TAUROLITHOCHOLIC ACID AND CHLORPROMAZINE CHOLESTASIS IN THE RHESUS-MONKEY

Taurolithocholic acid (TLC) and chlorpromazine (CPZ) cholestasis were studied in reversible primate models in order to determine the level of injury, changes in canalicular permeability, and the effects of taurocholic acid (TC) on the production of cholestasis. TLC produced dose-dependent cholestasis. Reductions in bile acid secretion rate and concentration, larger decreases in [14C]erythritol clearance than in total bile flow, and increased bicarbonate concentration in bile indicated that the cholestasis was canalicular in origin. TC prevented cholestasis; it also caused an increased secretion of TLC in bile, but the TLC:TC concentration ratio was unchanged, providing evidence that TC is beneficial because it hastens excretion of TLC from the liver cell in micelles. Permeability to [3H]inulin was increased during the recovery period. CPZ caused reductions in bile flow, bile acid secretion rate, and [14C]erythritol clearance, and almost completely eliminated biliary bicarbonate secretion, suggesting a mixed canalicular and ductular form of cholestasis. When TC was given with CPZ, no reductions in bile acid secretion rate or [14C]erythritol clearance were found but bicarbonate secretion was markedly reduced, bicarbonate concentration diminished, and bile acid concentration increased, i.e., TC protected against the canalicular component of CPZ cholestasis and unmasked the ductular component. Permeability to inulin was increased in three of four animals. TLC cholestasis occurs predominately at the canalicular level, whereas CPZ probably affects bile flow at the ductular level as well. TC protects the hepatocyte against the effects of both agents.