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PubMed1984

Mechanism of peroxisomal 24-hydroxylation of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid in rat liver.

We recently showed that the peroxisomal fraction of rat liver has a high capacity to catalyze conversion of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid into cholic acid and that 3 alpha,7 alpha,12 alpha,24-tetrahydroxy-5 beta-cholestanoic acid is an intermediate in this conversion. With use of 2H2O and 18O2, evidence is presented here that the formation of 3 alpha,7 alpha,12 alpha,24-tetrahydroxy-5 beta-cholestanoic acid involves intermediary formation of a delta 24-unsaturate intermediate followed by hydration.

Animals↗

PubMed1981

Isolation of two cholic acid-binding proteins from rat liver cytosol using affinity chromatography.

Using an affinity matrix coupled with cholic acid, two proteins that recognise bile acids were isolated from rat liver cytosol. One protein of molecular weight 68 000 was immunologically identical to rat albumin. The other protein was of molecular weight 46 000. On discontinuous sodium dodecyl sulphate-polyacrylamide gel electrophoresis the 46 000 molecular weight protein dissociated to a single band with an RF value identical to the Yb subunit of the bromosulphophthalein-binding fraction (Y-fraction) of whole liver cytosol. The monomers of purified ligandin under these conditions resolved into two bands which corresponded to the Ya and Yc subunits of liver cytosol Y-fraction. Anti-serum to the purified ligandin reacted monospecifically with purified ligandin and whole liver cytosol, but did not cross-react with the Yb dimer eluted from the affinity column. The Yb dimer was shown to possess glutathione-S-transferase activity with a substrate specificity distinct from ligandin but similar to glutathione-S-transferase C. Cholic acid inhibited the catalytic activity of the transferase.

Animals↗

PubMed1986

Isocholic acid formation from 7 alpha,12 alpha-dihydroxy-3-keto-5 beta-cholanoic acid with human liver enzyme.

The formation of isocholic acid from 7 alpha, 12 alpha-dihydroxy-3-keto-5 beta-cholanoic acid by human liver preparations was examined in vitro. Liver preparations were incubated with 7 alpha, 12 alpha-dihydroxy-3-keto-5 beta-cholanoic acid at pH 7.4 in a phosphate buffer containing NADPH or NADH. The products formed were analyzed by gas chromatography and gas chromatography/mass spectrometry. Results showed that 7 alpha,12 alpha-dihydroxy-3-keto-5 beta-cholanoic acid was reduced mainly to isocholic acid and to cholic acid in a smaller amount in the presence of NADPH, while it was reduced only to cholic acid in the presence of NADH. The reducing enzyme participating in the formation of isocholic acid was localized largely in the cytosol and had more specificity to the unconjugated form as substrate than to the conjugated forms. 3-Keto bile acid analogues, 3-keto-5 beta-cholanoic and 7 alpha-hydroxy-3-keto-5 beta-cholanoic acids were not reduced to the corresponding iso-bile acids by the cytosol in the same conditions used in the isocholic acid formation and the activity of the enzyme catalyzing the reduction of 7 alpha,12 alpha-dihydroxy-3-keto-5 beta-cholanoic acid to isocholic acid was not inhibited by the addition of 3-keto-5 beta-cholanoic acid or 7 alpha-hydroxy-3-keto-5 beta-cholanoic acid to the reaction mixture. Furthermore, on column chromatography of Affi-Gel Blue, the peak of the enzyme catalyzing the reduction of 7 alpha,12 alpha-dihydroxy-3-keto-5 beta-cholanoic acid to isocholic acid was clearly distinguished from that of the enzyme catalyzing the reduction of 3-keto-5 beta-cholanoic acid to isolithocholic acid and that of alcohol dehydrogenase. These results indicate that this enzyme catalyzing the reduction of 7 alpha,12 alpha-dihydroxy-3-keto-5 beta-cholanoic acid to isocholic acid is different from the enzyme(s) catalyzing the reduction 3-keto-5 beta-cholanoic and 7 alpha-hydroxy-3-keto-5 beta-cholanoic acids to the corresponding iso-bile acids and from alcohol dehydrogenase, and has a stereospecific character for 7 alpha,12 alpha-dihydroxy-3-keto-5 beta-cholanoic acid.

