Effect of ursodeoxycholic acid on the kinetics of cholic acid and chenodeoxycholic acid in patients with primary sclerosing cholangitis

Treatment of patients with cholestatic liver diseases with ursodeoxycholic acid has been shown to have beneficial effects that may be related to a shift in the balance between hydrophilic and hydrophobic bile acids in favor of hydrophilic bile acids. During treatment of patients with primary sclerosing cholangitis with ursodeoxycholic acid, plasma concentrations of some endogenous bile acids decrease. To test whether the changes in plasma bile acids are due to decreases of their pool sizes or synthesis rates, we determined bile acid kinetics of cholic and chenodeoxycholic acid in six patients with primary sclerosing cholangitis, of whom four also had ulcerative colitis. All patients were studied before and 3 mo after the start of ursodeoxycholic acid treatment. Six healthy subjects served as controls. In patients with primary sclerosing cholangitis, pool sizes of cholic and chenodeoxycholic acid were considerably smaller than those in healthy controls; after ursodeoxycholic acid treatment they were unchanged. Fractional turnover and synthesis of cholic acid increased significantly after ursodeoxycholic acid administration. Fractional turnover of chenodeoxycholic acid also increased significantly, whereas synthesis of this bile acid was unchanged. Our data indicate that in patients with primary sclerosing cholangitis, pool sizes of bile acids are reduced. The decrease of levels of endogenous bile acids in plasma under ursodeoxycholic acid treatment despite unchanged bile acid pool sizes indicates redistribution of the bile acids into the enterohepatic circulation, probably because of improved hepatic clearance after ursodeoxycholic acid treatment.     

Serum bile acids and ursodeoxycholic acid treatment in cystic fibrosis-related liver disease

Increased circulating levels of hepatotoxic bile acids may contribute to the cholestasis characteristic of cystic fibrosis-related liver disease. The aims of this study were to compare serum bile acid profiles in patients with cystic fibrosis with and without liver disease, and to evaluate the effect of treatment with ursodeoxycholic acid, a non-hepatotoxic bile acid, on liver biochemistry and serum bile acids in patients with cystic fibrosis-related liver disease. Fasting and postprandial serum bile acid levels were analysed in 15 patients (nine males; median age 18 years) with cystic fibrosis-related liver disease and compared with serum bile acid levels in 18 cystic fibrosis patients (12 males; median age 22 years) without liver disease and 10 control subjects. Fasting and postprandial serum levels of primary and secondary serum bile acids were analysed using high-performance liquid chromatography. Liver biochemistry and serum bile acids were measured in six cystic fibrosis patients with liver disease before and 6 months after treatment with ursodeoxycholic acid 20 mg/kg/day and compared with six control patients with cystic fibrosis-related liver disease. Total fasting and postprandial serum bile acid levels were significantly (P < 0.01) elevated in patients with liver disease compared to those without liver disease and controls. The fasting glycine conjugates of cholic acid, chenodeoxycholic acid and deoxycholic acid, and the fasting and postprandial taurine conjugates of cholic acid and chenodeoxycholic acid were significantly (P < 0.05) elevated in liver disease patients compared to patients without liver disease and controls. After 6 months' treatment with ursodeoxycholic acid, although the serum was significantly saturated with ursodeoxycholic acid and significant improvements in liver biochemistry were observed in the treatment group, there was no significant reduction in the levels of individual serum bile acids. Although circulating levels of potentially hepatotoxic serum bile acids are elevated in patients with cystic fibrosis-related liver disease, improvements in liver biochemistry associated with ursodeoxycholic acid treatment cannot be attributed solely to alterations in levels of endogenous bile acids.     

