Taurolithocholate-Induced Cholestasis: Taurocholate, but not Dehydrocholate, Reverses Cholestasis and Bile Canalicular Membrane Injury

Abstract

To determine whether taurocholate (TC) prevents taurolithocholate (TLC)-induced cholestasis through its choleretic action or by its micelle-forming properties, studies were performed comparing the effect of simultaneous equimolar infusions of either dehydrocholate (DHC), a nonmicelle-forming bile acid, or TC on TLC-induced changes in bile secretion and bile canalicular membrane morphology. When TC (0.8 μmole min-1) was simultaneously infused for 1 hr with TLC (0.6 μmole min -1), bile flow increased by 45% in contrast to combined DHC (0.8 μmole min-1) and TLC infusions where bile flow was observed to decline by 20%. When TLC was infused alone, bile flow declined by 65% and a parallel reduction in [14C] erythritol clearance was also observed although [3H]inulin clearance remained unchanged. This maintenance of the clearance of [3H]inulin corresponded with a 3-fold rise in bile to plasma [3H]inulin ratios from the preinfusion ratio of 0.079 ± 0.005 to 0.241 ± 0.050, 50 min after infusion of TLC. Using equations previously described to relate inert solute clearance to bile flow, the rise in bile to plasma [3H]inulin ratios and the maintenance of [3H]inulin clearance was best explained by an increase in diffusion permeability of the biliary tract. Simultaneous infusions of TC prevented TLC-induced changes in inulin permeability to a greater extent than simultaneous infusions of DHC. TC also reversed the injurious effect of TLC on the scanning electron microscopic appearance of the bile canalicular membrane whereas DHC only partially prevented these changes. These results suggested that TLC induces cholestasis in part by increasing biliary membrane permeability to bile, and that TC may prevent TLC cholestasis and canalicular membrane injury primarily by its capacity to solubilize TLC in mixed micelles.