Bile Acids and Salts↗

PubMed1990

Evaluation of the ileal absorption capacity for bile acids in the rabbit.

The intestinal absorption of bile acids has so far been studied from the measurement of the biliary secretion after their intestinal infusion. In the present investigation, the ileal absorption capacity for two different bile acids has been evaluated by means of an intestinal perfusion technique and the simultaneous blood drainage from the mesenteric vein corresponding to the isolated loop. Taurocholic acid and unconjugated cholic acid were infused at different concentrations (0.5-10.0 mM), at a flow rate of 4 ml/min/cm intest. Taurocholic acid absorption increased to a maximum with dose, then reaching a plateau, suggesting that a saturable process had taken place. Cholic acid uptake showed a saturable, possibly active, process, together with a nonsaturable one. These results are consistent with the physicochemical properties of the two bile acids. The technique seems so far suitable for the study of the intestinal absorption of substances undergoing the enterohepatic circulation, since it provides a direct measure of the absorbed fraction, without any distortion arising from the hepatic uptake and biliary secretion.

Animals↗

PubMed1989

Benign recurrent intrahepatic cholestasis: altered bile acid metabolism.

Altered bile acid metabolism has been claimed to play a role in the etiology of benign recurrent intrahepatic cholestasis (BRIC). Therefore, we studied bile acid metabolism in detail in 10 patients with this syndrome. Pool sizes of both primary bile acids were estimated simultaneously, using deuterated cholic acid and chenodeoxycholic acid. The pool sizes of cholic acid and chenodeoxycholic acid, expressed in micromoles per kilogram body weight, were significantly contracted in BRIC patients during a cholestasis-free period: 8.0 +/- 4.2 and 11.7 +/- 4.7, respectively, versus 24.1 +/- 11.7 and 22.9 +/- 7.8 in controls. Fractional turnover rates (per day) for cholic acid and chenodeoxycholic acid were increased: 0.70 +/- 0.29 and 0.58 +/- 0.27, respectively, versus 0.29 +/- 0.12 and 0.23 +/- 0.10 in controls. Bile acid pool composition expressed as percentages in BRIC patients was cholic acid 34 +/- 17, chenodeoxycholic acid 38 +/- 9, deoxycholic acid 27 +/- 18, and lithocholic acid 1 +/- 1, with a glycine to taurine conjugation ratio of 6.7 +/- 4.9. Corresponding values for 32 controls were cholic acid 57 +/- 13, chenodeoxycholic acid 29 +/- 9, deoxycholic acid 14 +/- 9, and lithocholic acid less than 1, with a glycine to taurine conjugation ratio of 2.4 +/- 1.3. Fecal bile acid loss, in micromoles per kilogram body weight per day, was 11.2 +/- 9.0 in BRIC patients compared with 2.8 +/- 1.4 in controls. The serum 7 alpha-hydroxycholesterol level (nanomoles per liter) was significantly increased in BRIC patients: 326 +/- 179 versus 171 +/- 90 in controls. These results suggest that in BRIC patients spillover of bile acids into the colon occurs, which leads to increased fecal bile acid loss and a reduced bile acid pool size. Increased serum 7 alpha-hydroxycholesterol is probably indicative of an accelerated bile acid synthesis rate due to increased activity of cholesterol 7 alpha-hydroxylase, the enzyme catalyzing the first step in the major pathway of bile acid synthesis. The results of our study suggest that in BRIC patients a contracted bile acid pool increases the susceptibility of the liver for cholestatic agents.

Adult↗

PubMed2004

Absorption of the cholic acid-conjugated peptide hormone cholylsecretin from the rat ileum in vivo.

