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Teleosts have high olfactory sensitivity to bile salts. To assess whether this phenomenon is involved in intra-specific chemical communication alone, or is part of a more ;broad range' sensitivity to bile salts produced by heterospecifics, we investigated possible differences in the odour of bile between the sexes and among different species - the eel (Anguilla anguilla), goldfish (Carassius auratus) and Mozambique tilapia (Oreochromis mossambicus) - using the electro-olfactogram (EOG). We also identified the main bile constituents by liquid chromatography and mass spectrometry. There were marked differences in olfactory response of the eel to thin-layer chromatography fractions of bile from both sexes, and mature and immature conspecifics. Smaller differences were seen in the potency of fractions of bile from male and female goldfish and tilapia. Eels, goldfish and tilapia demonstrated similar olfactory sensitivity to bile from a range of different species, with no apparent correlation between the olfactory potency of bile and a phylogenetic closeness and/or similarity of diet of the donor to the receiver. The three species were able to detect odorants in thin-layer chromatography fractions of heterospecific bile even in the absence of activity in conspecific bile. Eels, goldfish and tilapia responded to both sulphated C(27) bile salts (5beta-scymnol-sulphate and 5alpha-cyprinol sulphate) and to taurine-conjugated C(24) bile salts (taurochenodeoxycholic acid, taurolithocholic acid and taurocholic acid), irrespective of whether these bile salts were present in conspecific bile. Together, these results suggest that teleosts have a broad-range olfactory sensitivity to bile salts, with potential roles in both intra-specific chemical communication and in inter-specific interactions.

Background & Aims: Dihydroxy bile acids induce a bicarbonate-rich hypercholeresis when secreted into canalicular bile in unconjugated form; the mechanism is cholehepatic shunting. The aim of this study was to identify a xenobiotic that induces hypercholeresis by a similar mechanism., Methods: Five organic acids (sulindac, ibuprofen, ketoprofen, diclofenac, and norfloxacin) were infused into rats with biliary fistulas. Biliary recovery, bile flow, and biliary bicarbonate were analyzed. Sulindac transport was further characterized using Tr(-) rats (deficient in mrp2, a canalicular transporter for organic anions), the isolated perfused rat liver, and hepatocyte membrane fractions., Results: In biliary fistula rats, sulindac was recovered in bile in unconjugated form and induced hypercholeresis of canalicular origin. Other compounds underwent glucuronidation and were not hypercholeretic. In the isolated liver, sulindac had delayed biliary recovery and induced prolonged choleresis, consistent with a cholehepatic circulation. Sulindac was secreted normally in Tr(-) rats, indicating that its canalicular transport did not require mrp2. In the perfused liver, sulindac inhibited cholyltaurine uptake, and when coinfused with cholyltaurine, induced acute cholestasis. With both basolateral and canalicular membrane fractions, sulindac inhibited cholyltaurine transport competitively., Conclusions: Sulindac is secreted into bile in unconjugated form by a canalicular bile acid transporter and is absorbed by cholangiocytes, inducing hypercholeresis. At high flux rates, sulindac competitively inhibits canalicular bile salt transport; such inhibition may contribute to the propensity of sulindac to induce cholestasis in patients.

The biliary bile acid composition of 30 species of pigeons and doves belonging to seven genera in the avian order Columbiformes was determined using TLC, HPLC, GLC/MS, LSIMS, and NMR. In 23 of 25 species of fruit pigeons and doves, chenodeoxycholic acid was the major bile acid (> 50%). In only 1 species (Ptilinopus ornatus) was cholic the major bile acid. A number of species (7 of 15 species in the genus Ptilinopus, and 6 of 9 species in the genus Ducula) contained 1 beta,3 alpha,7 alpha-trihydroxy-5 beta-cholan-24-oic acid in proportions ranging from 2 to 43%. This 1 beta-hydroxy derivative of chenodeoxycholic acid has not been previously identified as a major biliary bile acid in vertebrates. Five of 15 species of the genus Ptilinopus, 5 of 9 species of the genus Ducula, and the only species examined for the genus Gymnophaps contained 23R-hydroxy chenodeoxycholic acid in detectable proportions, ranging from 1 to 4%. Bile acids were conjugated (in N-acyl linkage) with glycine and taurine in 28 species and with only taurine in 2 species. The fruit pigeons are the first non-mammalian genera identified to date in whom bile acids are conjugated with glycine, as well as with taurine. An incidental finding was that a gallbladder was present in 3 genera (Ptilinopus, Ducula, and Gymnophaps) and absent in 4 genera (Gallicolumba, Chalcophaps, Otidiphaps, and Treron).

