hyodeoxycholic-acid and muricholic-acid

Knowledge about in vivo effects of human circulating C-6 hydroxylated bile acids (BAs), also called muricholic acids, is sparse. It is unsettled if the gut microbiome might contribute to their biosynthesis. Here, we measured a range of serum BAs and related them to markers of human metabolic health and the gut microbiome. We examined 283 non-obese and obese Danish adults from the MetaHit study. Fasting concentrations of serum BAs were quantified using ultra-performance liquid chromatography-tandem mass-spectrometry. The gut microbiome was characterized with shotgun metagenomic sequencing and genome-scale metabolic modeling. We find that tauro- and glycohyocholic acid correlated inversely with body mass index (P = 4.1e-03, P = 1.9e-05, respectively), waist circumference (P = 0.017, P = 1.1e-04, respectively), body fat percentage (P = 2.5e-03, P = 2.3e-06, respectively), insulin resistance (P = 0.051, P = 4.6e-4, respectively), fasting concentrations of triglycerides (P = 0.06, P = 9.2e-4, respectively) and leptin (P = 0.067, P = 9.2e-4). Tauro- and glycohyocholic acids, and tauro-a-muricholic acid were directly linked with a distinct gut microbial community primarily composed of Clostridia species (P = 0.037, P = 0.013, P = 0.027, respectively). We conclude that serum conjugated C-6-hydroxylated BAs associate with measures of human metabolic health and gut communities of Clostridia species. The findings merit preclinical interventions and human feasibility studies to explore the therapeutic potential of these BAs in obesity and type 2 diabetes.

Topics: Adiposity; Bile Acids and Salts; Body Mass Index; Cholic Acids; Chromatography, High Pressure Liquid; Clostridium; Deoxycholic Acid; Female; Gastrointestinal Microbiome; Humans; Logistic Models; Male; Metagenomics; Middle Aged; Obesity; Tandem Mass Spectrometry; Taurocholic Acid; Waist Circumference

Bile salts (BSs), in addition to their physiological role in the digestion of lipids in vertebrates, are also of significant importance in biomedical investigations. For predicting biological-pharmacological activity and physico-chemical properties of BSs it is important to develop such molecular descriptors that adequately describe the structural characteristics of the steroid skeleton. The present study encompassed the following bile acids (BAs): cholic, chenodeoxycholic, deoxycholic, hyodeoxycholic, ursodeoxycholic, hyocholic, and ursocholic acid, as well as oxo derivatives of certain BAs. For all of them, Heuman hydrophobicity indices (HI(BA)) (RP-HPLC parameters) were determined, and a detailed conformational analysis of the steroid skeleton showed that HI(BA) has the discrimination power for BAs based on the size of the hydrophobic surface on the β side and the lateral L7 and L12 sides of the steroid skeleton. Also, HI(BA) discerns the regiochemical characteristics of OH and oxo groups. Based on a survey of the structural factors of the steroid skeleton that influence the HI(BA) values of the tested BAs, we constructed a new molecular descriptor, CHIBA, with the characteristics of 2D and 3D topological descriptors. In respect of the structure of the steroid skeleton, the descriptor CHIBA behaves as a reversed-phase chromatographic descriptor of BAs.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acid; Cholic Acids; Chromatography, Reverse-Phase; Deoxycholic Acid; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Conformation; Principal Component Analysis; Regression Analysis; Ursodeoxycholic Acid