Materials and biomaterials for interventional radiology

The C24 bile acids (BA) in the serum of 22 healthy human fetuses between weeks 20 and 37 of gestation were determined by capillary GC-MS. Fetal blood samples were taken in utero from the umbilical cord monitored by echography. There was no correlation between total bile acids (TBA) and gestational age. The TBA concentration was 5.14 +/- 2.13 microM. Primary BA (cholic acid and chenodeoxycholic acid) were the main BA (66.78 +/- 13.47%) with chenodeoxycholic acid being the main one. There were low concentrations of secondary BA (deoxycholic acid and lithocholic acid) (10.28 +/- 7.85%), which formed by intestinal bacterial 7 alpha-dehydroxylation of primary BA in the adult, despite the germ-free gut. The tertiary BA (ursodeoxycholic acid) was also detected (12.06 +/- 9.64%). There was 6 alpha-hydroxylation of chenodeoxycholic acid and of lithocholic acid to produce hyocholic acid and hyodeoxycholic acid respectively. Two 1 beta-hydroxylated BA were detected at different times of gestation. Cholic acid was rarely found in the 6 alpha- and 1 beta-hydroxylated forms. These additional hydroxylations could help to protect the fetal liver against the accumulation of cytotoxic bile acids at a time when other detoxification pathways are poorly developed. Traces of unsaturated bile acids like 3 beta-hydroxy-5-cholenoic acid were detected, showing that 27-hydroxylation of cholesterol does occur.     

Formation of bile acids in man. Metabolism of 7alpha-hydroxy-4-cholesten-3-one in normal subjects with an intact enterohepatic circulation

The formation of bile acids in man is thought to involve a series of reactions in which the initial steps are the same for both cholic acid and chenodeoxycholic acid. The point of bifurcation of the pathway is postulated to occur after the formation of 7alpha-hydroxy-4-cholesten-3-one. To test the hypothesis that the entire synthesis of both bile acids proceeds through this intermediate we studied the metabolism of labeled 7alpha-hydroxy-4-cholesten-3-one in eight normal subjects with an intact enterohepatic circulation. If all the production of cholic acid and chenodeoxycholic acid takes place via 7alpha-hydroxy-4-cholesten-3-one, the areas under the specific decay curves of cholic acid and chenodeoxycholic acid should be identical following a single injection of this labeled intermediate. However, in 6 of the 8 subjects studied the area under the cholic acid specific activity decay curve was significantly less than the area under the chenodeoxycholic acid specific activity decay curve. These results that the production of cholic acid in man may not always involve the intermediate 7alpha-hydroxy-4-cholesten-3-one.     

Serum bile acids in cholestasis of pregnancy

Using routine liver function tests, cholestasis of pregnancy was diagnosed in 86 pregnant women with pruritus. Serum aminotransferase levels were elevated in all cases, ASAT in 99%, and ALAT in 100%. In these patients serum concentrations of cholic, chenodeoxycholic, and deoxycholic acid were determined using a gas chromatographic method and were compared with those in a group of 40 uncomplicated pregnancies. Of these bile acids, cholic acid levels were most frequently elevated, ie, in 92% of the patients. The frequency of elevation of serum levels of alkaline phosphatase, and total and conjugated bilirubin was lower. Thus, it appears that in addition to serum aminotransferase levels the serum cholic acid concentration is a sensitive indicator of cholestasis of pregnancy. The cholestasis series was divided into 3 subgroups of increasing severity of cholestasis as assessed by maternal serum cholic acid levels, and the occurrence of signs of fetal distress was compared between these subgroups. The only intrauterine fetal loss in the series belonged to the severe cholestasis group. The incidence of meconium-stained amniotic fluid also increased significantly in this group, and 21 of the 24 cases with other signs of fetal distress were in the groups of moderate and severe cholestasis.     

Sulfate bile acids in germ-free and conventional mice

Sulfated and non-sulfated bile acids were determined in the intestines and in the feces of 7-month-old germ-free and conventional male mice. 1. The bile acid pools in the gall bladder and small intestine were 21.13 mg/100g body weight in germ-free and 11.50 mg in conventional mice. The bile acid pools in the cecum and large intestine of germ-free mice were 3.03 mg/100 g body weight as compared to 1.24 mg in conventional mice. Fecal bile acid excretion was 2.93 mg and 4.12 mg/100 g body weight in 24 h in germ-free and conventional mice respectively. 2. The major bile acids from germ-free mice were cholic acid, alpha-muricholic acid and beta-muricholic acid. Small amounts of chenodeoxycholic and allocholic acid were also present. In addition to these primary bile acids the following secondary bile acids were identified in conventional mice: lithocholic, deoxycholic and omega-muricholic acid. 3. In both germ-free and conventional animals significant amounts of chenodeoxycholic and cholic acid were present as the 7-monosulfate esters. The sulfate esters of these bile acids did not exceed 2% of the total bile acids in the small intestine, but accounted for approximately 50% of the bile acids in the cecum and the large intestine. In contrast, the muricholic acids were nearly exclusively found in the non-sulfate fraction. 4. Alkaline hydrolysis without prior solvolysis of the sulfate esters resulted in loss of bile acids and production of artifacts. Hence, the bile acids of the mouse cannot be analysed by methods involving alkaline deconjugation unless a solvolysis step is included in the procedure.     

