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PubMed1996

Vasopressin reduces taurochenodeoxycholate-induced hepatotoxicity by lowering the hepatocyte taurochenodeoxycholate content.

BACKGROUND/AIMS: Vasopressin has been reported to reduce bile flow, but its effects on bile acid secretion and bile acid-related hepatotoxicity are still unclear. We therefore investigated the influence of vasopressin on the hepatotoxicity and biliary excretion of taurochenodeoxycholic acid in primary cultured rat hepatocytes and isolated perfused rat liver models. METHODS/RESULTS: 1) Addition of vasopressin to hepatocyte cultures significantly decreased lactate dehydrogenase release as compared to cultures exposed to 1 mM taurochenodeoxycholic acid alone, and also reduced intracellular taurochenodeoxycholic acid content from 19.3 +/- 2.2 to 13.0 +/- 1.6 nmol/mg protein. After 30 min of preincubation with 1 mM taurochenodeoxycholic acid, rinsing and reculture of hepatocytes in bile acid-free medium resulted in gradual decrease in the intracellular level of the bile acid, and addition of vasopressin (10(-9) M) to the reculture medium accelerated this process. 2) Superimposition of vasopressin (330 pmol/l) for 10 min on taurochenodeoxycholic acid infusion (1.0 mumol/min: 25 mumol/l) caused a rapid increase in bile flow and biliary excretion of taurochenodeoxycholic acid (697 +/- 42 vs 584 +/- 27 nmol/10 min per g liver) from perfused rat livers, and significantly reduced lactate dehydrogenase release. 3) Superimposition of the PKC blocker H-7 (5 mumol/l) on taurochenodeoxycholic acid infusion (1.0 mumol/min: 25 mumol/l) caused a gradual increase in bile flow and biliary excretion of taurochenodeoxycholic acid. Furthermore, an additional infusion of vasopressin (100 pmol/l) for 10 min in the presence of H-7 produced a greater increase in bile flow and biliary excretion of taurochenodeoxycholic acid as compared with H-7 alone (754 +/- 71 vs. 657 +/- 26 nmol/g liver). 4) Continuous infusion of vasopressin (330 pmol/l) significantly increased the late peak (10-50 min) of horseradish peroxidase excretion from perfused livers (from 8.48 +/- 1.02 to 21.7 +/- 6.02 ng/g liver). CONCLUSIONS: These findings suggest that vasopressin exerts a protective effect against taurochenodeoxycholic acid-induced hepatotoxicity by stimulating the secretion of this bile acid via intracellular vesicular transport systems.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1977

Synthesis and characteristics of the specific monosulfates of chenodeoxycholate, deoxycholate and their taurine or glycine conjugates.

The isomeric monosulfates of chenodeoxycholate, deoxycholate, and their taurine or glycine conjugates, were synthesized and characterized. Reaction with chlorosulfonic acid in pyridine for 2 minutes mainly afforded the 3-monosulfates. To prepare the 7- or the 12-monosulfates, the 3-hydroxyl group was protected by carbethoxylation prior to sulfation of the 7- or 12-hydroxyl group for 24 h to 5 days; after sulfation, the protecting 3-carbethoxy function was removed by mild alkaline hydrolysis. The crude bile salt monosulfates were purified by chromatography on silica gel and on Sephadex LH-20 and were crystallized from methanolethanol-ethyl acetate. The results of elemental analysis demonstrated that the compounds were disodium dihydroxy bile salt monosulfates. Thin layer chromatography of the sulfates, and gas-liquid chromatography after oxidation and solvolysis, showed that the substances were pure and that the sulfate group was at the expected position.

Bile Acids and Salts↗
PubMed1990

Tauroursodeoxycholate prevents taurolithocholate-induced cholestasis and toxicity in rat liver.

Ursodeoxycholate has been advocated for the treatment of cholestatic liver diseases. The coinfusion of tauroursodeoxycholate with taurolithocholate in the perfused rat liver completely prevented the decrease of bile flow and the increase of oxygen uptake found with taurolithocholate only. Bile flow and bile salt secretion were increased with the coinfusion of both bile acids as compared with the infusion of tauroursodeoxycholate only (+4.30 microliters/g liver per 30 min) with 16 and 32 mumol/l tauroursodeoxycholate (+1.55 microliters/g liver per 30 min with 80 and 160 mumol/l). Morphological examination revealed a 50% decrease of the number of necrotic cells in the periportal area. Tauroursodeoxycholate did not inhibit the uptake of taurolithocholate, but increased its transcellular passage and biotransformation. Thus, tauroursodeoxycholate prevents taurolithocholate-induced cholestasis and liver cell toxicity probably by an intracellular mechanism.