Bile acids (BA) are essential modulators of lipid, glucose, and cholesterol homeostasis, but they exert cytotoxic effects in the cholestatic liver. Glucuronidation, catalyzed by the UDP-glucuronosyltransferase (UGT) enzymes is a pharmacologically relevant BA detoxification process. The present study characterized the BA-conjugating activity of the little-studied human UGTs of subfamily 2A: UGT2A1, 2A2, and 2A3. Recombinant UGT2As, expressed in baculovirus-infected insect cells, were assayed for the glucuronidation of six major bile acids: chenodeoxycholic acid (CDCA), cholic acid (CA), lithocholic acid (LCA), deoxycholic acid (DCA), hyocholic acid (HCA) and hyodeoxycholic acid (HDCA). UGT2A3 exhibited detectable but very low activity with all the tested BA substrates. UGT2A1 was highly efficient in forming LCA-3 and LCA-24G, CDCA-24, DCA-24, HCA-24, and HDCA-24G, whereas UGT2A2 was the most active enzyme for CA-24G and CDCA-24G formation and also was able to generate HDCA-6G, HDCA-24G, LCA-24G, and HCA-24G. The Km values of UGT2A1 varied between 102.2 ± 14.3 µM and 2.4 ± 1.2 mM. With the exception of CA-24G, a low affinity substrate for UGT2A2, all the Km values for UGT2A2 were in the 100 to 400 µM range. We demonstrate the high reactivity of the human UGT2A1 and UGT2A2 for bile acid glucuronidation. The physiologic importance of these reactions to BA disposition remains, however, to be clarified in vivo.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acid; Cholic Acids; Deoxycholic Acid; Glucuronosyltransferase; Humans; Lithocholic Acid

Previous studies showed glucose and insulin signaling can regulate bile acid (BA) metabolism during fasting or feeding. However, limited knowledge is available on the effect of calorie restriction (CR), a well-known anti-aging intervention, on BA homeostasis. To address this, the present study utilized a "dose-response" model of CR, where male C57BL/6 mice were fed 0, 15, 30, or 40% CR diets for one month, followed by BA profiling in various compartments of the enterohepatic circulation by UPLC-MS/MS technique. This study showed that 40% CR increased the BA pool size (162%) as well as total BAs in serum, gallbladder, and small intestinal contents. In addition, CR "dose-dependently" increased the concentrations of tauro-cholic acid (TCA) and many secondary BAs (produced by intestinal bacteria) in serum, such as tauro-deoxycholic acid (TDCA), DCA, lithocholic acid, ω-muricholic acid (ωMCA), and hyodeoxycholic acid. Notably, 40% CR increased TDCA by over 1000% (serum, liver, and gallbladder). Interestingly, 40% CR increased the proportion of 12α-hydroxylated BAs (CA and DCA), which correlated with improved glucose tolerance and lipid parameters. The CR-induced increase in BAs correlated with increased expression of BA-synthetic (Cyp7a1) and conjugating enzymes (BAL), and the ileal BA-binding protein (Ibabp). These results suggest that CR increases BAs in male mice possibly through orchestrated increases in BA synthesis and conjugation in liver as well as intracellular transport in ileum.

Topics: Animals; Bile Acids and Salts; Blood Glucose; Body Weight; Caloric Restriction; Carrier Proteins; Cholesterol 7-alpha-Hydroxylase; Cholic Acids; Deoxycholic Acid; Dose-Response Relationship, Drug; Enterohepatic Circulation; Homeostasis; Intestines; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; RNA, Messenger; Tandem Mass Spectrometry

To evaluate bile acid (BA) metabolism in detail, we established a method for analyzing BA composition in various tissues and intestinal contents using ultra performance liquid chromatography/electrospray ionization mass spectrometry (UPLC/ESI-MS). Twenty-two individual BAs were determined simultaneously from extracts. We applied this method to define the differences in BA metabolism between two rat strains, WKAH and DA. The amount of total bile acids (TBAs) in the liver was significantly higher in WKAH than in DA rats. In contrast, TBA concentration in jejunal content, cecal content, colorectal content, and feces was higher in DA rats than in WKAH rats. Nearly all BAs in the liver were in the taurine- or glycine-conjugated form in DA rats, and the proportion of conjugated liver BAs was up to 75% in WKAH rats. Similar trends were observed for the conjugation rates in bile. The most abundant secondary BA in cecal content, colorectal content, and feces was hyodeoxycholic acid in WKAH rats and omega-muricholic acid in DA rats. Analyzing detailed BA profiles, including conjugation status, in a single run is possible using UPLC/ESI-MS. This method will be useful for investigating the roles of BA metabolism under physiological and pathological conditions.