Postprandial serum bile acids in healthy man. Evidence for differences in absorptive pattern between individual bile acids

The serum concentrations of cholic acid (C), chenodeoxycholic acid (CD), and deoxycholic acid (D) before and after a standardised meal were determined in five healthy female subjects using a highly specific and accurate gas chromatographic-mass spectrometric technique. The C level rose significantly 60 minutes after the meal, reached a peak after 90 minutes, and had returned to the original level after 150 minutes. In contrast, the serum concentrations of CD and D displayed a significant rise by 30 minutes, reached a peak after 90 minutes, but had not returned to fasting levels after 150 minutes. The serum bile acid responses after a meal suggest that there is considerable absorption of dihydroxy bile acids in the proximal small intestine in man.     

Composition of biliary lipids and kinetics of bile acids after cholecystectomy in man

Postcholecystectomy biliary lipid composition and bile acid kinetics were studied in 24 women and 4 men. Hepatic bile was collected periodically for as long as 4 months without interrupting the enterohepatic circulation and without infecting the biliary system. In 23 patients with cholesterol gallstones, fasting biliary cholesterol made up 10.2% of total lipids in the steady state; in 5 patients with bilirubinate stones, saturation of fasting hepatic bile with cholesterol was lower (8.7% of total lipids). The percentage of deoxycholic acid after cholecystectomy was not higher than that of seven healthy, noncholecystectomized controls. Postcholecystectomy studies of diurnal variation of biliary lipids (7 patients) showed that postprandial hepatic bile had a significantly lower cholesterol saturation than fasting bile. Pool sizes of cholic and chenodeoxycholic acids were low (average 0.4 g/70 kg, each); total synthesis for both bile acids was normal (average 460 mg/day/70 kg), but fractional turnover rates of the two primary bile acids increased after cholecystectomy, probably due to more frequent recycling of the small bile acid pool.     

Quantitative estimations of the contribution of different bile acid pathways to total bile acid synthesis in the rat

BACKGROUND & AIMS: Cholesterol degradation to bile acids occurs via "classic" or "alternative" bile acid biosynthetic pathways. The aim of this study was to assess the contributions of these two pathways to total bile acid synthesis in vivo. METHODS: Rats with biliary fistulas were infused with squalestatin for 24 and 48 hours; specific activities of cholesterol 7 alpha-hydroxylase (C7 alpha H) and sterol 27-hydroxylase (S27H) and rates of bile acid synthesis were determined. RESULTS: Continuous squalestatin infusion (15 micrograms/h) decreased C7 alpha H specific activities to 4% and 12% of paired biliary fistula controls at 24 and 48 hours, respectively (P < 0.05) without any changes in S27H specific activities (82% and 95% of controls). At 24 hours, bile acid synthesis decreased to 43% (P < 0.05) but returned to 87% at 48 hours (P = NS). Cholic acid synthesis decreased at 24 hours but returned to control levels at 48 hours. Similar changes in C7 alpha H, S27H, and bile acid synthesis were observed in primary rat hepatocytes after addition of squalestatin (1.0 mumol/L). CONCLUSIONS: In the face of persistent suppression of C7 alpha H and the classic pathway, an alternative pathway becomes a main pathway of bile acid synthesis capable of generating cholic and chenodeoxycholic acids. The observed induction of bile acid synthesis via an alternative pathway or pathways represents an important mechanism for maintenance of cholesterol homeostasis in the rat.     

