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PubMed1990

Effects of bile acids on actin polymerization in vitro.

Bile acids are major determinants of canalicular bile secretion, and there are indications that choleretic bile acids increase bile canalicular contractions, in isolated rat hepatocytes. Therefore, we examined the influence of various bile acids on the rate of actin polymerization in vitro. The free forms of cholic acid, ursodeoxycholic acid, and chenodeoxycholic acid, as well as their taurine and glycine conjugates, were incubated with purified muscle actin, at a concentration of 100-300 nmoles/mg actin. The rate of actin polymerization was measured by viscometry and the fluorescence of the pyrene probe, linked to actin. Results showed that all bile acids slow the rate of polymerization, and that the effect was dose-dependent. However, the reduction by chenodeoxycholic acid was greater than that caused by the other bile acids. The results indicate that bile acids, particularly in high concentrations interact with actin, a finding that may be related to the increased bile canalicular contractility, and altered canalicular membrane morphology, induced by choleretic bile acids.

Actins↗

PubMed1980

Bile acid metabolism in fetal sheep; perinatal changes in the bile acid pool.

1. A chronic fetal bile fistula model was developed in sheep which allowed observations on fetal bile for periods of up to 10 days. A comparison of fetal, lamb and adult bile acids was made in bile fistula animals. 2. Bile was analysed by thin layer chromatography, gas liquid chromatography, and high pressure liquid chromatography. Fetal bile contained a much greater proportion of chenodeoxycholic acid (42.0 +/- 1. S.E. of mean 3.0% of total bile acids by high pressure liquid chromatography) than lamb bile (8.1 +/- 1.9%) or adult bile (5.4 +/- 0.6%). The corresponding figures for cholic acid were fetal: 45.8 +/- 2.9%, lamb: 89.1 +/- 2.9%, and adult: 75.2 +/- 2.6%. Deoxycholic acid, a secondary bile acid, was present in fetal bile (12.2 +/- 4.9%). In the lamb, deoxycholic acid comprised only 2.8 +/- 1.1% of total bile acids, compared with 19.3 +/- 2.9% in adult sheep. Taurine conjugates predominated in sheep bile, but this predominance was least marked in lamb bile. 3. The fetal bile acid pool (101 +/- 13 mu mole/kg) was significantly smaller than the neonatal pool (214 +/- 26 mu mole/kg, P < 0.01). This increase in pool size, together with the increased proportion of cholic acid, suggests a rapid rise in cholic acid synthesis soon after birth. 4. Bile acid synthetic rates were estimated from bile acid secretion rates at the nadir of the washout curves. The values obtained were 0.71 +/- 0.18 mu mole/kg.hour (adult), 0.47 +/- 0.16 mu mole/kg.hour (lamb), and 0.35 +/- 0.08 mu mole.hour (fetus). 5. In the fetus and in pregnant adult sheep, the normal increase in bile acid synthesis in response to depletion of the bile acid pool was much less marked. 6. In the fetus, biliary secretion of cholesterol and phospholipid ran parallel with bile acid secretion. Bile lipid composition was similar to that in the adult. 7. Fetal bile water production was higher, relative to bile acid secretion, than lamb or adult bile water secretion.

Animals↗

PubMed1976

[Alterations of bile acid metabolism during treatment with chenodeoxycholic acid. Studies of the role of the appearance of ursodeoxycholic acid in the dissolution of gallstones (author's transl)].

Nine patients with radiolucent stones in the gallbladder were investigated before and during treatment with chenodeoxycholic acid (CDC). During treatment the biliary composition of bile acids changed considerably. Before the ingestion of CDC,bile acids consisted predominantly of cholic acid, deoxycholic acid and CDC; lithocholic acid was present in small amounts only. In the course of treatment CDC or this bile acid together with ursodeoxycholic acid (UDC) became the major biliary bile acid. The content of CDC increased from 47.5 +/- 4.21 to 79.2 +/- 6.37 SEM %, whereas that of UDC increased from 2.7 +/- 1.15 to 13.4 +/- 6.4%. The unsulfated lithocholic acid increased slightly from 0.7 +/- 0.22 to 2.7 +/- 0.41%. The bile acid pool expanded by an average of 130%. The degree of expansion of the pool varied considerably among the different patients. The largest increase in the pool size, however, occurred in the patients with the largest content of UDC in bile. Gallstone dissolution was observed in five patients. Among these five were those patients with the highest content of UDC, Corresponding 8.6, to 29.4 and 51.7%, respectively. These findings suggest that, in addition to CDC, UDC has a cholelitholytic effect in vivo. Of interest also was the observation that the patients in whom the size of the bile acid pool increased only very little showed no dissolution of gallstones. Both the stool weight and the fecal excretion of the isotopes, after the administration of radioactively labeled bile acids, increased only slightly during the treatment with CDC. The cholelitholytically efficacious dose of 20 mg/kg/day of CDC applied in this study appears to be useful in that 94% of it was abosrbed.