AIMS: Previously, we demonstrated that gastrin peptides as long as 34 amino acids were absorbed from the ileum of rat after conjugation to the C24 position of cholic acid and that these peptides retained full biological activity. As absorption was specific to the ileum, it was inferred that the conjugated hormone was taken up by the bile salt transporters. We have now extended these experiments to a member of a different family of hormones, viz. secretin, a 27-amino acid hormone that stimulates serous secretions from the exocrine pancreas. METHODS: After conjugation to cholic acid, the degree of cholylsecretin absorption from the ileum of anaesthetized rats was assessed from the increase in pancreatic secretions. RESULTS: A complication to the study was that intra-ileal infusion of native secretin caused a transient increase in the levels of pancreatic secretions. This was in contrast to the effects of intra-ileal infusion of cholylsecretin which did not cause this transient increase but, instead, gave rise to a delayed increase in pancreatic secretions which was sustained over several hours during which cholylsecretin was detected in plasma in high concentration by mass spectrometry. The pancreatic response to cholylsecretin was abolished by co-infusion of 50 mm taurocholate, employed to compete with the bile salt transporters, although a transient increase in pancreatic secretions similar to that caused by secretin was now generated. This was shown to arise from an action of taurocholate per se causing the release of endogenous secretin which is present in rat ileum. CONCLUSIONS: We, therefore, concluded that cholylsecretin had been absorbed from the rat ileum by uptake by bile salt transporters.

Absorption↗

PubMed1991

Importance of peroxisomes in the formation of chenodeoxycholic acid in human liver. Metabolism of 3 alpha,7 alpha-dihydroxy-5 beta-cholestanoic acid in Zellweger syndrome.

Infantile Zellweger syndrome belongs to the group of peroxisomal disorders that lack peroxisomes. Both trihydroxycoprostanic acid (THCA), the precursor to cholic acid, and dihydroxycoprostanic acid (DHCA), the precursor to chenodeoxycholic acid, accumulate in this disease. In previous studies, we have shown that liver peroxisomes are required for the conversion of THCA into cholic acid both in vitro and in vivo by measuring a defective conversion in infants with Zellweger syndrome. In our present study, the conversion of DHCA into chenodeoxycholic acid has been measured in an infant with Zellweger syndrome to evaluate the importance of liver peroxisomes for the formation of chenodeoxycholic acid. Coprostanic acidemia was present from the second day of life with high levels of THCA and only trace amounts of DHCA. The conversion of i.v. administered [3H]DHCA into chenodeoxycholic acid was only 7% compared with the 80% conversion in an analogous study in an adult. There was, however, a rapid incorporation of 3H into biliary THCA and, after a lag phase, the 3H was incorporated into biliary cholic acid. After 72 h, 15% of [3H]DHCA was converted to cholic acid. The pool size of DHCA was 1.2 mg/m2 and the pool size of both cholic acid and chenodeoxycholic acid was markedly reduced. The renal excretion of cholic acid was more efficient than that of the less polar chenodeoxycholic acid. More polar metabolites of DHCA and THCA are formed in alternative metabolic pathways facilitating renal excretion of these toxic intermediates. We conclude that liver peroxisomes are essential for a normal conversion of DHCA into chenodeoxycholic acid.

Bile↗

PubMed1997

Involvement of trihydroxyconjugated bile salts in cholesterol assimilation by bifidobacteria.

To determine the conditions of cholesterol assimilation,various strains of Bifidobacterium species were cultured in the presence of cholesterol and bile salts. During culturing, Bifidobacterium breve ATCC 15700 assimilates cholesterol in the presence of oxgall at pH values lower than 6. This strain was selected to study the influence of conjugated (taurocholic acid) and deconjugated (cholic acid) bile salts on cholesterol assimilation. B. breve ATCC 15700 assimilated cholesterol(up to 51%) when cultures were undertaken in the presence of taurocholic acid, whereas less than 13% of the initial amount ofcholesterol was measured in the cells in the presence of cholic acid. Cultured in the presence of six individual di- or trihydroxyconjugated bile salts, bifidobacteria strains assimilated cholesterol. This assimilation appeared to be more important in the presence of trihydroxyconjugated bile salts (tauro- and glycocholic acids). It is concluded thattrihydroxyconjugated bile salts are involved in the assimilation of cholesterol by bifidobacteria.

