PEPTIDOLEUKOTRIENES INCREASE THE EFFLUX OF GLUTATHIONE FROM PERFUSED-RAT-LIVER

The effect of peptidoleukotrienes (LT) on the efflux of glutathione (GSH) from the perfused rat liver was investigated. LTD(4), C-4 and E(4) were infused at a final concentration of 20 nM into the portal vein of rat livers perfused with Krebs-Henseleit buffer. Perfusion pressure, efflux of glucose and release of LDH increased during the infusion of LTC(4) and D-4 and returned to baseline upon cessation of the infusion of LT. In contrast, the efflux of GSH did not change during the infusion of LT, but increased from 15 +/- 2 to 26 +/- 4 nmol/min.g liver 20 min after cessation of the infusion of LTC(4).LTE(4) did not increase the efflux of LDH, glucose, lactate, or GSH. During the LTC(4)- and LTD(4)-induced rise in perfusion pressure bile-flow decreased transiently by one third. The biliary excretion of GSH, however, decreased by an average of 75 % and recovered more slowly than the cholestasis. In the presence of the selective LTD(4) receptor antagonist LY171883 the effects of LTC(4) and LTD(4) were largely abolished. The delayed effects of LT on GSH efflux suggest that LT shift the efflux of GSH from the canalicular towards the sinusoidal side of the hepatocyte independent of other effects of LT on hepatic function. The sustained increase in efflux of GSH resulting from LT will raise the extracellular concentration of this antioxidant, such that more GSH is available at sites of inflammation to detoxify reactive oxygen species released by activated inflammatory cells.