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  • Title: Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver.
    Author: Böhme M, Müller M, Leier I, Jedlitschky G, Keppler D.
    Journal: Gastroenterology; 1994 Jul; 107(1):255-65. PubMed ID: 8020669.
    Abstract:
    BACKGROUND/AIMS: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.
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