33 DEFECTIVE BILE SECRETION OF BILE ACID GLUCURONIDES IN RATS WITH HEREDITARY CONJUGATED HYPERBILIRUBINEMIA: IMPLICATIONS FOR THE MECHANISM OF CHOLESTAIS

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Bile acids glucuronides have been identified in human bile, plasma and urine. We investigated the biliary secretion of lithocholate-3-0-glucuronide (LCG) and of cholate-3-0-glucuronide (CG), as well as the cholestatic potency of LCG in normal Wistar rats and in Wistar rats with hereditary conjugated hyperbilirubinemia. These rats show an impaired biliary secretion of bilirubin conjugates and other organic anions, but have a normal bile acid secretion. Bile secretion of an i.v. administered dose of (3H)LCG was strongly reduced in the mutant rats; 24% recovery in bile at 1h after injection vs. 96% in control rats. Corresponding values for biliary recovery of (3H)CG at 1h were 71% and 98% resp. Bile secretion of (3H)LCG was delayed by i.v, infusion of dibromosulphthalein (DBSP, 1.1 umol/min/kg) in control rats, whereas that of a simultaneously administered tracer dose of (14C)taurocholic acid was slightly accelerated. Low doses of LCG (0.5-2.0 mg) caused a transient reduction of bile flow in control rats, followed by a choleresis. A dose of 4 mg caused an almost complete cessation of the bile flow within 30 min. In contrast, LCG at the same dosages did not affect bile production in the mutants. It is concluded that bile acid-3-0-glucuronides share transport systems for biliary secretion with bilirubin and DBSP. Our data indicate that transport across the canalicular membrane is of importance for the development of LCG-induced cholestasis.