Topics: Animals; Bile; Bile Acids and Salts; Cholic Acids; Chromatography, High Pressure Liquid; Chromatography, Liquid; Deoxycholic Acid; Gastrointestinal Contents; Glycine; Intestinal Mucosa; Liver; Male; Rats; Spectrometry, Mass, Electrospray Ionization; Taurine

Multidrug Resistance Protein 3 (MRP3) transports bile salts and glucuronide conjugates in vitro and is postulated to protect the liver in cholestasis. Whether the absence of Mrp3 affects these processes in vivo is tested.. Mrp3-deficient mice were generated and the contribution of Mrp3 to bile salt and glucuronide conjugate transport was tested in (1): an Ussing-chamber set-up with ileal explants (2), the liver during bile-duct ligation (3), liver perfusion experiments, and (4) in vitro vesicular uptake experiments.. The Mrp3((-/-)) mice show no overt phenotype. No differences between WT and Mrp3-deficient mice were found in the trans-ileal transport of taurocholate. After bile-duct ligation, there were no differences in histological liver damage and serum bile salt levels between Mrp3((-/-)) and WT mice, but Mrp3-deficient mice had lower serum bilirubin glucuronide concentrations. Glucuronide conjugates of hyocholate and hyodeoxycholate are substrates of MRP3 in vitro and in livers that lack Mrp3, there is reduced sinusoidal secretion of hyodeoxycholate-glucuronide after perfusion with hyodeoxycholate.. Mrp3 does not have a major role in bile salt physiology, but is involved in the transport of glucuronidated compounds, which could include glucuronidated bile salts in humans.

Topics: Animals; Bile Acids and Salts; Bile Ducts; Bilirubin; Biological Transport; Cholic Acids; Deoxycholic Acid; Glucuronides; Ileum; Immunoblotting; Immunohistochemistry; Ligation; Liver; Male; Mice; Mice, Inbred Strains; Multidrug Resistance-Associated Proteins; Taurocholic Acid

The aim of the present study was to investigate the influence of dietary-fibre (DF)-rich barley-based diets on bile acids (BA) and neutral sterols (NS) in the intestinal tract of rats. For this purpose, young male Wistar rats (n 50; ten per group) weighing about 67 g were fed either a barley-free diet (control group) or diets containing 500 g barley meal extrudates/kg or a barley meal-Novelose mixture (groups A-D) for 6 weeks. These barley products contained 7-24 g resistant starch/100 g and 7-12 g (1 --> 3),(1 --> 4)-beta-glucan/100 g. More steroids were transported towards the lower parts of the intestinal tract when higher concentrations of macromolecular DF were present in the diets (P < 0.001). Tauroconjugated and primary BA dominated in the contents of the small intestine. Intense enzymic conversion of BA occurred in the caecum and colon. The fermentation of DF affected indirectly the amount of formed secondary BA. The main BA present in the caecal contents were muricholic acids, hyodeoxycholic acid and cholic acid. The BA spectrum in the colonic contents was different from that in the caecum. A higher concentration of NS appeared in the intestinal contents of the groups fed the barley-based diets than in the controls (P < 0.005). The microbial conversion of cholesterol to coprostanol, cholestanone and coprostanone was influenced by the amount and composition of the DF in the gut. DF in the diet may affect the concentration and spectrum of steroids in the intestinal tract. The results are relevant for the discussion of mechanisms behind the cholesterol-lowering effects of DF.

Topics: Animals; Bile Acids and Salts; Cecum; Cholesterol; Cholic Acids; Colon; Deoxycholic Acid; Diet; Dietary Fiber; Hordeum; Intestinal Mucosa; Intestine, Small; Male; Rats; Rats, Wistar; Starch; Steroids; Sterols