Ploidy disturbances as an early indicator of intrinsic malignancy in endometrial carcinoma

Ursodeoxycholic acid is an efficient treatment for putatively immune-mediated liver diseases, but its mechanism of action is unknown. We studied human mononuclear cell proliferation as an in vitro model for cell-mediated immunity in the presence of ursodeoxycholic acid, its glycoconjugate and tauroconjugate and chenodeoxycholic acid at concentrations of 5, 25 and 50 mumol/L. Proliferation was inhibited in a dose-dependent manner compared with control values (15% to 54% depending on the bile acid, concentration and mitogen used), except at 5 mumol/L where inhibition was significant with only one mitogenic stimulus of the three used. With one mitogen (phorbolester) the inhibition was additive with that of cyclosporine. The number of cell-surface receptors studied was not modified by bile acids. Interleukin-2 production was decreased 35% to 60% by ursodeoxycholic acid and its conjugates. The proliferation of the interleukin-2-dependent cell line CTLL-2 was also inhibited. The immunosuppression was reversible except at a chenodeoxycholic acid concentration of 50 mumol/L. Because bile acids are able to partition into membranes and change their properties, we speculate that this allows them to interact with cell-surface receptors or signaling systems within the membrane or on its inner face, thus impairing their function. This would inhibit the numerous extracellular messages that lymphocytes need to proliferate.     

Postprandial serum concentration of individual bile acids in man. Influence of ileal resection

For the purpose of characterizing the importance of intestinal function in the maintenance of the enterohepatic circulation of individual bile acids, the serum concentrations of cholic acid (C), chenodeoxycholic acid (CD), and deoxycholic acid (D) were determined after a standardized meal. Two groups of subjects were included: 10 healthy controls and 7 patients with ileal resections 20-80 cm long. The bile acid concentrations were determined using a highly specific and accurate gas chromatographic-mass spectrometric technique with the aid of deuterium-labelled internal standards. In patients with ileal resections, only a moderate and early increase was seen in C concentration after a meal, whereas the CD elevation was more pronounced and prolonged. The D concentrations were reduced both after fasting and postprandially. The data indicate that ileal resection results in essentially complete absence of active bile acid resorption and that intestinal uptake via nonionic diffusion is probably dominant, resulting in postprandial rise of mainly CD in serum.     

Individual bile acids in portal venous and systemic blood serum of fasting man

The serum concentrations of cholic acid (C), chenodeoxycholic acid (CD), and deoxycholic acid (D) were determined in peripheral venous and portal venous blood from 10 otherwise healthy patients undergoing elective cholecystectomy. A highly specific and accurate gas chromatographic-mass spectrometric technique was used. Peripheral venous serum contained 0.49 +/- 0.16 (mean +/- SEM) mumole per liter of C, 1.55 +/- 0.32 mumoles per liter of CD, and 1.44 +/- 0.57 mumoles per liter of D. Arterial serum, obtained from 5 of the subjects, did not show any differences in bile acid concentrations compared to venous serum. In contrast, the portal venous content of each bile acid was several-fold greater, 6.14 +/- 1.20 mumoles per liter of C, 8.40 +/- 1.84 mumoles per liter of CD, and 6.18 +/- 2.27 mumoles per liter of D. The hepatic uptake of C was estimated to be about 90%, whereas that of CD and D was lower, about 70%. This difference in hepatic uptake between the individual bile acids was reflected in the relative composition of the total bile acids, which was 30:39:31 (C:CD:D) in portal venous serum and 13:50:37 in peripheral serum. Compared to common duct bile obtained simultaneously, the portal vein contained a greater proportion of CD. The relevance of the data obtained to our present concept of the enterohepatic circulation of bile acids is discussed, and it is suggested that the higher fasting level of CD compared to C in peripheral serum results from the combination of a lower fractional hepatic extraction and a higher portal venous input to the systemic circulation.     

Hepatoprotection in ethinylestradiol-treated rats is provided by tauroursodeoxycholic acid, but not by ursodeoxycholic acid

Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) have been suggested as potential treatments for drug-induced cholestasis. It was therefore decided to study the effects of administration of UDCA or TUDCA on individual serum bile acid concentration, conventional liver tests and associated hepatic ultrastructural changes in ethinylestradiol-treated (EE) rats mg/kg per day). Control rats were treated s.c. with propylene glycol. EE-treated rats were randomly assigned to receive daily i.p. injections of placebo, TUDCA or UDCA. Four rats in each group were treated for 4 consecutive days, and a second four for 14 days. After 4 days of treatment, the serum levels of cholic acid and taurocholic acid were significantly increased in EE-treated rats. None of the conventional liver tests were significantly different among the four groups. After 14 days of treatment the serum levels of cholic acid, chenodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, bilirubin, alkaline phosphatase and gamma glutamyltransferase were significantly raised in EE and EE plus UDCA treated rats. EE plus TUDCA treated rats, however, had no significant changes in these individual serum bile acids or conventional liver tests. The ultrastructure of livers from EE plus TUDCA treated rats was similar to those of controls. On the other hand, EE and EE plus UDCA rats both showed a significant reduction in sinusoidal microvilli. These results show that treatment of rats for 4 days with EE induces significant rises in the serum concentrations of two individual bile acids and that TUDCA protects against this.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sensitive analysis of serum 3alpha, 7alpha, 12alpha,24-tetrahydroxy- 5beta-cholestan-26-oic acid diastereomers using gas chromatography-mass spectrometry and its application in peroxisomal D-bifunctional protein deficiency

The final steps in bile acid biosynthesis take place in peroxisomes and involve oxidative cleavage of the side chain of C27-5beta-cholestanoic acids leading to the formation of the primary bile acids cholic acid and chenodeoxycholic acid. The enoyl-CoA hydratase and beta-hydroxy acyl-CoA dehydrogenase reactions involved in the chain shortening of C27-5beta-cholestanoic acids are catalyzed by the recently identified peroxisomal d-bifunctional protein. Deficiencies of d-bifunctional protein lead, among others, to an accumulation of 3alpha,7alpha,12alpha, 24-tetrahydroxy-5beta-cholest-26-oic acid (varanic acid). The ability to resolve the four C24, C25 diastereomers of varanic acid has, so far, only been carried out on biliary bile acids using p -bromophenacyl derivatives. Here, we describe a sensitive gas chromatography-mass spectrometry (GC/MS) method that enables good separation of the four varanic acid diastereomers by use of 2R-butylester-trimethylsilylether derivatives. This method showed the specific accumulation of (24R,25R)-varanic acid in the serum of a patient with isolated deficiency of the d-3-hydroxy acyl-CoA dehydrogenase part of peroxisomal d-bifunctional protein, whereas this diastereomer was absent in a serum sample from a patient suffering from complete d-bifunctional protein deficiency. In samples from both patients an accumulation of (24S,25S)-varanic acid was observed, most likely due to the action of l-bifunctional protein on Delta24E-THCA-CoA. This GC/MS method is applicable to serum samples, obviating the use of bile fluid, and is a helpful tool in the subclassification of patients with peroxisomal d-bifunctional protein deficiency.     

Bile acids with differing hydrophilic-hydrophobic properties do not influence cytokine production by human monocytes and murine Kupffer cells

Bile acids have been proposed to exert immunological effects of potential pathogenic or therapeutic relevance, yet the experimental evidence remains preliminary. We reexamined the effects of a variety of bile salts with differing hydrophilic-hydrophobic properties on the production of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) from monocytes and Kupffer cells. Monocytes from healthy human donors and Kupffer cells from 5-week-old mice were incubated for up to 18 hours with or without varying concentrations of bile salts and lipopolysaccharide (LPS). Monocyte viability was > or = 95% with up to 250 mumol/L sodium ursodeoxycholate and < or = 90% with 200 mumol/L chenodeoxycholate, decreasing sharply at higher concentrations. Kupffer cells were more vulnerable, particularly to chenodeoxycholate (viabilities of 25% and 0% at concentrations of 100 mumol/L and 200 mumol/L, respectively). In monocytes incubated in the presence of 20% fetal calf serum, neither ursodeoxycholate and chenodeoxycholate, nor a variety of other unconjugated and conjugated bile acids, tested up to their maximal noncytotoxic concentrations, influenced the IL-6 and TNF alpha production, at any level of LPS stimulation. Similar to monocytes, incubation of murine Kupffer cells with ursodeoxycholate and chenodeoxycholate did not influence cytokine release. In contrast, the addition of 10 nmol/L dexamethasone to monocytes significantly decreased TNF-alpha and IL-6 release (69 +/- 11% and 48 +/- 15%, respectively). When monocytes were incubated with 200 mumol/L chenodeoxycholate in the presence of lower concentrations of fetal calf serum (10% and 5%, respectively) a significant inhibition of cytokine release was observed, whereas incubation with ursodeoxycholate did not cause any effect. Flow cytometry using fluoresceinated LPS showed that chenodeoxycholate does not interact with the CD14 receptor, thus excluding the possibility of an interference with the LPS uptake by monocytes. Incubation with [14C]-chenodeoxycholate showed that the intracellular bile acid uptake was inversely related to the concentration of fetal calf serum, being negligible (< 3 fmol/cell) at the highest level. In conclusion, bile acids with widely different hydrophobicities are incapable of influencing the release of IL-6 and TNF alpha by monocytes and Kupffer cells, provided they are studied at noncytotoxic concentrations and in the presence of physiological amounts of proteins.     

