CHOLESTASIS AND ALTERATIONS OF GLUTATHIONE METABOLISM INDUCED BY TACROLIMUS (FK506) IN THE RAT

Background. Tacrolimus (FK506) is an immunosuppressive agent used for the prevention of allograft rejection after organ transplantation. The aim of this study was to investigate the effects of chronic tacrolimu s treatment on bile secretion in rats. Methods. Tacrolimus was adminis tered intraperitoneally at doses of 0.2, 0.5, and 0.8 mg/kg/day for 6 weeks. Results. Bile flow was significantly reduced at doses of 0.5 mg /kg and 0.8 mg/kg (-25% and -32%, respectively). Bile acid secretion w as not significantly modified, but bicarbonate secretion decreased at doses of 0.5 mg/kg and 0.8 mg/kg (-23% and -29%, respectively). Glutat hione secretion was significantly reduced at doses of 0.5 mg/kg (-29%) and 0.8 mg/kg (-49%), Liver glutathione concentration was reduced at the higher dose (-17%), Liver gamma-glutamyl-cysteinyl synthetase acti vity was elevated (+22%, +10%, and +15%) and gamma-glutamyl transpepti dase activity was reduced (-18%, -40%, and -25%) at all doses. Dichlor ofluorescein and thiobarbituric acid-reactive substance concentrations were not significantly modified. Liver glutathione peroxidase activit y increased at doses of 0.5 mg/kg (+65%) and 0.8 mg/kg (+56%), Kidney concentration of thiobarbituric acid-reactive substances was significa ntly increased at doses of 0.5 mg/kg (+17%) and 0.8 mg/kg (+12%), Conc lusions, Our data indicate that tacrolimus at high doses induces chole stasis by inhibiting primarily biliary excretion of glutathione and, t o a lesser extent, bicarbonate, The decrease in biliary glutathione se cretion is not due to a lower synthesis or degradation and could be re lated to its increased sinusoidal efflux.