Animals↗

PubMed1995

Chemopreventive effects of calcium but not aspirin supplementation in cholic acid-promoted colon carcinogenesis: correlation with intermediate endpoints.

Epidemiological studies have suggested that increased intake of calcium (Ca) or aspirin (ASA) is associated with a reduced risk for colon cancer. To delineate a possible mechanism of action, the present study used male F344 rats in an azoxymethane (AOM)-induced colon tumor model to study the single and interactive effects of Ca and ASA on cholic acid-promoted experimental colon carcinogenesis. Following initiation with AOM, a promotion diet containing 0.5% cholic acid was fed for 34 weeks until the adenoma development stage. Cholic acid was used as a surrogate for high-fat diets and to promote carcinogenesis. Diets were supplemented with CaCO3 (2% Ca by weight), 250 p.p.m. ASA, or both. After 34 weeks, the diets were switched during the progression stage and rats were killed at week 51. Several intermediate endpoints were examined during the course of AOM carcinogenesis to determine their reliability as predictors of colon cancer risk. Intermediate endpoints included colon crypt height measurement, colon mucosal ornithine decarboxylase (ODC) and colon mucosal protein kinase C (PKC) activities. The biomarkers were examined at the beginning of the study at 2 weeks, and thereafter at 5, 15, 30 and 40 weeks of dietary treatment. Animals were necropsied at week 51 and tumor incidence and numbers were analyzed for correlation with biomarkers. Survival was highest in the group fed CaCO3 during the promotion stage and tumor burden was lowest in groups fed CaCO3 during this stage. Supplementation during the progression stage was ineffective. The cholic acid promotion model resulted in increased ODC which was inhibited by intervention during the promotion stage with Ca, but not ASA. PKC was also activated by cholic acid feeding, and this effect was modulated by intervention in the promotional stage with Ca or ASA. Colon tumor incidence and burden was increased by cholic acid promotion and decreased by Ca, but not affected by ASA. In summary, Ca is a more effective chemopreventive agent in cholic acid-promoted colon carcinogenesis than ASA, impacting both incidence and tumor number. Colonic ODC, but not PKC may be a suitable predictor of risk and response in chemoprevention trials for colon cancer.

Animals↗

PubMed1984

Enzymic measurement of primary bile acids and the primary bile acid ratio in serum with the IL-Multistat III Fluorescence Light-Scattering Centrifugal Analyzer.

Enzymic fluorimetric methods are described for the determination of primary bile acids and of chenodeoxycholic acid (CDC) and cholic acid (C) in serum. Bile acids are extracted from 0.3 mL of serum in a simple 5-min step with use of Sep-Pak C cartridges. Total primary bile acids are measured by an equilibrium technique after reaction with beta-NAD in the presence of 7 alpha-hydroxysteroid dehydrogenase. Chenodeoxycholic acid (and its conjugates) is measured by a reaction-rate technique employing the same reaction as above but under different experimental conditions. A small contribution of cholic acid (and its conjugates) to the reaction rate is eliminated by simple calculations. Cholic acid is calculated by difference of the two determinations. In both assays NADH fluorescence is measured with the Multistat centrifugal analyzer. Absolute recovery of bile acids from serum was about 87%. Day-to-day standard deviations for CDC and C were 1.6 and 2.0 mumol/L at serum concentrations of 22.1 and 24.1 mumol/L respectively. Comparison data with a cholylglycine RIA procedure gave the following correlation coefficients (x = RIA, y = proposed method): r = 0.980 (RIA vs total primary bile acids), r = 0.918 (RIA vs CDC) and r = 0.989 (RIA vs C). The methods described appear more practical for use on a routine basis than methods in the literature for the calculation of the primary bile acid ratio.

