Abstract
Biliary secretion of bile acid glucuronides was studied in control rats and in rats with a congenital defect in hepatobiliary transport of organic anions (GY rats). In control animals, hepatobiliary transport of [3H]lithocholic acid 3-O-glucuronide and [3H]cholic acid 3-O-glucuronide was efficient (greater than 95% in 1 h) and comparable to that of [14C]taurocholic acid. Secretion of both glucuronides was impaired in GY rats (24% and 71% at 1 h), whereas that of taurocholate was similar to control values. However, recovery of the glucuronides in bile was nearly complete within 24 h; virtually no radioactivity was found in urine. In control rats, biliary secretion of lithocholic acid 3-O-glucuronide, but not that of cholic acid 3-O-glucuronide or taurocholate, could be delayed by simultaneous infusion of dibromosulphthalein. In mutant rats, dibromosulphthalein infusion was also able to inhibit secretion of cholic acid 3-O-glucuronide. [3H]Hydroxyetianic acid, a C20 short-chain bile acid, was secreted by control rats as a mixture of 20% carboxyl-linked and 80% hydroxyl-linked (3-O-)glucuronide; secretion was very efficient (99% in 1 h). In GY rats, secretion was drastically impaired (16% at 1 h and 74% over a 24-h period). Initially, the mutant secreted more carboxyl- than hydroxyl-linked glucuronide, but the ratio reached that of control animals after 24 h. The rates of formation of both types of hydroxyetianic acid glucuronide by hepatic microsomes from mutant rats were similar or even slightly higher than those of control microsomes. These findings indicate that bile acid 3-O-glucuronides, but probably not carboxyl-linked glucuronides, are secreted into bile by a transport system shared with organic anions such as conjugated bilirubin and dibromosulphthalein, but different from that for amino acid-conjugated bile acids.
Highlights
Biliary secretion of bile acid glucuronides was studied in control rats and in rats with a congenital defect in hepatobiliary transport of organic anions (GY rats)
We have recently demonstrated that the biliary secretion, but not the hepatic uptake, of 3a-sulfated bile acids is impaired in “Groningen Yellow” (GY) rats, and that this inhibition becomes more pronounced with a decreasing number of hydroxyl groups on the bile acid's steroidal nucleus [29]
We studied the biliary secretion of lithocholic acid 3-0-glucuronide (LCG) and cholic acid 3-0-glucuronide (CG), as well as the short-chain bile acid hydroxyetianic acid, and compared each with the secretion of E
Summary
The objective of the studies was to examine the biliary secretion of [3H]CG, [3H]LCG, and [ " C ] E in GY and control rats. The effects of co-infusion of dibromosulphthalein (DBSP) on biliary secretion of glucuronidated lithocholic and cholic acid was investigated. For this purpose, unlabeled and labeled compounds were prepared and administered intravenously in trace amounts to unanesthetized control and GY rats prepared with a permanent external biliary fistula. The sample, a mixture of 3a- and 36-hydroxy acids, was methylated with diazomethane and dried; the methyl esters of the 3a- and 36-hydroxy compounds were separated by preparative thin-layer chromatography on LK5 plates (Whatman Chemical Separation Inc., Clifton, NY), developed with benzene-acetone 95:5. The methanol was evaporated under NP,water was added, and the sample was extracted with ether as described above. Cross-breeding experiments have been recently performed and showed that both strains carry the same genetic defect
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