Chenodeoxycholic Acid↗

PubMed1983

Zellweger's cerebro-hepato-renal syndrome--variations in expressivity and in defects of bile acid synthesis.

Two siblings with Zellweger's cerebro-hepato-renal syndrome are reported. The two children both had multiple anomalies associated with Zellweger's syndrome such as characteristic facial appearance, cerebral dysfunction, muscular hypotonia, liver abnormalities, failure to thrive, marasm and early death. One of the children, a girl, lacked several anomalies that were present in her brother. In one of the children bile acid analysis was performed by use of gas chromatography-mass spectrometry. 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid (THCA) and varanic acid, both precursors of cholic acid, were found. The defect bile acid synthesis may be due both to liver mitochondrial abnormalities and to the absence of liver peroxisomes, conditions known to occur in Zellweger's syndrome.

Abnormalities, Multiple↗

PubMed1984

Inhibitory effect of unconjugated bile acids on the intestinal transport of 5-methyltetrahydrofolate in rat jejunum in vitro.

The effect of the unconjugated bile acids, cholic, deoxycholic, chenodeoxycholic, and ursodeoxycholic acids, and of the conjugated bile acid taurocholic acid on the mucosal-to-serosal transport and tissue uptake of the naturally occurring folate derivative, 5-methyltetrahydrofolate (5-CH3H4PteGlu) was examined in everted sacs of rat jejunum. Each of the unconjugated bile acids examined inhibited the transport and tissue uptake of 5-CH3H4PteGlu in a concentration dependent manner. At low concentrations (0.01-0.1 mM) of cholic and deoxycholic acids, no structural or functional damage to the intestinal mucosa occurred and the transport of 5-CH3H4PteGlu was inhibited competitively with Ki values of 0.114 mM and 0.055 mM for cholic and deoxycholic acids, respectively. The greater inhibition of 5-CH3H4PteGlu transport by unconjugated bile acids at 1 mM can be attributed to observed structural and functional damage to the intestinal mucosa. The addition of 2 mM lecithin to the mucosal medium failed to prevent the inhibitory effect of 0.1 mM deoxycholic acid on the transport of 0.5 microM 5-CH3H4PteGlu. Compared with the effect of unconjugated bile acids, the conjugated bile acid taurocholic acid (0.01-5 mM) showed no effect on the transport and tissue uptake of 5-CH3H4PteGlu. The results of this study show that intestinal transport and tissue uptake of 5-CH3H4PteGlu are inhibited by unconjugated bile acids in a dose-dependent fashion. The clinical and physiological implications of these observations are discussed.

Animals↗

PubMed1990

Effects of novel bile salts on cholesterol metabolism in rats and guinea-pigs.

Novel bile salts (quaternary ammonium conjugates) inhibited cholic acid binding and transport in everted ileal sacs in vitro. The cationic piperazine conjugate of lithocholic acid (di-iodide salt, compound 8, BRL 39924A) appeared most active, inhibiting binding by 29% and transport by 59% in guinea-pig ileum (200 microM). BRL 39924A also inhibited taurocholate uptake into guinea-pig ileal sacs and cholate uptake into rat ileal sacs and was selected for further study in vivo. In hyperlipidaemic rats, BRL 39924A significantly raised cholesterol 7 alpha-hydroxylase activity and decreased hepatic accumulation of exogenous cholic acid. HDL cholesterol concentration in the serum increased and the level of VLDL plus LDL cholesterol decreased. In hyperlipidaemic guinea-pigs. BRL 39924A lowered serum total cholesterol and triglyceride levels. Although metabolic changes were less than those achieved with the bile acid sequestrant, cholestyramine, the doses of BRL 39924A used were much lower (100-500 mg/kg body wt). Selective inhibition of receptor mediated bile acid uptake may be associated with local side-effects but these novel bile salts are useful pharmacological tools to examine the effects of receptor blockade on lipoprotein metabolism.

