Inhibition of biliary glutathione secretion by cyclosporine A in the rat: possible mechanisms and role in the cholestasis induced by the drug

Abstract

Background/Aims: Biliary glutathione appears to be a major osmotic factor in the generation of bile acid-independent bile flow. This study was designed to investigate its importance in cyclosporine A-induced cholestasis in both acute and short-term-treated rats. Methods: Adult male Wistar rats were treated as follows: (i) with a single i.v. dose of cyclosporine or its vehicle (acute assays); (ii) with cyclosporine, its vehicle or physiological saline, i.p., for 7 days once per day (short-term treatment assays). Bile flow and biliary glutathione levels were determined under anesthesia both before and after intrabiliary hydrolysis of the tripeptide had been inhibited. Results: Acute cyclosporine administration, at a dose of 20 mg/kg, brought about an abrupt and marked fall in bile flow and bile acid secretion simultaneously with a rapid decrease in the biliary concentration and secretion rates of total, reduced and oxidized glutathione. When the rats were treated with cyclosporine A for 1 week, at a dose of 10 mg/kg per day, similar cholestatic and inhibitory effects on the biliary secretion of glutathione were noted both before and after the intrabiliary catabolism of the tripeptide had been inhibited with acivicin; in addition, the hepatic content of glutathione was also reduced. The cholestatic effect of the drug was associated with reductions in the four bile flow fractions evaluated: bile acid- and glutathione-dependent bile flow and bile acid- and glutathione-independent bile flow. Conclusions: These findings indicate that cyclosporine-induced cholestasis in the rat is due not only to alterations in the hepatobiliary transport of bile acids but also to an impairment of bile formation dependent on the biliary secretion of glutathione, possibly through inhibition of the canalicular transport of the tripeptide.