Abstract
Hepatobiliary functions during administration of the thiol-oxidizing agents t-butyl hydroperoxide, hydrogen peroxide, diamide and menadione were monitored in the isolated rat liver perfused with a recirculating fluorocarbon emulsion. Because these agents are detoxified largely by glutathione-dependent mechanisms, efflux of reduced glutathione and glutathione disulfide into bile and perfusate was measured, along with bile flow, excretion of endogenous bile acids, lactate dehydrogenase release and the bile/perfusate ratios of [14C]sucrose (a marker of junctional permeability) and [3H]polyethylene glycol-900 (a substance concentrated in bile, presumably by a vesicular transport pathway). All agents enhanced the rate of glutathione efflux from the liver, reflecting increased formation of glutathione disulfide. At low doses of the thiol-oxidants, most of the additional glutathione released by the liver appeared in bile, whereas at higher doses the fraction appearing in the sinusoidal circulation increased. This enhanced glutathione disulfide release was associated with a decrease in endogenous bile acid excretion and in the bile/perfusate ratio of [3H]polyethylene glycol, and an increase in the bile/perfusate ratio of [14C]sucrose. These deleterious changes were reversible, and were noted at doses that had no effect on lactate dehydrogenase release, and only small effects on perfusion pressure. Bile flow was decreased by t-butyl hydroperoxide and H2O2, and increased by diamide (100 mumol) and menadione (20 mumol). These results indicate that alterations in hepatic thiol-redox status lead to an impairment of bile acid excretion, junctional integrity and bile formation. These functional parameters appear sensitive to the effects of oxidizing agents, and probably contribute to the pathogenesis of hepatobiliary dysfunction during the metabolism of certain drugs and xenobiotics.
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