Animals↗

PubMed1994

Biochemical studies of inherited diseases related to abnormal cholesterol metabolism. II: Absence of unusual C28 and C29 bile acid homologs in bile and urine of sitosterolemia.

Bile acids, bile alcohols and sterols excreted in bile and urine from a patient with sitosterolemia were studied. Glycine- and taurine-conjugated cholic acid, deoxycholic acid and chenodeoxycholic acid were identified as the major constituents of both the bile and urine. Lesser amounts of unconjugated cholic acid and 3 alpha, 7 alpha, 12 alpha, 24-tetrahydroxy-5 beta-cholestan-26-oic acid were found in the bile, but cholic acid was the only unconjugated bile acid in the urine. Relatively high proportions of campesterol and sitosterol compared to cholesterol were excreted in the bile, while cholesterol was the only sterol detected in the urine. Bile alcohols were not detected in the bile, but the following bile alcohols were excreted in the urine as glucurono-conjugates: 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol; 27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentol; 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol; 5 beta-cholestane- 3 alpha,7 alpha,12 alpha,24,25-pentol; 5 beta-cholestane- 3 alpha,7 alpha,12 alpha,25,26-pentol. In neither the bile nor urine, were C28 and C29 bile acid homologs detected. Thus, the main route for the excretion of plant sterols in sitosterolemia is thought to be secretion into the bile as neutral sterols.

Bile↗

PubMed1978

The lack of active bile acid transport in AS-30 D ascites hepatoma cells.

The uptake of cholic acid as well as taurocholic acid into AS-30 D ascites hepatoma cells showed linearity with respect to incubation concentrations. It has been suggested that these processes can be described as simple diffusion. In further experiments it could be shown that ascites hepatoma cells were unable to conjugate cholic acid. These results may have significance in the phalloidin action on hepatocytes.

Animals↗

PubMed1981

Effects of feeding chenodeoxycholic acid on metabolism of cholesterol and bile acids in germ-free rats.

The aim of this investigation was to study the influence of chenodeoxycholic acid administration on cholesterol and bile acid synthesis in germ-free rats. Seven rats were fed a basal diet and 2 groups of 4 rats received the same diet supplemented with 0.4 and 1% chenodeoxycholic acid, respectively. After 6 weeks, feces were collected in one 3- and one 4-day pool for analysis of cholesterol and bile acids. When the sampling period was finished, the rats were killed and the liver microsomal fractions isolated. The activities of HMG CoA reductase and cholesterol 7 alpha-hydroxylase were determined, the 7 alpha-hydroxylase by a mass fragmentographic method. The 2 dominating bile acids in the untreated rats were cholic acid and beta-muricholic acid. During treatment with chenodeoxycholic acid, 60--70% of this bile acid was converted into alpha- and beta-muricholic acid, indicating a high activity of the 6 beta-hydroxylase. The excretion of cholic acid was almost completely inhibited and the 7 alpha-hydroxylase activity was decreased ca 75% in the rats fed 1% chenodeoxycholic acid. The activity of the hepatic HMG CoA reductase as unchanged. The fecal excretion of cholesterol increased 2--3 times. An accumulation of cholesterol was seen in the rats treated with 1% chenodeoxycholic acid, which was probably a result of the decreased catabolism of cholesterol to bile acids.

Animals↗

PubMedDate not supplied

Biosynthesis of bile acids in mammalian liver.

The biosynthesis of bile acids in mammalian liver and its regulation, together with the physiological role of bile acids, are reviewed in this article. Bile acids are biosynthesized from cholesterol in hepatocytes. Several steps are involved including epimerisation of the 3beta-hydroxyl group, reduction of the delta4 double bond to the 5beta-H structural arrangement, introduction of alpha-hydroxyl groups at C7 or C7 and C12 and, finally, oxidative degradation of the side chain by three carbon atoms. This gives the primary bile acids, cholic and chenodeoxycholic acids. Cholesterol-7alpha-hydroxylation is the rate determining step in the biosynthesis of cholic and chenodeoxycholic acids. Feedback regulation of cholesterol biosynthesis occurs by various mechanisms including termination of the synthesis of specific cytochromes P-450, modulation of specific cytosol proteins, short-term changes in the process of phosphorylation-dephosphorylation and changes in the capacity of the cholesterol pool as a substrate. Prior to being exported from the liver, bile acids are conjugated with glycine and taurine to produce the bile salts. After excretion into the intestinal tract, primary bile acids are partly converted to secondary bile acids, deoxycholic and lithocholic acids, by intestinal microorganisms. The majority of bile acids is absorbed from the intestinal tract and returned to the liver via the portal blood, so that only a small fraction is excreted in the feces. Bile acids returned to the liver can be reconjugated and reexcreted into the bile in the process of enterohepatic recycling. In addition to the physiological function of emulsifying lipids in the intestinal tract, bile acids are particularly important in respect of their ability to dissolve and transport cholesterol in the bile.