Animals↗
PubMed1978

A rapid, sensitive method for accurate analysis of individual bile acids in biological fluids by high performance thin-layer chromatography and densitometry.

1. A rapid new micromethod for quantitative analysis of individual bile acids in duodenal juice by high performance thin-layer chromatography (HPTLC) and densitometry is described and evaluated by comparison with standard TLC and spectrophotometry. 2. Advantages of HPTLC over TLC include more rapid separation, better resolution and more sensitive detection (5 - 10 fold), without the need for prior extraction. Densitometry provides simple, direct and rapid quantitation. 3. The method is accurate and reliable over a range of bile acid concentrations. In the 0.5 mM range, recovery was greater than 89%, and coefficients of variation for within-day analysis were 2 - 12% and for between-day analysis were 6 - 18% for the individual bile acids. Twenty analyses can be performed by one worker in a single day. 4. We conclude that the method offers several advantages over most currently described techniques, is suitable for routine use and is deserving of wider application.

Bile Acids and Salts↗
PubMed1997

Composition and concentration of bile acid reflux into the esophagus of patients with gastroesophageal reflux disease.

BACKGROUND: Reflux of duodenal contents into the esophagus of patients with gastroesophageal reflux disease has been suggested by pH and bilirubin monitoring but is rarely directly measured. A portable device has been developed and was used to collect and quantitate material refluxed into the esophagus under ambulatory conditions during a prolonged time period. The objective of this study was to use this device to quantitate the composition and concentration of bile acids refluxed into the esophagus of patients with gastroesophageal reflux disease. METHODS: Esophageal aspiration was performed on 43 normal subjects and 37 patients with reflux disease during a 17-hour period. Aspiration was performed through a modified 16F Salem sump tube, positioned 5 cm above the lower esophageal sphincter and connected to a portable, battery powered pump that aspirated continuously at 100 mm Hg pressure. Validation studies showed that minimal amounts of saliva and swallowed liquids were aspirated and that gastric pressure was not altered. Postprandial, upright, and supine collections were performed. Total bile acids were assayed by a standard enzymatic assay; specific conjugated bile acids were analyzed by high-performance liquid chromatography. RESULTS: There was no difference in the total aspiration volume between normal volunteers and patients with gastroesophageal reflux disease, although patients tended to have a higher volume in the supine and postprandial periods. Bile acids could be detected in 58% of normal subjects and 86% of patients (p < 0.003). The mean concentration of bile salt exposure (micromole per liter) was higher in patients during the postprandial and supine periods. The mean bile acid reflux rate (micromole per hour) during all three aspiration periods was significantly higher in patients. On a molar basis the composition of the bile acids was 60% glycocholic acid, 16% glycodeoxycholic acid, and 15% glycochenodeoxycholic acid. Taurocholic, taurodeoxycholic, taurochenodeoxycholic, and glycolithocholic acid constituted the remaining 10%. CONCLUSIONS: Patients with reflux disease have an increased concentration of bile acids in their esophageal aspirates. Most of the exposure occurs during the postprandial and supine periods. A variety of bile acids were detected, most of which were in their glycine conjugated form.

Adult↗
PubMed2005

Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans.

How genetic and environmental factors interact in Parkinson disease is poorly understood. We have now compared the patterns of vulnerability and rescue of Caenorhabditis elegans with genetic modifications of three different genetic factors implicated in Parkinson disease (PD). We observed that expressing alpha-synuclein, deleting parkin (K08E3.7), or knocking down DJ-1 (B0432.2) or parkin produces similar patterns of pharmacological vulnerability and rescue. C. elegans lines with these genetic changes were more vulnerable than nontransgenic nematodes to mitochondrial complex I inhibitors, including rotenone, fenperoximate, pyridaben, or stigmatellin. In contrast, the genetic manipulations did not increase sensitivity to paraquat, sodium azide, divalent metal ions (Fe(II) or Cu(II)), or etoposide compared with the nontransgenic nematodes. Each of the PD-related lines was also partially rescued by the antioxidant probucol, the mitochondrial complex II activator, D-beta-hydroxybutyrate, or the anti-apoptotic bile acid tauroursodeoxycholic acid. Complete protection in all lines was achieved by combining d-beta-hydroxybutyrate with tauroursodeoxycholic acid but not with probucol. These results show that diverse PD-related genetic modifications disrupt the mitochondrial function in C. elegans, and they raise the possibility that mitochondrial disruption is a pathway shared in common by many types of familial PD.