The biliary bile acid composition of gallbladder bile obtained from six species of bears (Ursidae), the Giant panda, the Red panda, and 11 related carnivores were determined by reversed phase liquid chromatography and gas chromatography-mass spectrometry. Bile acids were conjugated solely with taurine (in N-acyl linkage) in all species. Ursodeoxycholic acid (3 alpha, 7 beta-dihydroxy-5 beta-cholan-24-oic acid) was present in all Ursidae, averaging 1-39% of biliary bile acids depending on the species; it was not detected or present as a trace constituent (< 0.5%) in all other species, including the Giant panda. Ursodeoxycholic acid was present in 73 of 75 American Black bears, and its proportion averaged 34% (range 0-62%). Ursodeoxycholic acid averaged 17% of biliary bile acids in the Polar bear (n = 4) and 18% in the Brown bear (n = 6). Lower proportions (1-8%) were present in the Sun bear (n = 2), Ceylon Sloth bear (n = 1), and the Spectacled bear (n = 1). Bile of all species contained taurine-conjugated chenodeoxycholic acid and cholic acid. In some related carnivores, deoxycholic acid, the 7-dehydroxylation product of cholic acid, was also present. To determine whether the 7 beta hydroxy group of ursodeoxycholic acid was formed by hepatic or bacterial enzymes, bile acids were determined in hepatic bile obtained from bears with chronic biliary fistulae. Fistula bile samples contained ursodeoxycholic acid, chenodeoxycholic acid, and a trace amount of cholic acid, all as taurine conjugates, indicating that ursodeoxycholic acid is a primary bile acid formed in the liver in Ursidae.(ABSTRACT TRUNCATED AT 250 WORDS)

Using the isolated perfused rat and hamster liver, the relationship between bile flow, bile acid secretion rate and bile acid biotransformation after the injection of a small, bolus dose of radioactive ursodeoxycholate or of its C23 homolog, norursodeoxycholate, was examined. Ursodeoxycholate was promptly secreted into bile mostly as amino acid conjugates; less than 3% was secreted in unchanged form in the rat and less than 2% in the hamster. In contrast, norursodeoxycholate was secreted slowly, and biotransformed into glucuronide conjugates and unconjugated trihydroxy derivatives; it was also secreted in part in unchanged form. In the rat, 7% was secreted in unconjugated trihydroxy derivatives and 3% in unchanged form; in the hamster, 7% was secreted as unconjugated trihydroxy derivatives and 4% in unchanged form. The secreted bile acid species that showed the highest correlation with bile flow by far was always the unconjugated form in both rat and hamster. By multiple regression analysis, the apparent choleretic activity (microliters of induced bile flow per micromoles recovered bile acid molecules) indicated marked hypercholeresis for the unconjugated bile acid marked hypercholeresis for the unconjugated bile acid with values ranging from 100 to 300 microliters/mumol. Bile flow also correlated with total bile acid recovery for ursodeoxycholate in rat and norursodeoxycholate in hamster, but in all studies the apparent choleretic activity was far lower. Other calculations indicated that most bile flow during the first 30 min was induced by secretion of the unconjugated bile acid species in all experiments, the proportion ranging from 50% to 90%. The results indicate that when a bolus of ursodeoxycholate or norursodeoxycholate is presented to the perfused rodent liver, the secretion of the unchanged bile acid appears to be responsible for most of the bile flow, probably by a cholehepatic shunting mechanism.

In the perfused rat liver, ursodeoxycholate in high dose produces an HCO3- -rich hypercholeresis which we have shown previously to be inhibited by replacement of perfusate Na+ with Li+ or by addition of amiloride (or amiloride analogues). In the present studies, we have determined whether such inhibition is associated with altered ursodeoxycholate biotransformation. Under control conditions, ursodeoxycholate infusion produced a 3.7-fold increase in bile flow and a 9.2-fold increase in biliary HCO3- output. By thin-layer chromatography, ursodeoxycholate radioactivity in bile was present in unconjugated form (15%) or as glycine or taurine amidates. Glucuronide conjugates of ursodeoxycholate accounted for less than 1% of biliary bile acids. Li+/Na+ substitution decreased ursodeoxycholate-stimulated bile flow and HCO3- secretion by greater than 90%, but decreased recovery of ursodeoxycholate and metabolites by only 25%. Amiloride or amiloride analogues decreased ursodeoxycholate-stimulated choleresis and HCO3- output by 38%-76%, yet did not cause decreased recovery of ursodeoxycholate and metabolites. Inhibition of the hypercholeresis was associated with a decrease in unconjugated ursodeoxycholate to less than 2% of total biliary bile acids, a striking increase in ursodeoxycholate glucuronides, and a reciprocal decrease in glycine and taurine amidates. With Li+/Na+ substitution, the predominant metabolites were a mixture of the 24-ester and the 3-aketal (ethereal) glucuronide (29%), and amidation with glycine appeared to be selectively inhibited; with amiloride or its analogues, only the 3-ethereal glucuronide was formed (20%-60% of biliary bile acids), and both taurine and glycine amidation were inhibited. Thus, maneuvers that decrease Na+/H+ exchange inhibit ursodeoxycholate hypercholeresis and cause replacement of unconjugated ursodeoxycholate in bile by its glucuronide. The secretion of unconjugated ursodeoxycholate, a lipophilic bile acid, appears to be necessary for hypercholeresis induced by high-dose ursodeoxycholate infusion.