane-exposed animals compared with controls. In isolated perfused liver experiments, livers from halothane-exposed animals did not differ in hepatic oxygen uptake or in perfusion pressure at the end of experiments, but bile flow and biliary bile salt concentrations were reduced. Hepatic calcium content was increased in halothane-exposed guinea pigs compared with controls, and further experiments were performed to explore the reason for this. As determined by infusion of 45Ca to steady-state perfusate concentrations, hepatic calcium clearance was increased in halothane-exposed guinea pigs compared with controls (0.37 +/- 0.06 vs. 0.28 +/- 0.02 mL/min, P < .01). Decreased biliary excretion of calcium was also noted and was entirely attributable to reduced bile flow. However, although decreased excretion contributed to hepatic accumulation of calcium, it was quantitatively less important than enhanced hepatic uptake. As indicated by passage of a bolus of horseradish peroxidase from perfusate into bile, hepatic tight junction permeability was increased five-fold after halothane exposure. It is concluded that cholestasis, as exemplified by reduced bile flow, is an early feature of the liver injury produced by halothane in guinea pigs and is associated with increased tight junction permeability. Although the decrease in bile flow contributes to an early increase in hepatic calcium content, entry of calcium from the perfusion compartment is quantitatively more important.
Storr Liver Unit, Department of Medicine, University of Sydney, NSW, Australia.
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Frost
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Mahoney
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Field
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Farrell
D000818:Animals; D001646:Bile / Q000378:metabolism / Q000502:physiology*; D001647:Bile Acids and Salts / Q000097:blood; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism; D006168:Guinea Pigs; D006221:Halothane / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects*; D006735:Horseradish Peroxidase / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism
D001647:Bile Acids and Salts; D006735:Horseradish Peroxidase; D002118:Calcium; D006221:Halothane