Adult↗

PubMed1990

Changes in the serum levels of primary bile acids in dairy cows.

Serum cholic acid (SCA) and serum chenodeoxycholic acid (SCDCA) concentrations were determined in healthy dairy cows by radioimmunoassay (RIA). The levels of these two primary bile acids were correlated with the cows' reproductive status. The lowest concentrations were measured in dry cows (SCA: 7.8 +/- 3.3 mumol/l, SCDCA.: 1.5 +/- 1.0 mumol/l). In freshly calved cows SCA and SCDCA was 17.8 +/- 6.9 mumol/l and 2.3 +/- 1.0 mumol/l, respectively, while in milking cows SCA and SCDCA was 15.8 +/- 5.7 and 2.3 +/- 0.8 mumol/l, respectively. SCA concentration showed a characteristic change on the days immediately after calving: on calving day it was close to the mean SCA concentration found for dry cows, then it underwent a striking abrupt rise and reached the value typical of post-parturient cows by post-partum (PP) day 4-5. Cholic acid was found to be the major primary bile acid in the blood of dairy cows. In dry cows the SCA:SCDCA ratio is 5:1. If the serum bile acid concentration rises, the SCA:SCDCA ratio will increase further.

Animals↗

PubMed1981

Microbial synthesis of 1 beta- and 15 beta-hydroxylated bile acids.

Lithocholic, deoxycholic, and cholic acids were incubated with the molds Absidia coerulea Bain (CBS 105.08, I), three strains of Rhizoctonia solani Kühn (CBS 130.14 (II), CBS 341.36 (III), CBS 325.47 (IV)), and Penicillium species ATCC 12556 (V). The products were analyzed by gas-liquid chromatography and partially characterized by gas-liquid chromatography-mass spectrometry. Lithocholic acid was most extensively hydroxylated while cholic acid yielded only traces of hydroxylated metabolites. I, II, III, and V hydroxylated at position C-1; I at C-6; I and II at C-7; III at C-12; and I, II, IV, and V at C-15. Hydroxylations at unidentified positions were observed for all molds, and oxidoreductions at C-7 and C-12 were carried out by I, II, and III. The two major trihydroxycholanoates formed by V from deoxycholic acid were characterized by chemical, mass spectrometric, and nuclear magnetic resonance techniques as 1 beta, 3 alpha, 12 alpha- and 3 alpha, 12 alpha, 15 beta-trihydroxy-5 beta-cholanoic acids. The former bile acid was identical with the 1,3,12-trihydroxycholanoic acid present in human urine.

Biotransformation↗

PubMed1988

Bile acid synthesis: down-regulation by monohydroxy bile acids.

The regulation of bile acid synthesis was studied in rabbits after interruption of the enterohepatic circulation by choledochoureteral anastomosis. Total daily bile acid output was 772 +/- 130 (SD) mumol/24 h, of which greater than 95% was glycocholic acid. Administration of deoxycholic or cholic acid or their conjugates (300-800 mumol) or gall-bladder bile failed to down-regulate endogenous bile acid synthesis. In contrast, chenodeoxycholic acid administration did down-regulate bile acid synthesis, but this effect was related to the formation and excretion of lithocholic acid. This observation was confirmed by the finding that i.v. infusion of 10-20 mumol of either lithocholic acid or 3 beta-hydroxy-5-cholenoic acid significantly reduced cholic acid synthesis. Thus monohydroxy bile acids, derived from either hepatic or intestinal sources, participate in the down-regulation of bile acid synthesis.

Animals↗

PubMed1993

Bile acid transformations by Alcaligenes recti.

