Factors influencing the inhibition of biliary glutathione efflux induced by biliary obstruction

The aim of this study was to investigate mechanisms responsible for the inh ibition of biliary glutathione efflux in rats with secondary biliary cirrho sis. Rats were studied after bile duct obstruction for 28 days. The biliary secretion of reduced glutathione (GSH), oxidised glutathione (GSSG) and cy steine were completely inhibited in biliary obstructed rats. Hepatic gamma glutamyltranspeptidase (gamma -GT) activity increased significantly, but fo llowing its inhibition by acivicin administration GSH, GSSG and cysteine we re still absent in bile. Biliary obstruction resulted in a significant incr ease of the permeability of the paracellular pathway, as shown by the highe r bile/plasma ratio and hepatic clearance of [C-14]sucrose. GSH and GSSG we re, however, significantly lower in the carotid artery and hepatic vein of obstructed animals and the arteriovenous difference across the liver was re duced. The concentration of GSH was significantly reduced and that of GSSG increased in the liver of obstructed rats. Biliary obstruction induced an i ncrease in the hepatic concentration of cysteine and an inhibition of both gamma glutamylcysteine synthetase and methionine adenosyl transferase activ ities. Dichlorofluorescein (DCF) and the GSSG/GSH ratio and thiobarbituric acid reactive substances (TBARS) concentration, markers of reactive oxygen species production and lipid peroxidation, respectively, were significantly increased. Our data indicate that increased degradation or blood reflux of glutathione do not participate in the disruption of its secretion into bil e and support the view that impairment of glutathione synthesis and oxidati ve stress could contribute to the decline in biliary glutathione output. (C ) 2000 Elsevier Science Inc. All rights reserved.