Cardiovascular and respiratory adjustments in normal volunteers during modified exercise tests in comparison to standard exercise tests

We investigated the effect of ursodeoxycholic acid on major histocompatibility complex class I gene expression in cultured human hepatoma cells. Ursodeoxycholic acid, which is now being used for the treatment of various autoimmune liver diseases, paradoxically increased the mRNA level of major histocompatibility complex class I. However, endogenous bile acids, for example, chenodeoxycholic acid, increased major histocompatibility complex class I mRNA expression more strongly compared with ursodeoxycholic acid. Concerning the interplay between ursodeoxycholic and chenodeoxycholic acids, these bile acids additively induced major histocompatibility complex class I mRNA expression. In contrast, when the total concentration of ursodeoxycholic and chenodeoxycholic acids was kept constant, the expression of major histocompatibility complex class I mRNA appeared to decrease in a dose-dependent manner with an increasing ratio of ursodeoxycholic acid. These findings indicate that the beneficial action of ursodeoxycholic acid may be related to this relative decrease in major histocompatibility complex class I gene expression.     

Decreased fecal bile acid output in patients with coronary atherosclerosis

In most patients with atherosclerosis, the underlying metabolic derangement remains undefined. Animal experiments have suggested that the ability to produce and excrete large amounts of bile acids may be an adaptation mechanism to cholesterol overload protecting against the atherogenic effects of cholesterol. However, there are very few data on bile acid excretion in human atherosclerosis. In the present study, we have investigated fecal bile acid secretion in subjects with and without coronary artery disease. The target group consisted of 30 patients with proven coronary artery disease and the control group consisted of 27 matched subjects without clinical or laboratory evidence of coronary atherosclerosis. Fecal bile acids were measured by gas-liquid chromatography from 24-hr stool collections under a controlled diet. The patients excreted significantly less bile acids than the controls (325+/-135 vs. 592+/-223 mg/day, respectively, p < 0.0001). The difference was primarily due to a reduced excretion of secondary bile acids. Less than 50% of deoxycholate was excreted by patients (180+/-81 mg/day) as compared to controls (367+/-168 mg/day, p < 0.0002), while lithocholic acid excretion was 111+/-62 mg/day in patients vs. 190 +/-70 mg/day in controls (p < 0.005). The fecal output of the two primary bile acids, cholic and chenodeoxycholic acid, did not differ significantly between patients and controls. The fecal output of total bile acids correlated with that of both secondary bile acids in patients as well as in controls. These findings suggest that patients with coronary heart disease are unable to excrete adequate amounts of bile acids to rid themselves of excess cholesterol, even if they are able to maintain a plasma cholesterol level comparable to that of healthy controls.     

Simultaneous systemic lupus erythematosus and dermatitis herpetiformis

The binding in vitro of the sodium salts of cholic acid, chenodeoxycholic acid, deoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, and glycodeoxycholic acid by alfalfa, bran, cellulose, lignin, and cholestyramine was measured. Cholestyramine bound an average of 81.3% of all the bile acids and salts tested whereas cellulose bound only negligible amounts (1.4%). Of the other substances tested, lignin bound 29.2%, alfalfa, 15.9% and bran, 9.0%. No distinct pattern of binding was discerned. It is therefore apparent that the validity of statements concerning the effect of fiber on bile salf metabolism rests upon the specificity of the composition of the fiber involved and the bile acids or salts tested.     

