The readers NIH.
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Financing, Government↗
Biomedical subjects
A F Hofmann
Publications and source records attributed to A F Hofmann.
Conjugated bile acid uptake by Xenopus laevis oocytes induced by microinjection with ileal Poly A+ mRNA.
Apical membranes of ileal enterocytes contain the major Na+/bile acid cotransporter activity in mammals. Microinjection of guinea pig ileal mucosal Poly A+ mRNA (25 ng) into Xenopus oocytes resulted in 22,23-3H-cholyltaurine uptake at day 3 after injection (453 fmol/oocyte-hr), while control viral mRNA (25 ng) gave an uptake rate of 133 fmol/oocyte-hr. The transport rate increased in direct relationship to the concentration of injected mRNA, cholyltaurine, or Na+ in the incubation media. Uptake of cholyltaurine using rabbit ileal mucosal Poly A+ mRNA was 3891 fmole/oocyte-hr compared to rabbit jejunal-mucosa Poly A+ mRNA (control) injections inducing 728 fmol/oocyte-hr. Such expression of the ileal Na+/bile acid cotransporter may facilitate cloning of this key mammalian gene.
Animals↗
Lithocholic acid accumulation.
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Animals↗
Acute effects of topical methyl tert-butyl ether or ethyl propionate on gallbladder histology in animals: a comparison of two solvents for contact dissolution of cholesterol gallstones.
Experiments were performed in anesthetized rabbits and piglets to assess gallbladder mucosal injury during irrigation with methyl tert-butyl ether, a C5 ether, or ethyl propionate, a C5 ester--two organic solvents used in the contact dissolution of cholesterol gallstones. In 44 New Zealand White rabbits, the gallbladder was exposed to individual solvents or saline solution through a transhepatic catheter for 2 hr. Gallbladders were then harvested and fixed immediately or after a recovery period of 1, 4 or 8 days. Tissue sections were examined under light microscopy, and severity of injury was graded with predefined criteria by two pathologists blinded to the animals' treatment regimens. Histological assessment showed severe mucosal injury such as necrosis of the cells at the villus tips immediately after 2 hr of exposure to either solvent. After 4 days, injury had decreased significantly; after 8 days, complete mucosal healing had taken place. A similar study was performed in 32 piglets. Solvent or saline solution was oscillated in and out of the gallbladders of these piglets with a computer-controlled syringe pump at a pressure less than the leakage pressure of the gallbladder. Histological assessment was performed on tissue samples obtained immediately after the procedure or 8 days later. Both solvents caused severe mucosal injury; however, after 8 days complete mucosal healing had occurred, so that gallbladders exposed to solvent were indistinguishable from gallbladders exposed to saline solution, which was used as control. We conclude that both methyl tert-butyl ether and ethyl propionate cause moderate to severe epithelial injury but that the gallbladder epithelium regenerates within a few days.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of replacement therapy with cholylsarcosine on fat malabsorption associated with severe bile acid malabsorption. Studies in dogs with ileal resection.
The efficacy of cholylsarcosine, a synthetic deconjugation-resistant and nonsecretory conjugated bile acid analog for the treatment of fat malabsorption caused by severe bile acid malabsorption, was assessed in an animal model. In two dogs, the ileum and ileocecal valve were resected, causing severe diarrhea, steatorrhea, bile acid malabsorption, and progressive weight loss. Cholylsarcosine was administered as the water-soluble sodium salt by mixing with the dog food. Various doses were explored as well as varying intakes of dog food. Fat absorption was assessed by gravimetric measurement of fecal fat; a nonabsorbable recovery marker (polyethylene glycol mol wt 4000) was used to correct for incomplete fecal collections. Cholylsarcosine caused a 5- to 30-fold increase in fat absorption but had no significant effect on weight loss or fecal weight. Duodenal content was collected during digestion of a meal via a surgically placed Thomas cannula; the aspirates were dilute, acidic, and had a low bile acid concentration. The bile acid concentration increased modestly when cholylsarcosine was administered, but remained below the critical micellization concentration. The results indicate that oral administration of cholylsarcosine improved dietary fat absorption in a canine model of severe bile acid malabsorption with associated steatorrhea and bile acid deficiency in the proximal small intestine. Studies with this compound in patients with nutritional problems because of steatorrhea and severe bile acid malabsorption appear warranted.
Absorption↗
Sugar absorption by the biliary ductular epithelium of the rat: evidence for two transport systems.
