DIFFERENTIAL-EFFECTS OF CYCLOSPORINE A ON THE TRANSPORT OF BILE-ACIDSBY HUMAN HEPATOCYTES

Cyclosporin A (CsA) treatment has been reported to cause rises in seru m bile acids both in humans and rats. It has also been shown to suppre ss bile flow in situ in rats and inhibit the transport of bile salts b y rat hepatocytes. The purpose of this study was to examine the influe nce of CsA on uptake of radiolabelled cholate (CA), glycocholate (GC) and taurocholate (TC) by isolated human hepatocytes. CsA did not signi ficantly change V(max) for CA uptake [0.23 +/- 0.01 vs 0.25 +/- 0.02 n mol/mg protein/min for control and CsA (10 muM), respectively], but si gnificantly increased K(m) (37 +/- 2 vs 86 +/- 8 muM). Similarly, V(ma x) for TC uptake was not affected (0.51 +/- 0.02 vs 0.67 +/- 0.05 nmol /mg protein/min) while K(m) was significantly increased [46 +/- 3 vs 1 09 +/- 11 muM for control and CsA (10 muM), respectively]. On the othe r hand, neither V(max) nor K(m) for GC uptake was affected by CsA. The data indicate a competitive pattern of inhibition induced by CsA on C A and TC uptake. Furthermore, CsA was found to cause a dose-related in hibition of accumulation of both cholate and taurocholate, but not GC accumulation. None of the concentrations of CsA showed a significant e ffect on the integrity of the human hepatocytes as assessed by ALT (al anine aminotransferase), AST (aspartate aminotransferase) and LDH (lac tate dehydrogenase) release. The findings, in human hepatocytes, are g enerally consistent with the observations reported from rodent studies . They strongly support the contention that serum bile acid increases in CsA-treated patients are due to interference with the hepatocellula r transport and accumulation of particular bile acids.