HEPATOBILIARY EXCRETION OF ORGANIC-ANIONS IN DOUBLE-MUTANT RATS WITH A COMBINATION OF DEFECTIVE CANALICULAR TRANSPORT AND URIDINE 5'-DIPHOSPHATE-GLUCURONYLTRANSFERASE DEFICIENCY

Abstract

Mutant rats with a selective defect for the hepatobiliary excretion of organic anions (GT+TR- rats) are valuable models to study hepatic transport processes. However, retained conjugates in the livers of these rats may secondarily affect hepatic uptake, metabolism, and excretion of other compounds and this may confound the interpretation of test results. We have developed double mutants (GT-TR-) rats with both a conjugation and an excretion defect by cross-breeding uridine 5'-diphosphate-glucuronyl-transferase-deficient GT-TR+ Gunn rats with transport-deficient GT+TR- rats. Phenotypically, GT-TR- rats and Gunn rats are alike in that both have unconjugated hyperbilirubinemia. Intravenous administration of tetrabromosulphthalein, bilirubin diglucuronide, and bilirubin monoglucuronide revealed a significant difference in that the clearance of these compounds was reduced to 10%, 10%, and 20%, respectively, in GT-TR- rats when compared with Gunn rats. The hepatic elimination of tetrabromosulphthalein in GT-TR- rats and in GT+TR- rats is impaired to the same extent. Thus, both have a similar hepatic excretion defect. However, bile flow and bile acid excretion in GT+TR- rats are more depressed than in GT-TR- rats: bile flow, 88 +/- 3 vs. 36 +/- 1 microliters/min.kg and bile acid excretion, 3.4 +/- 0.2 vs. 1.5 +/- 0.1 mumol/min.kg in GT-TR- and GT+TR- rats, respectively. This suggests that accumulated glucuronides in the liver inhibit bile flow and bile acid excretion. To test whether conjugated bilirubin and the photoisomers of unconjugated bilirubin are excreted via the same transport pathways, the effect of phototherapy was studied in GT-TR- rats and in Gunn rats. Photoexposure caused a 120% increase in biliary excretion of bilirubin isomers in Gunn rats and only 40% in GT-TR- rats. This shows that the biliary excretion of bilirubin photoisomers is indeed affected by the hepatic excretion defect of GT-TR- rats and suggests that hepatic excretion of bilirubin photoisomers proceeds via the same route as other organic anions such as conjugated bilirubin and tetrabromosulphthalei