Sugar absorption by the biliary ductular epithelium under steady-state conditions was examined using isolated perfused rat liver. The test sugar and mannitol (as a putative marker of paracellular entry) were added to the glucose-free recirculating perfusate each at a concentration of 5 mmol/L, and apparent active biliary ductular absorption equated with the change in concentration of the test sugar relative to that of mannitol. A metabolizable hexose (D-glucose), pentose (D-xylose), and three nonmetabolizable hexoses (alpha-methyl-glucoside, 3-o-methyl-glucose, and L-glucose) were used. All five monosaccharides were well absorbed at constant rates for 2 hours with apparent rates of absorption (mumol.kg body weight-1.min-1, mean +/- SE) of D-glucose, 0.24 +/- 0.01; L-glucose, 0.20 +/- 0.02; 3-o-methyl-glucose, 0.19 +/- 0.02; alpha-methyl-glucoside, 0.16 +/- 0.03; and D-xylose, 0.10 +/- 0.04. The addition of phloridzin to the perfusate inhibited D-glucose absorption in part but did not inhibit L-glucose absorption. When perfusate Na+ was replaced by N-methylglucamine, the bile-plasma ratio of mannitol remained unchanged, as did the apparent absorption rate of D-glucose and 3-o-methyl-glucose. In contrast, absorption of L-glucose and alpha-methyl-D-glucoside gradually ceased. The addition of 15 mmol/L glucose to the perfusate caused decreased bile flow and increased taurocholate concentration in bile, suggesting that glucose absorption by the biliary ductules induced water reabsorption. It is concluded that sugars are absorbed by the biliary ductular system by Na(+)-dependent and Na(+)-independent transport systems, the substrate affinities of which differ from those reported for apical membrane hexose transport systems in renal tubular and intestinal epithelia. Ductular absorption of solutes such as glucose that enter bile passively may have biological use, because ductular absorption decreases the concentration of substrates for bacterial growth in gallbladder bile. On the other hand, ductular absorption of solutes induces reabsorption of biliary water, resulting in decreased bile flow; this might contribute to cholestasis during prolonged hyperalimentation with solutions containing glucose.
Absorption↗
Effect of cholylsarcosine on hepatic cholesterol and bile acid synthesis and bile secretion in rats.
The regulatory and secretory properties of cholylsarcosine (C-sar), a synthetic conjugated bile acid analogue that resists deconjugation and dehydroxylation, were compared with those of the natural conjugates of cholic acid. After continuous intraduodenal infusion of cholylsarcosine (C-sar), cholyltaurine (C-tau), or cholylglycine (C-gly) at 36 mumol/100 g.h, the infused bile acid in each case became the predominant biliary bile acid. After 48 hours, infusion of C-sar, C-tau, and C-gly suppressed the activity of cholesterol 7 alpha-hydroxylase (C7 alpha H; rate-limiting for bile acid synthesis) by 65%, 78%, and 92%, respectively, compared with biliary fistula controls. After C-sar infusion, levels of C7 alpha H protein, messenger RNA, and transcriptional activity were depressed to the same extent as specific activity, indicating that C-sar, like C-tau, down-regulates C7 alpha H principally at the level of gene transcription. All three bile acids also suppressed activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (rate-limiting for cholesterol synthesis). Both short- and long-term, the three cholyl conjugates caused similar increases in bile flow and in biliary secretion of cholesterol and phospholipid. It is concluded that in the rat, cholyl conjugates per se can suppress cholesterol and bile acid biosynthesis without prior conversion to deoxycholate. The effects of C-sar on hepatic cholesterol and bile acid synthesis as well as on induced bile flow and biliary lipid secretion are essentially identical to those of the naturally occurring cholyl conjugates.
Animals↗
Systemic and local toxicity in the rat of methyl tert-butyl ether: a gallstone dissolution agent.