Comparative studies of metabolism of simultaneously administered chenodeoxycholic acid and ursodeoxycholic acid in hamsters

We present the comparative studies of metabolism of chenodeoxycholic acid and ursodeoxycholic acid and their taurine conjugates in the liver and fecal culture from hamsters. When [24-14C]chenodeoxycholic acid and [11,12-3H]ursodeoxycholic acid were simultaneously instilled into the jujunal loop of bile fistula hamsters, both bile acids administered were recovered mainly as their conjugates with taurine and glycine in the fistula bile. The recovery of chenodeoxycholic acid was slightly but significantly higher than that of ursodeoxycholic acid. Chenodeoxycholic acid was more efficiently conjugated with glycine than ursodeoxycholic acid. The glycine/taurine ratio in the biliary chenodeoxycholic acid was 1.9, and that in ursodeoxycholic acid was 1.6. In addition, as much as 6.2% of ursodeoxycholic acid was excreted as the unconjugated form; on the other hand only 2.4% of unconjugated chenodeoxycholic acid was excreted. When [24-14C]chenodeoxycholyltaurine and [11,12-3H]ursodeoxycholyltaurine were simultaneously administered into the ileum loop of bile fistula hamsters, both bile salts were absorbed and secreted efficiently into the bile at the same rate. These results indicate that slightly lower recovery of ursodeoxycholic acid in the bile could be due to the less effective conjugation of ursodeoxycholic acid than chenodeoxycholic acid in the liver. Deconjugation by fecal culture from a hamster proceeded more rapidly in chenodeoxycholyltaurine than ursodeoxycholyltaurine. 7-Dehyroxylation to form lithocholic acid by fecal culture was also faster in chenodeoxycholic acid than ursodeoxycholic acid. The formation of 7-oxolithocholic acid from ursodeoxycholic acid was lesser than from chenodeoxycholic acid. In summary, bacterial deconjugation followed by 7-dehydroxylation to form lithocholic acid seems to be achieved more efficiently with chenodeoxycholic acid than ursodeoxycholic acid.     

Elevated levels of bile acids in colostrum of patients with cholestasis of pregnancy are decreased following ursodeoxycholic acid therapy [see comemnts

BACKGROUND/AIMS: Intrahepatic cholestasis of pregnancy is characterised by increased levels of serum bile acids. Ursodeoxycholic acid therapy corrects the serum bile acid profile. The aims of this study were: (i) to investigate bile acid excretion into colostrum of women with intrahepatic cholestasis of pregnancy; (ii) to compare concentrations of bile acids in serum and colostrum of non-treated and ursodeoxycholic acid-treated patients; and (iii) to clarify whether ursodeoxycholic acid is eliminated into colostrum following treatment. METHODS: Bile acids were assessed by gas chromatography and high-performance liquid chromatography in serum collected at delivery, and in colostrum obtained at 2+/-1 days after labour, from patients with intrahepatic cholestasis of pregnancy, non-treated (n=9) and treated (n=7) with ursodeoxycholic acid (14 mg/kg bw per day, for 14+/-7 days) until parturition. RESULTS: The concentration of total bile acids in colostrum from patients with intrahepatic cholestasis of pregnancy was higher than in normals (23.3+/-14.8 micromol/l vs. 0.7+/-0.2 micromol/l, p<0.01) and cholic acid was a major species (19.0+/-13.1 micromol/l), reflecting the elevated concentrations in maternal serum (48.9+/-21.0 micromol/l, total bile acids; 33.9+/-16.7 micromol/l, cholic acid. Following ursodeoxycholic acid administration, total bile acids and cholic acid levels in colostrum diminished to 5.7+/-2.5 micromol/l and 3.6+/-1.5 micromol/l, respectively; the proportion of cholic acid decreased (60.6+/-8.0% vs. 76.8+/-5.0%, p<0.05). The ursodeoxycholic acid concentration in colostrum was maintained following treatment; its increased percentage (9.4+/-3.2% vs. 1.0+/-0.2%, p<0.01) was still lower than in maternal serum (20.8+/-3.6%, p<0.05). Only a small proportion (<1%) of lithocholic acid was found in colostrum following therapy. CONCLUSIONS: Bile acid concentrations are elevated and cholic acid is the major species accumulating in colostrum, reflecting serum bile acid profiles in intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid therapy decreases endogenous bile acid levels in colostrum.