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 tacrolimus treatment on bile secretion in rats.


METHODS
Tacrolimus was administered 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 was not significantly modified, but bicarbonate secretion decreased at doses of 0.5 mg/kg and 0.8 mg/kg (-23% and -29%, respectively). Glutathione 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 activity was elevated (+22%, +10, and +15%) and gamma-glutamyl transpeptidase activity was reduced (-18%, -40%, and -25%) at all doses. Dichlorofluorescein and thiobarbituric acid-reactive substance concentrations were not significantly modified. Liver glutathione peroxidase activity increased at doses of 0.5 mg/kg (+65%) and 0.8 mg/kg (+56%). Kidney concentration of thiobarbituric acid-reactive substances was significantly increased at doses of 0.5 mg/kg (+17%) and 0.8 mg/kg (+12%).


CONCLUSIONS
Our data indicate that tacrolimus at high doses induces cholestasis by inhibiting primarily biliary excretion of glutathione and, to a lesser extent, bicarbonate. The decrease in biliary glutathione secretion is not due to a lower synthesis or degradation and could be related to its increased sinusoidal efflux.
Department of Physiology, Pharmacology and Toxicology, University of León and Hospital of León, Spain.
S
S
Sanchez-Campos
R
R
Lopez-Acebo
P
P
Gonzalez
J M
JM
Culebras
M J
MJ
Tuñon
J
J
Gonzalez-Gallego
D000818:Animals; D001646:Bile / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D002779:Cholestasis / Q000139:chemically induced*; D005978:Glutathione / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D005978:Glutathione; D016559:Tacrolimus