Animals↗

PubMed2001

Transcriptional regulation of the human sterol 12alpha-hydroxylase gene (CYP8B1): roles of heaptocyte nuclear factor 4alpha in mediating bile acid repression.

Sterol 12alpha-hydroxylase catalyzes the synthesis of cholic acid and controls the ratio of cholic acid over chenodeoxycholic acid in the bile. Transcription of CYP8B1 is inhibited by bile acids, cholesterol, and insulin. To study the mechanism of CYP8B1 transcription by bile acids, we have cloned and determined 3389 base pairs of the 5'-upstream nucleotide sequences of the human CYP8B1. Deletion analysis of CYP8B1/luciferase reporter activity in HepG2 cells revealed that the sequences from -57 to +300 were important for basal and liver-specific promoter activities. Hepatocyte nuclear factor 4alpha (HNF4alpha) strongly activated human CYP8B1 promoter activities, whereas cholesterol 7alpha-hydroxylase promoter factor (CPF), an NR5A2 family of nuclear receptors, had much less effect. Electrophoretic mobility shift assay identified an overlapping HNF4alpha- and CPF-binding site in the +198/+227 region. The human CYP8B1 promoter activities were strongly repressed by bile acids, and the bile acid response element was localized between +137 and +220. Site-directed mutagenesis of the HNF4alpha-binding site markedly reduced promoter activity and its response to bile acid repression. On the other hand, mutation of the CPF-binding site had little effect on promoter activity and bile acid inhibition. A negative nuclear receptor, small heterodimer partner markedly inhibited transactivation of CYP8B1 by HNF4alpha. Mammalian two-hybrid assay confirmed that HNF4alpha interacted with small heterodimer partner. Furthermore, bile acids and farnesoid X receptor reduced the expression of nuclear HNF4alpha in HepG2 cells and rat livers and its binding to DNA. Bile acids and farnesoid X receptor also inhibited mouse HNF4alpha gene transcription. In summary, our data revealed the critical roles HNF4alpha play on CYP8B1 transcription and its repression by bile acids. Bile acids repress human CYP8B1 transcription by reducing the transactivation activity of HNF4alpha through interaction of HNF4alpha with SHP and reduction of HNF4alpha expression in the liver.

Base Sequence↗

PubMed1974

Bile acid kinetics in relation to sex, serum lipids, body weights, and gallbladder disease in patients with various types of hyperlipoproteinemia;.

Bile acid kinetics were determined in 15 normolipidemic and 61 hyperlipidemic subjects with the aid of [(14)C]cholic acid and [(3)H]chenodeoxycholic acid. The diet was standardized and of natural type. The total bile acid formation was within normal limits in patients with hyperlipoproteinemia types IIa and IIb. On the average the production of cholic acid (C) represented less than 50% of the total bile acid synthesis in both groups. The corresponding value recorded for the controls was 64+/-2% (mean+/-SEM). The synthesis of C in hyperlipoproteinemia type IIa was significantly below normal. Of the 27 patients with the type IV pattern, 18 had a synthesis of C and C + chenodeoxycholic acid (CD) that exceeded the upper range recorded for the controls. In these subjects the C formation represented 73+/-3% of the total bile acid synthesis. Similar findings were also encountered in the five patients with the type V lipoprotein pattern studied. The bile acid pool size of the 11 patients with hyperlipoproteinemia type IV, who had been cholecystectomized or suffered from cholelithiasis, was 900 mg smaller on the average than that of the other subjects with the same type of hyperlipoproteinemia. However, the pool size in the former subjects still tended to be higher than that of the control subjects without evidence of gallbladder "disease". In all groups of subjects the formation of bile acids tended to be higher in the male than in the female subjects. Bile acid synthesis showed no linear correlation to actual body weight, relative body weight, or body surface area. A moderate weight reduction in five patients (one with type IIb and four with type IV pattern) was followed by a 50% reduction of the C and CD synthesis.

Adult↗

PubMed2003

Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine.

