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.
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.
Authors: L Benkoel; F Chanussot; F Dodero; C De la Maisonneuve; P Bongrand; A M Benoliel; R Lambert; J Brisse; A Chamlian Journal: Dig Dis Sci Date: 2000-06 Impact factor: 3.199
Authors: M D Delle Monache; A Gigliozzi; A Benedetti; L Marucci; A Bini; C Francia; E Papa; E Di Cosimo; F Fraioli; A M Jezequel; D Alvaro Journal: Dig Dis Sci Date: 1999-11 Impact factor: 3.199