Methyl tert-butyl ether (MTBE) is an organic solvent that has been used to dissolve gallstones via a percutaneous transhepatic catheter into the gallbladder. To test whether MTBE might cause serious tissue injury if accidentally infused outside the gallbladder, the effect of MTBE (0.2 ml/kg) injected into the hepatic parenchyma, or administered intravenously or intraperitoneally, was examined in the rat. The toxicity of isopropyl acetate (IPA), an organic solvent with a similar chemical structure, was examined similarly. Intracaval injection of MTBE caused the highest mortality (100%). Mortality was less (59%) after intrahepatic injection and still less (17%) after peripheral vein injection. Most animals died instantaneously from cardiorespiratory arrest. Almost all animals that were injected with MTBE intrahepatically or intravenously showed localized areas of congestion, hemorrhage, and interstitial edema in the lungs. These changes were more severe in rats which survived for 24 hr than in those which died sooner. In those rats receiving intrahepatic injections, most rats which survived for 24 hr had liver necrosis at the site of injection. Intraperitoneal injection of MTBE produced 100% survival with only 1/5 rats showing a mild pulmonary injury at autopsy. IPA had toxic effects similar to those evoked by MTBE. To test whether tumor necrosis factor was involved in organ injury, serum levels were measured; they remained unchanged. These experiments indicate that two organic solvents, MTBE and IPA, are cytotoxic to local tissues and cause severe, and often fatal, lung damage when infused into a central vein. Less toxicity occurred if solvents were given into a peripheral or portal vein or intraperitoneally.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetates↗
Physicochemical and physiological properties of cholylsarcosine. A potential replacement detergent for bile acid deficiency states in the small intestine.
The properties of cholylsarcosine (the synthetic N-acyl conjugate of cholic acid with sarcosine [N-methylglycine]) were examined to determine its suitability as a bile acid replacement agent for conditions of bile acid deficiency in the small intestine, which causes fat malabsorption. Previous studies in rodents had shown that the compound was well transported by the liver and ileum and underwent neither deconjugation nor dehydroxylation during enterohepatic cycling. By 1H-nuclear magnetic resonance, cholylsarcosine was found to exist in dilute aqueous solution as an almost equimolar mixture of two geometric isomers--cis and trans (around the amide bond)--in contrast to cholylglycine, which was present entirely in the trans form. The critical micellization concentration was 11 mmol/liter, similar to that of cholylglycine (10 mmol/liter). By nonaqueous titrimetry, the pKa' of cholylsarcosine was 3.7, only slightly lower than that of cholylglycine (3.9). Cholylsarcosine was poorly soluble below pH 3.7, but highly soluble above pH 4. In vitro, cholylsarcosine behaved as cholylglycine with respect to promoting lipolysis by lipase/colipase. There was little difference between cholylsarcosine and cholylglycine in their solubilization of an equimolar mixture of oleic acid, oleate, and monoolein (designed to simulate digestive products of triglyceride) or in their solubilization of monooleyl-glycerol alone. When a [3H]triolein emulsion with either cholylsarcosine or cholyltaurine was infused intraduodenally in biliary fistula rats, recovery of 3H in lymph was 52 +/- 10% (mean +/- SD) for cholylsarcosine and 52 +/- 11% for cholyltaurine. When perfused into the colon of the anesthetized rabbit, cholylsarcosine (5 mmol/liter) did not influence water absorption or permeability to erythritol, in contrast to chenodeoxycholate, which induced vigorous water secretion and caused erythritol loss. We conclude that cholylsarcosine possesses the physicochemical and physiological properties required for a suitable bile acid replacement in deficiency states.
Animals↗
Ionized calcium in gallbladder bile: new insights into a clear and ever-present danger.
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Bile↗
A proposed nomenclature for bile acids.
A proposal is made for a system of nomenclature of the more common unconjugated and conjugated bile acids. Acceptable trivial names for bile acids are tabulated, and guidelines are proposed for using these existing trivial names as roots to create acceptable semi-systematic names for other bile acids, as well as for new natural bile acids that will be discovered in the future. The term alpha-hyocholic is recommended to replace hyocholic, and beta-hyocholic to replace omega-muricholic. The term murideoxycholic acid is recommended for 3 alpha,6 beta-dihydroxy-5 beta-cholan-24-oic acid. Proposals are also made for bile acids with epimeric hydroxy groups, for unsaturated bile acids, and for bile acids with oxo- and/or hydroxy-oxo- substituents on the nucleus and/or on the side chain. For conjugated bile acids, the term "aminoacyl amidates" is recommended to replace "amidates" for bile acids conjugated in N-acyl linkage with amino acids. Nomenclature for other types of conjugates (sulfates, glucuronides, glucosides) is included as well as abbreviations. It is recommended that the historic tradition of naming a newly discovered bile acid after the species from which it was isolated be abandoned, and that in the future such a bile acid should be named using the principles contained in this paper.
Bile Acids and Salts↗
Bile acid solubility and precipitation in vitro and in vivo: the role of conjugation, pH, and Ca2+ ions.