BACKGROUND/AIMS: Adaptive changes in transporter expression in liver and kidney provide alternative excretory pathways for biliary constituents during cholestasis and may thus attenuate liver injury. Whether adaptive changes in ATP-binding cassette (ABC) transporter expression are stimulated by bile acids and their nuclear receptor FXR is unknown. METHODS: Hepatic, renal and intestinal ABC transporter expression was compared in cholic acid (CA)- and ursodeoxycholic acid (UDCA)-fed wild-type (FXR(+/+)) and FXR knock-out mice (FXR(-/-)). Expression was assessed by reverse transcription-polymerase chain reaction, immunoblotting and immunofluorescence microscopy. RESULTS: CA feeding stimulated hepatic Mrp2, Mrp3, Bsep and renal Mrp2 as well as intestinal Mrp2 and Mrp3 expression. Lack of Bsep induction by CA in FXR(-/-) was associated with disseminated hepatocyte necrosis which was not prevented by compensatory induction of Mrp2 and Mrp3. With the exception of Bsep, UDCA stimulated expression of hepatic, renal and intestinal ABC transporters independent of FXR without inducing liver toxicity. CONCLUSIONS: Toxic CA and non-toxic UDCA induce adaptive ABC transporter expression, independent of FXR with the exception of Bsep. Stimulation of hepatic Mrp3 as well as intestinal and renal Mrp2 by UDCA may contribute to its therapeutic effects by inducing alternative excretory routes for bile acids and other cholephiles.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1988

Altered bile acid profiles in duodenal bile and urine in diabetic subjects.

The bile acid composition in duodenal bile was analysed in 22 diet-treated and 11 insulin-treated middle-aged patients with diabetes mellitus and in 20 normoglycaemic controls. In 10 subjects with diabetes mellitus the bile acid profile in urine was also investigated. In the non-insulin-dependent diabetic patients the percentage of cholic acid was reduced and that of deoxycholic acid increased. As a highly significant finding there was a three-fold increase of the percentage of 12-ketolithocholic acid in duodenal bile in non-insulin-dependent diabetics, whereas the bile acid composition in insulin-dependent diabetics was similar to that in a control group. The percentage of 12-ketolithocholic acid in duodenal bile was positively correlated to the percentage in urine. In nine of the subjects studied, 12-ketolithocholic acid was the major individual bile acid in urine. It constituted 36.3 +/- 4.4% of the bile acids analysed and the excretion was 6.1 +/- 2.3 mumol 24 h-1. Together with 3 alpha, 12 beta-dihydroxy-5 beta-cholanoic acid it was predominantly present in the glycine conjugate fraction, whereas in bile its conjugation was similar to that of the other bile acids. The results may reflect an increased formation of secondary bile acids from cholic acid combined with a metabolic disturbance in non-insulin-dependent diabetics affecting the oxidoreduction of bile acids at C-12.

Adult↗

PubMedDate not supplied

Inhibited serum phospholipase A2 activity in hyperbilirubinemia.

BACKGROUND/AIMS: Phospholipase A2 activity is reported to be related to the physiology of various disorders, and the activity is modified by deoxycholic acid. METHODOLOGY: Serum phospholipase A2 activity was measured by counting the radioactivity of 14C-palmitic acid released from L-3-phosphatidylcholine (1-palmitoyl-2-14C-palmitoyl) in 40 patients with hyperbilirubinemia due to malignant neoplasms and benign cholestasis. Phospholipase A2 activity in serum from healthy subjects was also measured after incubation with 5-30 mg of bilirubin per dL or 0.1-5 mM of cholic acid for 60 min at 37 degrees C. RESULTS: Serum phospholipase A2 activity was significantly lower in patients with hyperbilirubinemia. There were negative correlations between serum phospholipase A2 activity and concentration of total bilirubin (r = 0.668; P < 0.0001) or total bile acids (r = 0.423; P < 0.05) in patients with hyperbilirubinemia. In 12 patients who underwent percutaneous transhepatic biliary drainage, the low serum phospholipase A2 activity was reversed while bilirubin concentrations decreased. Incubation of sera from healthy subjects with more than 3 mM cholic acid significantly reduced phospholipase A2 activity (P < 0.01), whereas incubation with bilirubin had no effect. CONCLUSIONS: Inhibition of serum phospholipase A2 activity in patients with hyperbilirubinemia may be caused by increased serum cholic acid concentration.