Metabolism of cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and deoxycholic acid by the grown cells of the bacterium Alcaligenes recti suspended in water was studied. Each isolated metabolite was characterized by the application of various spectroscopic methods. Cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and deoxycholic acid yielded methylated derivatives 3 alpha-methoxy-7 alpha, 12 alpha-dihydroxy-5 beta-cholanoic acid, 3 alpha-methoxy-7 alpha-hydroxy-5 beta-cholanoic acid, 3 alpha-methoxy-7 beta-hydroxy-5 beta-cholanoic acid, and 3 alpha-methoxy-12 alpha-hydroxy-5 beta-cholanoic acid, respectively. In addition, cholic acid furnished 7 alpha, 12 alpha-dihydroxy-3-oxochol-4-en-24-oic acid; chenodeoxycholic acid gave 7 alpha-hydroxy-3-oxo-5 beta-cholanoic acid and 7 alpha-hydroxy-3-oxochol-4-en-24-oic acid while ursodeoxycholic acid yielded 7 beta-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxochola-4,6-dien-24-oic acid. The formation of various metabolites showed that two competitive enzymic reactions, i.e., selective methylation of the 3 alpha-hydroxy group and dehydrogenation in the A/B rings, were operative. The methylation process was found to be enzymic involving an S-adenosyl-L-methionine (AdoMet)-dependent methyl transferase, and this reaction appeared to be inhibitory to the process of degradation of the ring system. In the other reaction sequence, degradation of the ring system was initiated by dehydrogenation of the 3 alpha-hydroxy group. A 7 beta-dehydratase activity producing the delta 6 double bond was also noticeable in the metabolism of ursodeoxycholic acid.

Alcaligenes↗

PubMed1975

Effect of glucose administration on cholesterol and bile acid metabolism in rats.

Glucose administered to fasted rats caused a marked stimulation in hepatic cholesterogenesis and cholesterol 7 alpha-hydroxylation, and an increase in biliary excretion of cholesterol and total bile acids. The excretion of cholic acid was not incluenced during the first few hr after glucose administration, but was significantly increased after 5 hr. Chenodeoxycholic acid showed a similar change, but the increase was only ca. one tenth of that of cholic acid. The excretion of deoxycholic acid was markedly increased by 1 hr, but gradually decreased thereafter. Pretreatment with neomycin abolished the increase in deoxycholic acid by fasting and glucose administration. Other bile acid components showed no significant change. It thus was presumed that cholesterol endogenously synthesized in the liver was metabolized mainly to cholic acid. In contrast, exogenous cholesterol was metabolized mainly to chenodeoxycholic acid. During the period of the acute enhancement of cholic acid formation from the endogenous cholesterol, biliary excretion of deoxycholic acid was increased. This probably occurred through the depression of 7 alpha-rehydroxylation of deoxycholic acid, or through the enhancement of microbial formation of deoxycholic acid in the lumen, and through the increase of intestinal absorption.

Bile↗

PubMed1987

Ileal absorption of tyrosine-conjugated bile acids in Wistar rats.

We recently reported that tyrosine-conjugated bile acids, when injected intravenously into bile-fistula rats, are extracted by the liver and secreted intact into bile with an efficiency similar to that seen for taurocholate. Now the effect of tyrosine and glycyltyrosine conjugation of bile acids on ileal absorption has been studied in Wistar rats. 125I-labelled tyrosine- and glycyltyrosine-conjugated bile acid or [14C]taurocholate was injected in 400 microliters aliquots of physiological saline buffered to pH 7.8 into the ileal lumen of bile-fistula rats. Recovery of bile salts in bile was taken as proof of ileal absorption. In comparison with taurocholate, ileal absorption was about 10% less for cholyltyrosine and chenodeoxycholyltyrosine and about 50% less for deoxycholyltyrosine. Thus, tyrosine-conjugated bile acids are absorbed by the ileum and excreted into bile and may undergo enterohepatic circulation. Low recoveries of deoxycholyltyrosine relative to deoxycholylglycine suggested that side chain structure was important for ileal absorption of 3 alpha,12 alpha-dihydroxy bile acids. Elongation of cholic acid to form cholylglycyltyrosine markedly reduced 90-min cumulative ileal absorption relative to cholyltyrosine. Although initial rates of recovery of cholylglycyltyrosine were comparable to those of the other bile acids, very little further absorption was seen in the last hour of the experiment, suggesting that this compound was rapidly degraded within the intestinal lumen.

