Pathogenesis of lithocholate- and taurolithocholate-induced intrahepatic cholestasis in rats
Kakis, G.; Yousef, I.M.
Gastroenterology 75(4): 595-607
1978
ISSN/ISBN: 0016-5085 PMID: 213342 Document Number: 135085
The intrahepatic cholestasis induced by lithocholic acid and taurolithocholic acid is associated with a bizarre distortion of the bile canalicular membrane. The hypothesis that the physiological and morphological abnormalities observed are attributable to biochemical alterations of the bile canalicular membrane was investigated. Lithocholic acid and taurolithocholic acid were administered i.v. to male rats for 15, 30 or 60 min at a rate of 0.2 .mu.mol/min per 100 g body wt. The liver cell plasma membranes were subsequently separated into 2 fractions, 1 rich in the bile canalicular membrane. The lipid composition of the bile and the bile canalicular membrane was analyzed as well as membrane polypeptide profile and the activities of certain membrane enzymes. Lithocholic acid cholestasis was preceded by an initial choleresis in the first 30 min which was associated with an increased biliary secretion rate of bile acids but not phospholipid or cholesterol. Lithocholic acid infusion was associated with a significant and progressive decrease in Na+ + K+-ATPase, Mg2+-ATPase and leucine aminopeptidase activities of the bile canalicular membrane. Free lithocholic acid was incorporated into the membrane until it reached about 400 nmol of lithocholic acid/mg of membrane protein after 30 min of lithocholic acid infusion; the cholesterol content was increased by 6- to 7-fold with no changes in the membrane polypeptide profile or phospholipid content as compared to control membrane. Taurolithocholic acid did not induce an initial choleresis and did not change the biliary secretion rate of bile acids, phospholipid or cholesterol. Taurolithocholic acid did not alter the activity of any of the above membrane enzymes nor was it incorporated into the isolated bile canaliculus. It did result in a more than 2-fold increase in cholesterol content within 30 min; no change was observed in the membrane polypeptide profile or phospholipid content as compared to control membrane. The changes in the molecular structure of the bile canalicular membrane, specifically the increase in the cholesterol to phospholipid ratio, may be the cause for both the lamellar transformation of the bile canalicular membrane and the subsequent cholestasis in both models.