Separate transport systems for biliary secretion of sulfated and unsulfated bile acids in the rat.

Abstract

Biliary secretion of 3a-sulfated bile acids has been studied in Wistar rats with an autosomal recessive defect in the hepatic transport of bilirubin. Liver function, established by measurement of various enzymes in plasma, by enzyme histochemical methods, and by electron microscopy, appeared to be normal in these rats. Serum levels of unconjugated, monoglucuronidated, and diglucuronidated bilirubin were 0.62, 1.62, and 6.16 Mmol/ liter, respectively, compared with 0.17, 0.08, and 0.02 gmol/ liter in control rats. Biliary bilirubin secretion was strongly reduced in the mutant animals: 0.21±0.03 vs. 0.39±0.03 nmol/min per 100 g body wt in control rats. Despite normal biliary bile acid output, bile flow was markedly impaired in the mutant animals, due to a 53% reduction of the bile acid-independent fraction of bile flow. The transport maximum for biliary secretion of dibromosulphthalein (DBSP) was also drastically reduced (-53%).Biliary secretion of intravenously administered trace amounts of the 3a-sulfate esters of '4C-labeled taurocholic acid (-14%), taurochenodeoxycholic acid (-39%), taurolithocholic acid (-73%), and glycolithocholic acid (-91%) was impaired in the jaundiced rats compared with controls, in contrast to the biliary secretion of the unsulfated parent compounds. Hepatic uptake of sulfated glycolithocholic acid was not affected in the jaundiced animals. Preadministration of DBSP (15 gmol/100 g body wt) to normal Wistar rats significantly impaired the biliary secretion of sulfated glycolithocholic acid, but did not affect taurocholic acid secretion.We conclude that separate transport systems in the rat liver exist for biliary secretion of sulfated and unsulfated bile acids; the sulfates probably share secretory pathways with the organic anions bilirubin and DBSP. The described genetic defect in hepatic transport function is associated with a reduced capacity to secrete sulfated bile acids into bile; this becomes more pronounced with a decreasing number of hydroxyl groups on the sulfated bile acid's molecule.

ATP‐dependent transport of amphiphilic cations across the hepatocyte canalicular membrane mediated by mdr1 P‐glycoprotein

“…Mutant male Wistar rats with hepatobiliary transport defect (TR-or GY) [13,14] were from Dr. F. Kuipers (University of Groningen, The Netherlands). Animals were maintained on a standard diet with free access to food and water.…”

Enhanced Expression of the Human Multidrug Resistance Protein 3 by Bile Salt in Human Enterocytes

“…In the liver, intracellular bile salts are uptaken from circulating blood through the basolateral membrane transporter, NTCP, and they are excreted into the bile duct mainly by BSEP in the canalicular membrane of the hepatocytes (1). MRP2, a member of the MRP superfamily, expressed in the canalicular membrane of hepatocytes, may also export bile salts into the bile duct (11). In the gut, bile salts enter the enterocytes through the ileal apical membrane sodium-dependent bile acid transporter and interact with FXR, resulting in up-regulation of the gene encoding cytosolic ileal bile acid-binding protein, which facilitates intracellular transport of bile salts and protects enterocytes from the detergent effects of bile salts (7,12,13).…”

Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2

“…4,5 These mutants are also defective in the biliary excretion of other amphiphilic anions, 6 including glutathione S-conjugates such as leukotriene C 4 (LTC 4 ) 7 and glucuronidated or sulfated bile salts. 8,9 Adenosine triphosphate (ATP)-dependent transport of amphiphilic anions in canalicular membrane vesicles is deficient in GY/TR Ϫ and EHBR mutants. 6,10,11 ATP-dependent transport of labeled MGB and BGB was below detectability in mutant rat canalicular membrane vesicles.…”