Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs

Abstract

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.

Halothane-Induced Liver Injury in Outbred Guinea Pigs: Role of Trifluoroacetylated Protein Adducts in Animal Susceptibility

“…Other studies have suggested that susceptible guinea pigs develop liver injury when they are exposed to halothane because they are more sensitive to hepatic ischemia ( , ), cholestasis (), and disturbances in calcium homeostasis ( , ) than resistant guinea pigs. Although our findings indicate that TFA-protein adducts are a contributing factor to the susceptibility of guinea pigs to halothane-induced liver injury, it remains to be determined whether they cause liver injury by initiating these or other pathological processes.…”

“…Determination of the Extent of Liver Damage. Guinea pigs with serum ALT levels less than 2 times or greater than 5 times those of control animals, 48 h after halothane treatment, were classified as being either resistant or susceptible, respectively, to halothane-induced liver injury, as described previously ( , ). Animals with ALT that fell between these two limits were considered mildly susceptible.…”