The principles governing the in vitro solubility of the common natural conjugated and unconjugated bile acids and salts in relation to pH, micelle formation, and Ca2+ concentration are considered from a theoretical standpoint and then correlated first with experimental observations on model systems and second with the formation of precipitates containing bile acids in health and disease. In vitro, taurine-conjugated bile acids are soluble at strongly acidic pH; glycine-conjugated bile acids are poorly soluble at moderately acidic pH; and many of the common, natural unconjugated bile acids are insoluble at neutral pH. For both glycine-conjugated and unconjugated bile acids, solubility rises exponentially, with increasing pH, until the concentration of the anion reaches the critical micellization concentration (CMC) when micelle formation occurs and solubility becomes practically unlimited. In vivo, in health, conjugated bile acids are present in micellar form in the biliary and intestinal tract. Unconjugated bile acids formed in the large intestine remain at low monomeric concentrations because of the acidic pH of the proximal colon, binding to bacteria, and absorption across the intestinal mucosa. In diseases in which proximal small intestinal content is abnormally acidic, precipitation of glycine-conjugated bile acids (in protonated form) occurs. Increased bacterial formation of unconjugated bile acids occurs with stasis in the biliary tract and small intestine; in the intestine, unconjugated bile acids precipitate in the protonated form. If the precipitates aggregate, an enterolith may be formed. In vitro, the calcium salts of taurine conjugates are highly water soluble, whereas the calcium salts of glycine conjugates and unconjugated bile acids possess limited aqueous solubility that is strongly influenced by bile acid structure. Precipitation occurs extremely slowly from supersaturated solutions of glycine-conjugated bile acids because of metastability, whereas super-saturated solutions of unconjugated bile acids rapidly form precipitates of the calcium salt. In systems containing Ca2+ ions and unconjugated bile acids, pH is important, since it is the key determinant of the anion concentration. For bile acids with relatively soluble calcium salts (or with a low CMC), the concentration of the anion will reach the CMC and micelles will form, thus precluding formation of the insoluble calcium salt. For bile acids, with relatively insoluble calcium salts (or with a high CMC), the effect of increasing pH is to cause the anion to reach the solubility product of the calcium salt before reaching the CMC so that precipitation of the calcium salt occurs instead of micelle formation.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Solubility of calcium salts of unconjugated and conjugated natural bile acids.
The approximate solubility products of the calcium salts of ten unconjugated bile acids and several taurine conjugated bile acids were determined. The formation of micelles, gels, and/or precipitates in relation to Ca2+,Na+, and bile salt concentration was summarized by "phase maps." Because the ratio of Ca2+ to bile salt in the precipitates was ca. 1:2, and the activity of Ca2+ but not that of bile salt (BA-) could be measured, the ion product of aCa2+ [BA-]2 was calculated. The ion product (= Ksp) ranged over nine orders of magnitude and the solubility thus ranged over three orders of magnitude; its value depended on the number and orientation of the hydroxyl groups in the bile acid. Ion products (in units of 10(-9) mol/l)3 were as follows: cholic (3 alpha OH,7 alpha OH,12 alpha OH) 640; ursocholic (3 alpha OH,7 beta OH,12 alpha OH) 2300; hyocholic (3 alpha OH,6 alpha OH,7 alpha OH) 11; ursodeoxycholic (3 alpha OH,7 beta OH) 91; chenodeoxycholic (3 alpha OH,7 alpha OH) 10; deoxycholic (3 alpha OH,12 alpha OH) 1.5; 12-epideoxycholic (lagodeoxycholic, 3 alpha OH,12 beta OH) 2.2; hyodeoxycholic (3 alpha OH,6 alpha OH) 0.7; and lithocholic (3 alpha OH) 0.00005. The critical micellization temperature of the sodium salt of murideoxycholic acid (3 alpha OH,6 beta OH) was greater than 100 degrees C, and its Ca2+ salt was likely to be very insoluble. Taurine conjugates were much more soluble than their corresponding unconjugated derivatives: chenodeoxycholyltaurine, 384; deoxycholyltaurine, 117; and cholyltaurine, greater than 10,000. Calcium salts of unconjugated bile acids precipitated rapidly in contrast to those of glycine conjugates which were metastable for months. Thus, hepatic conjugation of bile acids with taurine or glycine not only enhances solubility at acidic pH, but also at Ca2+ ion concentrations present in bile and intestinal content.