3-Hydroxybutyric Acid↗
PubMed1989

Changes in the concentration and composition of biliary and serum bile acids in the young domestic fowl.

1. Concentrations of biliary and serum bile acids, their molecular compositions and serum cholesterol concentrations were determined in chicks at 2, 3, 4 and 6 weeks of age. 2. The concentration of biliary bile acid was maximal at 3 to 4 weeks, decreasing by 6 weeks of age. 3. The serum concentration of bile acid was maximal at three weeks of age. 4. Serum total cholesterol increased from two weeks and was maximal at 6 weeks of age. 5. Chenodeoxycholic acid was the predominant biliary unconjugated bile acid. 6. Tauro-chenodeoxycholic acid and tauro-cholic acid were the dominant molecular species of biliary and serum conjugated bile acid.

Age Factors↗
PubMed2001

Differences in Ca(2+) signaling underlie age-specific effects of secretagogues on colonic Cl(-) transport.

Taurodeoxycholic acid (TDC) stimulates Cl(-) transport in adult (AD), but not weanling (WN) and newborn (NB), rabbit colonic epithelial cells (colonocytes). The present study demonstrates that stimuli like neurotensin (NT) are also age specific and identifies the age-dependent signaling step. Bile acid actions are segment and bile acid specific. Thus although TDC and taurochenodeoxycholate stimulate Cl(-) transport in AD distal but not proximal colon, taurocholate has no effect in either segment. TDC increases intracellular Ca(2+) concentration ([Ca(2+)](i)) in AD, but not in WN and NB, colonocytes. In AD cells, TDC (5 min) action on Cl(-) transport needs intra- but not extracellular Ca(2+). NT, histamine, and bethanechol increase Cl(-) transport and [Ca(2+)](i) in AD, but not WN, distal colonocytes. However, A-23187 increased [Ca(2+)](i) and Cl(-) transport in all age groups, suggesting that Ca(2+)-sensitive Cl(-) transport is present from birth. Study of the proximal steps in Ca(2+) signaling revealed that NT, but not TDC, activates a GTP-binding protein, Galpha(q), in AD and WN cells. In addition, although WN and AD colonocytes had similar levels of phosphatidylinositol 4,5-bisphosphate, NT and TDC increased 1,4,5-inositol trisphosphate content only in AD cells. Nonresponsiveness of WN cells to Ca(2+)-dependent stimuli, therefore, is due to the absence of measurable phospholipase C activity. Thus delays in Ca(2+) signaling afford a crucial protective mechanism to meet the changing demands of the developing colon.

Aging↗
PubMed1977

The age dependence of bile acid metabolism in rats.

The age dependence of bile acid metabolism in rats was investigated and the following results were obtained. 1) Synthesis rate, pool size and total secretion decreased in old rats (24 month) significantly compared to young rats (6 weeks). 2) The quotient of taurine to glycine conjugates is is significant lower in old rats compared to young rats. 3) The lithogenic index remains unchanged in all age groups. 4) Old rats show a significantly higher Km for cholic acid uptake, whereas the diffusion coefficient is decreased. The possible influence of humoral factors on age dependent regulations of bile metabolism is discussed.

Age Factors↗
PubMed1984

Effects of four taurine-conjugated bile acids on mucosal uptake and lymphatic absorption of cholesterol in the rat.

