Preserved organic anion transport in mutant TR- rats with a hepatobiliary secretion defect

Abstract

The in vivo biliary secretion of a number of organic anions in mutant TR- rats was studied. The secretion of bilirubin glucuronide (BG), the glutathione conjugate of bromosulfophthalein, dibromosulfophthalein, and indocyanine green was reduced to 2, 15, 50, and 75% of normal, respectively. Surprisingly, the secretion of bilirubin ditaurate (BDT) was entirely normal under these conditions. In isolated TR- rat liver perfusion experiments (recirculating setup), the hepatobiliary secretion of BG and BDT was reduced to 1 and 50% of normal, respectively. There was considerable residual concentrative transport of BDT under these conditions (bile-to-perfusate concentration ratio of 190 +/- 60; normal, 730 +/- 480), whereas for BG the concentration step was completely abolished (bile-to-perfusate concentration ratio of 1.3 +/- 1.0; normal, 60 +/- 40). In a single-pass isolated TR- rat liver perfusion study, BDT secretion after bolus administration (1 mumol) was abnormal; the peak secretion was retarded to 20 min after injection (normal 7.5 min), and the secretion rate was decreased to 19% of normal. BDT, as an organic dianion, is a substrate for the "canalicular multispecific organic anion transporter" (cMOAT), a carrier protein that is defective in TR- rats. Its considerable residual secretion in certain experimental conditions suggests the preservation of a low-affinity pathway for secretion of some cMOAT substrates in TR- rats.