Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver.

Inhibition of bile salt transport across the hepatocyte during cholestasis induced by cyclosporin A has been shown. However, the contribution of the different bile salt transport systems in liver to cholestasis has remained controversial. The sensitivity of different bile salt transport systems in liver to cyclosporin-induced inhibition was determined by transport assays in plasma membrane vesicles and by in vivo studies in the rat. Cyclosporin A--induced inhibition of sodium-dependent uptake of bile salts across the sinusoidal membrane, of potential-dependent, and of adenosine triphosphate (ATP)-dependent bile salt transport across the canalicular membrane exhibited inhibition constants (Ki) of 5, 70, and 0.2 mumol/L, respectively. The nonimmunosuppressive cyclosporin analogue PSC 833 also preferentially inhibited the ATP-dependent bile salt transport with an inhibition constant of 0.6 mumol/L. Cyclosporin A and its analogue PSC 833 [(3'-oxo-4-butenyl-4-methyl-Thr1)-(Val2)-cyclosporin] (25 mg/kg each) served as tools to interfere with [14C]taurocholate secretion into bile in vivo, causing an accumulation of [14C]-taurocholate in liver and reducing bile flow to 50%. In mutant rats deficient in the transport of leukotriene C4 and related conjugates across the canalicular membrane, bile flow was reduced to 14%. The cyclosporins preferentially inhibit the ATP-dependent bile salt export carrier in the canalicular membrane. This inhibition reduces bile salt-dependent bile flow and causes intrahepatic cholestasis.