The importance of the bile acid structure on mucosal uptake and lymphatic absorption of cholesterol was investigated using four different taurine-conjugated bile acids. Pure synthetic conjugates of a trihydroxy bile acid, taurocholate, and three dihydroxy bile acids, tauroursodeoxycholate, taurochenodeoxycholate, and taurodeoxycholate were used to completely solubilize [14C]cholesterol and polar lipids for steady rate intraduodenal infusion for 8 hr in bile fistula rats. Lymph output and esterification of [14C]cholesterol and endogenous cholesterol were measured in hourly samples. A second group of bile fistula rats was given the same bile acids as the first group but without added cholesterol or other lipid, i.e., fasting lymph fistula group. Mucosal uptake of [14C]cholesterol was studied using recovery of [14C]cholesterol from lumen and mucosa after 1-hr infusions in conscious bile fistula rats. Lymph output of [14C]cholesterol was promoted more rapidly with taurocholate than with the dihydroxy conjugates and [14C]cholesterol output differed for the three groups given dihydroxy bile acids. The mass of cholesterol in lymph, measured chemically, varied in parallel with [14C]cholesterol absorption. For fasting lymph, infusion of dihydroxy bile acids failed to produce a significant change in endogenous cholesterol output when compared with rats given saline only. Taurocholate infusion markedly increased endogenous cholesterol in lymph of fasted rats. Under all conditions where cholesterol output was stimulated, the increase could be accounted for mainly as esterified cholesterol. Mucosal uptake of [14C]cholesterol during 1-hr infusions in conscious bile fistula rats was slower with the dihydroxy bile acids than with taurocholate. The results indicate the marked effect of the number and configuration of the hydroxyl groups on the solubilizing bile acid for cholesterol absorption.

Absorption↗
PubMed1980

Effects of sulfation patterns on intestinal transport of bile salt sulfate esters.

The absorption of 14C-labeled 3 alpha-, the 7 alpha- and the 3 alpha,7 alpha-sulfate esters of taurochenodeoxycholate by guinea pig small intestine was studied using in vivo and in vitro preparations. In vivo ileal perfusions showed that sulfation markedly decreased uptake by the ileal bile salt transport system and that the position and number of the sulfate radicals affected the degree of transport inhibition. The following relationships were found: transport of taurochenodeoxycholate (TCDC) greater than TCDC-3-sulfate greater than TCDC-7 sulfate greater than TCDC-3,7-disulfate with a decrease of approximately 90% between each pair. In vitro, jejunal perfusions demonstrated that sulfation also decreased passive flux. By use of an everted gut sac technique, the ability of ileum to move the sulfated bile salts against a concentration gradient was measured. Under these conditions transport of TCDC-3-sulfate was minimal, and that of the 7-sulfate and 3,7-disulfate was not observed. In view of the reported increased levels of sulfated bile salts after total or partial biliary tract obstruction, our results support the concept of sulfation as an adaptive mechanism for enhancing fecal elimination of bile salts.

Animals↗
PubMed1991

Bile composition of adult baboons is influenced by breast versus formula feeding.

We tested the hypothesis that infant cholesterol intake and breast- versus formula-feeding influence the bile cholesterol saturation index and bile acid conjugate composition in adult baboons at 7-8 years of age. We also measured the influence of the postweaning intake of dietary cholesterol and fat (saturated and unsaturated) on the effects of the infant diets. The 80 baboons were derived from six sires and 80 dams and randomly assigned at birth to breast-feeding or to one of three formulas containing about 2, 30, or 60 mg cholesterol/dl. After weaning at 16 weeks of age the animals were assigned to one of four adult diets, which contained 0.01 or 1.0 mg/kcal of cholesterol containing 40% of calories from saturated or unsaturated fat. The bile cholesterol saturation index was significantly higher at 7-8 years of age in baboons breast-fed as infants compared with those fed formula (87.0% versus 72.8%, p less than 0.004). The cholesterol saturation index was not significantly different among the three formula groups. Among baboons who were breast-fed and subsequently fed saturated fat as adults, the glycine/taurine (G/T) ratios of the bile acid conjugates were about three times those of baboons fed unsaturated fat (1.53 versus 0.47); whereas among formula-fed animals the type of fat did not influence the G/T ratio (interaction, p = 0.022). Adult baboons fed the three formulas in infancy had an inverse relationship of the G/T ratio to the level of formula cholesterol (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Unconjugated, glycine-conjugated, taurine-conjugated bile acid nonsulfates and sulfates in urine of young infants with cholestasis.