Bile Acids and Salts↗
Measurement of total fasting-state serum bile acids: comparison of a solid-phase bioluminescence enzymatic assay, a homogeneous fluorescence enzymatic assay and isotope dilution gas chromatography-mass spectrometry.
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Bile Acids and Salts↗
Inhibition of glutathione-conjugate secretion from isolated hepatocytes by dipolar bile acids and other organic anions.
The effect of a spectrum of organic compounds on the secretion of a model organic anion, dinitrophenylglutathione (GS-DNP), by hepatocytes was tested. Previous experiments have demonstrated that the secretion of GS-DNP from isolated rat hepatocytes is predominantly mediated by a canalicular transport system for this compound. Preincubation of isolated rat hepatocytes with the bile acids cholic acid (C), taurocholic acid (TC), tauroursodeoxycholic acid (TUDC) and glyco- or tauro-lithocholic acid (GLC or TLC) had no effect on the initial efflux rate of GS-DNP. In contrast, the 3-sulphates of GLC (SGLC) and TLC (STLC) did inhibit GS-DNP efflux; half-maximal inhibition with SGLC was reached with 10 microM. The 3-O-glucuronides of both cholate and lithocholate (GlucLC) were even more potent inhibitors of transport; 10 microM-GlucLC inhibited GS-DNP transport by 89%. Other cholephilic organic anions also inhibited GS-DNP secretion, albeit at higher concentrations; at 100 microM, bilirubin ditaurate, an analogue of bilirubin diglucuronide, inhibited transport by 48%. On the other hand, a number of cholephilic cationic and neutral compounds had no effect on GS-DNP efflux. The hepatobiliary secretion of oxidized glutathione (GSSG) was also investigated. In normal isolated perfused rat liver, extensive biliary secretion of GSSG was observed upon intracellular oxidation of reduced glutathione (GSH). GSSG was also actively secreted from isolated normal hepatocytes, and this secretion could be inhibited by 95% by incubation of the cells with 100 microM-SGLC. In contrast, biliary secretion was absent in the isolated perfused liver and in isolated hepatocytes from TR- mutant rats with a hereditary conjugated hyperbilirubinaemia. These results show that the canalicular efflux of GSSG and GS conjugates can be inhibited by a wide variety of polyvalent organic anions, but not by cations, neutral compounds and unianionic bile acids. This suggests that a multispecific organic-anion transporter is responsible for transport of these polyvalent anions, which is in close agreement with the fact that the biliary transport of all these compounds is defective in the mutant TR4 rat.
Animals↗
Replacement of cholesterol gallstones by murideoxycholyl taurine gallstones in prairie dogs fed murideoxycholic acid.
The effect of two hydrophilic bile acids, murideoxycholic acid (3 alpha,6 beta-dihydroxy-5 beta-cholanoic acid) and ursodeoxycholic acid, on cholesterol and bile acid metabolism and hepatic pathology and gallstone composition was studied in the prairie dog. Cholesterol gallstones were induced by feeding a diet containing 1.2% cholesterol for 75 days. The animals were divided into six groups, and gallstone regression was studied as follows: groups 2 and 5, chow plus 0.2% cholesterol; groups 3 and 6, chow plus 0.2% cholesterol plus 0.15% ursodeoxycholic acid; groups 4 and 7, chow plus 0.2% cholesterol plus 0.15% murideoxycholic acid. Animals in groups 2 to 4 were killed after an additional 6 wk; animals in groups 5 to 7 were killed after an additional 12 wk. Gallstone dissolution did not occur in any group. The gallstones in groups 2, 3, 5 and 6 were typical cholesterol aggregates, as determined by polarized light microscopy and Fourier transform infrared spectrometry. The gallstones of the murideoxycholic acid group were large, solitary, dark stones that appeared radiopaque under 22 kVp x-ray examination. Scanning electron microscopy showed that in these stones the cholesterol crystals had been replaced by an amorphous material, both within the stone and on the stone surface. Chemical analysis indicated that at the end of 12 wk the calcium/sodium salt of the taurine conjugate of murideoxycholic acid (murideoxycholyl taurine) comprised 70% of the stones; protein, cholesterol and small amounts of other bile salts were also present. In vitro studies confirmed the insolubility of the sodium and calcium salts of murideoxycholyl taurine. These studies indicate that the hydrophilic bile acids, murideoxycholic acid and ursodeoxycholic acid, did not achieve gallstone dissolution under the conditions used. In the animals fed murideoxycholic acid, an insoluble calcium salt of murideoxycholyl taurine replaced cholesterol as the major constituent of gallbladder stones. This is the first example of an insoluble dihydroxy taurine-conjugated bile acid; administration of the unconjugated bile acid induced precipitation of a kind of gallstone not previously reported. The final result was transformation of cholesterol stones to bile salt stones.
