Inhibition of hepatocytary vesicular transport by cyclosporin a in the rat: Relationship with cholestasis and hyperbilirubinemia



In an attempt to understand the hepatotoxicity associated with immunosuppressive therapy with cyclosporin A, we investigated the effects of acute cyclosporin A administration on biliary secretion, serum bile acid and bilirubin levels and the histological changes in the hepatic parenchyma in anesthetized male Wistar rats. The animals were divided into three experimental groups that received equal volumes (1 ml, intravenously) of physiological saline (controls), cyclosporin A vehicle (a fat emulsion, Intralipid, mixed with absolute ethanol) or cyclosporin A dissolved in the aforementioned mixture. In another series of assays, horseradish peroxidase was coinjected with cyclosporin A vehicle or with the solution containing cyclosporin A. Only after cyclosporin A administration was an immediate inhibition in bile flow and in the biliary concentrations and secretion of bile acids and bilirubin found. In addition, a delay in the peak time of the appearance of horseradish peroxidase together with a reduction in the biliary excretion rate and in the total amount of horseradish peroxidase excreted were observed during cholestasis. At 40 to 50 min after drug administration, all biliary parameters evaluated had returned to the pretest values. The relationship between bile flow and bile acid secretion showed that cyclosporin A–induced cholestasis is related to a decrease of both the bile acid–dependent and bile acid–independent fractions of bile flow. At the end of the cyclosporin A assays, the serum bile acid, total bilirubin and conjugated bilirubin concentrations were greater than those observed in the controls and Intralipid-treated animals. These effects were dose-dependent. Light microscopy and transmission electron microscopy studies did not reveal architectural hepatic abnormalities. We conclude that cyclosporin A interferes with the hepatocellular vesicle-mediated transport processes and postulate that apart from the previously proposed inhibition of the hepatic uptake of bile acids, the cyclosporin A–induced hyperbilirubinemia, cholestasis and bilirubinostasis in the rat are also related to an inhibition of transhepatocytary vesicular transport processes. (HEPATOLOGY 1990;12:83–91).