A direct assay system for conjugated bile acids using an enzymatic procedure and high-performance liquid chromatography was used for the analysis of urinary bile acid profiles in young infants with intrahepatic cholestasis (idiopathic neonatal hepatitis syndrome) or extra-hepatic biliary atresia. The major urinary bile acids were cholate and chenodeoxycholate conjugates, but a small amount of deoxycholate and 3 beta-hydroxy-5-cholenate conjugates were detected. Although there was no significant difference in total bile acid excretion between patients with intrahepatic cholestasis and extrahepatic biliary atresia, mean ratios of cholate to chenodeoxycholate and sulfated to total urinary bile acids were different between the two groups examined (5.63 +/- 2.83 vs. 2.50 +/- 1.25, p less than 0.05, 15.8 +/- 9.9 vs. 34.5 +/- 9.9%, p less than 0.005). The proportion of taurine-conjugated chenodeoxycholate in the sulfate fraction to the total bile acid was lower in intrahepatic cholestasis, compared with that in biliary atresia (7.7 +/- 7.5 vs 22.7% +/- 7.8%, p less than 0.005). The greater ratio of cholate to chenodeoxycholate and the reduced excretion of sulfated urinary bile acids in intrahepatic cholestasis was due to decreased taurine-conjugated chenodeoxycholate sulfate excretion.

Bile Acids and Salts↗
PubMed1983

Fasting and postprandial serum concentrations of glycine- and taurine-conjugated bile acids in Crohn's disease.

Fasting and postprandial serum concentrations of glycine and taurine conjugates of cholic, chenodeoxycholic, and deoxycholic acid were measured with a high-pressure liquid chromatographic-enzymatic assay in 17 patients with ileal Crohn's disease and in 17 controls. The postprandial concentrations of the taurine-conjugated bile acids in the patients were significantly lower than in the controls, whereas the concentrations of the glycine conjugates were not significantly different. The total glycine to taurine ratios of serum bile acids were significantly higher in the patients (means, 2.9 fasting and 4.8 postprandial) than in the controls (1.9 and 2.6). Of the patients, 65% had a postprandial total G/T ratio of serum bile acids which was above the control interval.

Adult↗
PubMed1999

Differences in the metabolism and disposition of ursodeoxycholic acid and of its taurine-conjugated species in patients with primary biliary cirrhosis.

The clinical effectiveness of ursodeoxycholate in the treatment of liver disease may be limited by its poor absorption and extensive biotransformation. Because in vitro and in vivo studies suggest that the more hydrophilic bile acid tauroursodeoxycholate has greater beneficial effects than ursodeoxycholate, we have compared for the first time the absorption, metabolism, and clinical responses to these bile acids in patients with primary biliary cirrhosis (PBC). Twelve female patients with PBC were sequentially administered tauroursodeoxycholate and ursodeoxycholate (750 mg/d for 2 months) in a randomized, cross-over study. Bile acids were measured in serum, duodenal bile, urine, and feces by gas chromatography-mass spectrometry (GC-MS). Biliary ursodeoxycholate enrichment was higher during tauroursodeoxycholate administration (32.6% vs. 29.2% during ursodeoxycholate; P <.05). Lithocholic acid concentration was consistently higher in all biological fluids during ursodeoxycholate administration. Fecal bile acid excretion was the major route of elimination of both bile acids; ursodeoxycholate accounted for 8% and 23% of the total fecal bile acids during tauroursodeoxycholate and ursodeoxycholate administration, respectively (P <.05). Tauroursodeoxycholate was better absorbed than ursodeoxycholate, and, although it was partially deconjugated and reconjugated with glycine, it underwent reduced biotransformation to more hydrophobic metabolites. This comparative study suggests that tauroursodeoxycholate has significant advantages over ursodeoxycholate that may be of benefit for long-term therapy in PBC.

Absorption↗
PubMed1988

Effect of various bile salts on calcium concentration and calcium carbonate saturation of rat bile.

To establish whether the calcium-binding capacities of the bile salts play an essential role in their stimulatory effects on biliary calcium secretion, we compared (1) the effects of tauro- and glycoconjugates of ursodeoxycholate (TUDC-GUDC) and cholate (TC-GC) on biliary calcium in bile fistula rats, and (2) the in vitro calcium-binding capacities of mixed micelles containing the same bile salts. The increase of biliary calcium depended on the infused bile salt in the following order: GUDC greater than GC = TUDC greater than GC). The same order was obtained in vitro, so that there was a linear relationship between the slopes of the [Ca] vs. [bile salts] regression lines in vivo and the binding percentages of the four bile salts. Biliary ionized calcium concentration was almost independent of bile salt concentration. However, hepatic bile was supersaturated with calcium carbonate in the presence of the four bile salts. Our results suggest that biliary calcium concentration increases in relation to the calcium-binding capacity of the various bile acids so that ionized biliary calcium remains in equilibrium with plasma. As a result, bile saturation with calcium is almost completely independent of bile salt secretion.

Animals↗