Animals↗
Activation of mast cells by bile acids.
To test whether bile acids interact with mast cells, dilute, aqueous solutions of five pure unconjugated natural bile acids and their corresponding glycine or taurine conjugates were incubated with murine PT-18 cells (a mast cell line functionally and cytochemically similar to mucosal mast cells) or with freshly isolated rat peritoneal mast cells. Bile acid solutions ranged in concentration from 0.3 to 10 mmol/L; histamine release was assessed by a fluorimetric assay, and cell lysis by cytosolic enzyme (lactate dehydrogenase) release. Lipophilic, dihydroxy bile acids (chenodeoxycholic acid and deoxycholic acid as well as their glycine and taurine conjugates) caused histamine release in a dose-related manner; cholic acid and its conjugates caused much less or no histamine release. Two hydrophilic bile acids (ursodeoxycholic acid and ursocholic acid and their conjugates) were virtually devoid of activity. Histamine release, which was independent of extracellular Ca2+, occurred at 0.3 mmol/L, well below the critical micellization concentration. For a given concentration, unconjugated bile acids and glycine-conjugated bile acids induced more histamine release than taurine-conjugated bile acids; maximal release was observed at 3 mmol/L for lipophilic, dihydroxy bile acids. To test whether bile acids could also cause histamine release from cutaneous mast cells in vivo, rats were injected intradermally with bile acid solutions and histamine release assessed by capillary leakage of Evan's blue dye. Cutaneous blueing was greater with cytotoxic bile acids, chenodeoxycholyglycine or deoxycholylglycine, than with ursodeoxycholylglycine and was inhibited by prior antihistamine treatment. Histamine release correlated highly and positively with lipophilicity and with bile acid surface activity. It was concluded that lipophilic but not hydrophilic bile acids possess concentration-dependent cytotoxicity toward mast cells causing histamine release, that unconjugated and glycine-conjugated bile acids are more potent than taurine-conjugated bile acids, and that mast cell histamine release is highly correlated with lipophilicity of bile acids as well as their surface activity.
Animals↗
Active absorption of conjugated bile acids in vivo. Kinetic parameters and molecular specificity of the ileal transport system in the rat.
Active transport of conjugated bile acids by the distal ileum is required for efficient enterohepatic cycling of bile acids. Experiments were performed in the rat to obtain accurate values for Tmax and Michaelis constant (Km) of the absorptive area of the rat ileum and to define the structural specificity of the transport system. The distal fifth (20 cm) of the small intestine from an anesthetized animal with a biliary fistula was perfused using solutions of 10 taurine-conjugated bile acids; a flow rate was used that was sufficiently high such that unstirred water layer effects were negligible and the intraluminal concentration remained unchanged throughout the perfused segment. The absorption rate was equated with the rate of hepatic bile acid secretion. Values of Tmax (mumol/min.kg) were markedly influenced by bile acid structure: cholyltaurine, 12.9; ursocholyltaurine, 9.6; ursodeoxycholyl taurine, 5.0; and lagodeoxycholyl-(3 alpha,12 beta-dihydroxy-cholanoic acid)-taurine, 1.2. Decreasing the length of the side chain of ursodeoxycholate conjugates from 8 to 6 carbon atoms was associated with a modest increase in Tmax values from 5.0 to 9.1 mumols/min.kg. Values of Km correlated with Tmax values and ranged from 0.5 to 5 mmol/L, being highest for those bile acids that were best transported. The Tmax for cholyltaurine transport was not reached when the intraluminal concentration was as high as its critical micellization concentration, precluding the definition of its Tmax; however, for ursocholyltaurine, with a critical micellization concentration of 40 mmol/L, saturation of transport was clearly shown. Kinetic parameters could not be obtained for two common dihydroxy conjugates (chenodeoxycholyltaurine and deoxycholyltaurine) because at a transport rate of 2 mumols/min.kg systemic toxicity and death occurred. These studies define the maximal transport capacity of the rat ileum for taurine-conjugated bile acids; they indicate that the ileal transport system in the rat is of low affinity and high capacity for taurine conjugates of hydrophilic bile acids, and they show that both nuclear substituents and side chain length influence the transport rate of taurine-conjugated bile acids.
Animals↗