Adult↗

PubMed1986

Late effects of abdominal radiation on intestinal uptake of nutrients.

The late effects of variable doses of abdominal irradiation on in vitro jejunal uptake were examined. The uptake of glucose, galactose, cholic acid, medium-chain length fatty acids, and decanol was studied 6 and 33 weeks following 300, 600, or 900 cGy abdominal irradiation. The intestinal morphological characteristics were similar 6 and 33 weeks after radiation. The uptake of cholic acid was unaffected by abdominal irradiation, but for glucose, galactose, and four fatty acids the direction and magnitude of the changes in uptake were influenced by the dose of irradiation and by the interval following exposure. The greater uptake of decanol at 6 weeks but lower uptake of decanol at 33 weeks reflected changes in the resistance of the intestinal unstirred water layer. These absorption changes suggest that the intestine may not be capable of correcting the transport abnormalities arising from sublethal doses of abdominal irradiation.

Abdomen↗

PubMed1985

Ontogeny of hepatic bile acid conjugation in the rat.

We studied the postnatal development of hepatic bile acid conjugation in the rat. Overall conjugating activity (homogenate assay) and the activity of the individual enzymes involved in the two step conjugation reaction (coenzyme A-bile acid thioester formation by microsomal cholyl-CoA ligase and amino acid transfer to this intermediate mediated by cytosolic cholyl-CoA:taurine N-acyltransferase were measured on days 1, 7, 14, 21, and 56 of life. Cholic acid conjugation was significantly lower in the suckling rat on days 1, 7, and 14 compared to the adult rat on day 56. At weaning (21 days) there was a marked increase in homogenate activity to a level higher than at 56 days. This peak in conjugating activity could be precociously induced on day 14 by cortisone acetate injection on days 10 through 13. Both cholyl-CoA ligase and cholyl-CoA:taurine N-acyltransferase activities were significantly lower during the first 14 days of life in comparison with 56 days. At 21 days of age there was a sharp increase in cholyl-CoA ligase activity to 1.5 times the activity in the adult; however, cholyl-CoA:taurine N-acyltransferase activity remained less than half of that found in the adult. We conclude that 1) cholic acid conjugation, as assessed by determination of either total conjugating activity or by the individual enzymatic steps, is decreased in the suckling rat; 2) the peak in conjugating activity noted at weaning may be mediated by the hormonal milieu, and 3) cholyl-CoA ligase activity closely parallels the increase in total activity and appears to be rate-limiting during development.

Acyltransferases↗

PubMed1993

Effect of ursodeoxycholic acid on intracellular pH regulation in isolated rat bile duct epithelial cells.

To determine if ursodeoxycholic acid (UDCA) induces a HCO3(-)-rich hypercholeresis by stimulating HCO3- secretion from bile duct epithelial (BDE) cells, we studied the effect of UDCA, sodium tauroursodeoxycholate (TUDCA), and cholic acid on intracellular pH (pHi) regulation and HCO3- excretion in BDE cells isolated from normal rat liver. Exposure of BDE cells to UDCA (0.5-1.5 mM) produced a dose-dependent initial acidification [from -0.05 to -0.16 pH units (pHu)], which was lower in Krebs-Ringer bicarbonate than in N-2-hydroxyethylpiperazine-N'-2- ethanesulfonic acid (HEPES), because of the higher cell-buffering power in the presence of HCO3-. In contrast, TUDCA (1 mM) had no effect on pHi in either media. BDE acidification induced by UDCA (1.5 mM) in KRB was not inhibited by Cl- depletion excluding activation of Cl(-)-HCO3- exchange. Most BDE cells spontaneously recovered their basal pHi during the UDCA infusion (0.5-1 mM) by a secondary activation of the Na(+)-H+ exchanger (amiloride inhibition of pHi recovery; n = 4), and pHi overshot basal levels by 0.1-0.2 pHu after UDCA withdrawal. The activity of Cl(-)-HCO3- exchange (Cl- removal/readmission maneuver) as well as the activities of Na(+)-H+ exchange and Na(+)-HCO3- symport (NH4Cl acid load in HEPES and KRB, respectively) were unaffected by UDCA (0.5 mM) compared with controls. Cholic acid (1.5 mM), which does not produce a hypercholeresis, also acidified BDE cells in KRB media. These studies indicate that UDCA does not stimulate HCO3- excretion from isolated rat BDE cells but modifies pHi in BDE cells as a weak acid.

Ammonium Chloride↗