Animals↗

PubMed1980

Intestinal microflora and bile acids. Effect of bile acids on the distribution of microflora and bile acid in the digestive tract of the rat.

The population levels of intestinal microflora and bile acid composition in the digestive tract were examined in rats fed bile acids to determine the relationships between gastrointestinal microflora and the host. The population level of Bacteroides was increased in the ceca of rats fed cholic acid or deoxycholic acid. In the ileum, the concentration of conjugated bile acid in rats fed cholesterol, cholic acid, hyodeoxycholic acid or lithocholic acid was higher than that in control rats, and was very low in ceca and feces of all the rats. The concentration of total free bile acid was much higher in the ceca than in the ilea of rats fed hyodeoxycholic acid or lithocholic acid. Cholic acid and deoxycholic acid were found in the ilea, ceca and feces of the cholic acid-fed rats. In the deoxycholic acid-fed rats, cholic acid was localized in the ileum. 7-Ketodeoxycholic acid was also found in the ceca of the cholic acid-fed rats. 12-Ketolithocholic acid was found in the feces of rats fed cholic acid or deoxycholic acid. 3-Ketocholanic acid was found in some samples from the lithocholic acid-fed rats. Therefore, some kinds of bile acids influence the population levels of gastrointestinal microflora and bile acid composition in the intestine.

Animals↗

PubMed1975

[Aspects of bile acid metabolism in liver diseases(author's transl)].

Although chemistry and physiology of bile acids have been elucidated during the last two decades, tests concerning bile acid metabolism are still rarely used in clinical medicine. The aim of this study therefore was, to investigate bile acid metabolism in patients with liver diseases and to find prognostic valuable parameters which can be recommended for clinical use. Following an introducing review of biosynthesis and kinetics of bile acids, normal values are presented for pool size and synthesis of the two primary bile acids, for bile lipid composition, plasma bile acid concentration and for clearance and conjugation of intravenously injected 14C-cholic acid, which have been measured in healthy subjects. Bile acids were determined by thin-layer-chromatography, gas-liquid-chromatography and by an enzymatic and fluorimetric method. In all patients investigated with acute hepatic necrosis, plasma disappearance of radioactivity was greatly prolonged after intravenous injection of 14C-cholic acid. By estimating free 14C-cholic acid and 14C-cholic acid conjugates in plasma individually, two groups of patients could be distinguished: in patients who survived hepatic coma, the clearance of free 14C-cholic acid was significantly more rapid and the percentage of glycine and taurine conjugates of 14C-cholic acid in plasma was significantly higher than in patients who died in coma. This prognostic significant differentiation was possible by measuring the relationship of conjugated: unconjugated radioactivity in one single plasma sample taken three hours after injection. In patients with cirrhosis of the liver the plasma disappearance rate of radioactivity during 60 minutes following injection of 14C-cholic acid was significantly correlated with serum-bilirubin, SGOT, serum-albumin, prothrombine-time, plasma bile acids, and a clinical scoring. 14C-deoxycholic acid was found in plasma of only a few patients 24 hours after injection of the labelled cholic acid, and was related to the relatively good liver function in these patients. It is concluded that the following tests of bile acid metabolism are of clinical interest: 1. Measuring plasma bile acid concentration may serve as a sensitive liver function test. 2. Estimation of the conjugation of intravenously injected 14C-cholic acid is of prognostic value in patients with fulminant hepatic failure. 3. Determination of the initial plasma disappearance rate of 14C-cholic acid injected intravenously and its transformation to 14C-cholic acid injected intravenously and its transformation to 14C-deoxycholic acid may help to classify patients with cirrhosis of the liver.

Adolescent↗