From the rat intestinal microflora we isolated a gram-positive rod, termed HDCA-1, that is a member of a not previously described genomic species and that is able to transform the 3alpha,6beta, 7beta-trihydroxy bile acid beta-muricholic acid into hyodeoxycholic acid (3alpha,6alpha-dihydroxy acid) by dehydroxylation of the 7beta-hydroxy group and epimerization of the 6beta-hydroxy group into a 6alpha-hydroxy group. Other bile acids that were also transformed into hyodeoxycholic acid were hyocholic acid (3alpha, 6alpha,7alpha-trihydroxy acid), alpha-muricholic acid (3alpha,6beta, 7alpha-trihydroxy acid), and omega-muricholic acid (3alpha,6alpha, 7beta-trihydroxy acid). The strain HDCA-1 could not be grown unless a nonconjugated 7-hydroxylated bile acid and an unidentified growth factor produced by a Ruminococcus productus strain that was also isolated from the intestinal microflora were added to the culture medium. Germfree rats selectively associated with the strain HDCA-1 plus a bile acid-deconjugating strain and the growth factor-producing R. productus strain converted beta-muricholic acid almost completely into hyodeoxycholic acid.

Topics: Animals; Bile Acids and Salts; Cholic Acids; Deoxycholic Acid; DNA, Bacterial; DNA, Ribosomal; Genes, rRNA; Germ-Free Life; Gram-Positive Rods; Intestines; Mice; Microscopy, Electron, Scanning; Phylogeny; Rats; RNA, Ribosomal, 16S; Sequence Analysis, DNA

We recently showed that feeding the cytoprotective bile acid ursodeoxycholic acid (UDCA) to rats resulted in significant reduction in polyps and especially cancers, both in number and size (D. L. Earnest et al., Cancer Res., 54: 5071-5074, 1994). Because fecal secondary bile acids [particularly deoxycholic acid (DCA)] are considered to promote formation of colon adenomas and cancer, we have now attempted to find a relationship between polyp reduction and fecal secondary bile acids after feeding UDCA to these rats. We examined the fecal bile acids in rats with polyps and compared them with fecal bile acids in control rats and also determined the bile acid composition in fecal aqueous phase, which is in direct contact with the colon epithelium and may be physiologically more active. Treatment with azoxymethane did not significantly alter fecal bile acid composition in the rats. Cholic acid feeding resulted in greatly increased proportions of DCA (82% of total bile acids versus 18% in control rats). On the other hand, UDCA feeding significantly reduced the proportion of fecal DCA (2% in control rats fed UDCA and 3% in rats also treated with azoxymethane). In control rats, 96% of the bile acids were present in the water-insoluble fraction and 4% in the water-soluble fraction. The major insoluble bile acids included DCA and hyodeoxycholic acid (73% of total bile acids). In contrast, the muricholic acids were concentrated in the soluble fraction (37%). When 0.4% UDCA was added to the diet, lithocholic acid increased in the insoluble fraction (40 versus 1%), but the hydrophilic UDCA and muricholic acids were enriched in the water-soluble fraction (37 and 43%, respectively). Thus, the hydrophobic bile acids were distributed predominantly in the water-insoluble fraction, whereas the hydrophilic bile acids were distributed preferentially in the water-soluble fraction. These data suggest that UDCA may prevent colon tumors and polyps by countering the toxic effect of DCA and enhancing the possible cytoprotective effects of UDCA and muricholic acids in the water-soluble fraction in the feces of rat.

Topics: Animals; Azoxymethane; Bile Acids and Salts; Cholic Acid; Cholic Acids; Colonic Polyps; Deoxycholic Acid; Feces; Lithocholic Acid; Male; Rats; Rats, Inbred F344; Retrospective Studies; Ursodeoxycholic Acid

The aim of this study was to analyse the Raman and infrared spectra of eight common mammalian bile acids in order to identify intermolecular interactions between hydroxyl and carbonyl groups. The results are considered in the light of the new hydrophilic/hydrophobic classification of bile acids. The alcohol OH group of the hydrophobic bile acids forms different intermolecular bonds. The most hydrophobic bile acid, lithocholic acid forms polymers, and this may explain its very low water solubility. The hydrophilic bile acids have some of their alcohol OH groups free of any intermolecular interaction. The strongly hydrophilic murideoxycholic acid also forms dimers, again consistent with a very low water solubility. The proposed structural arrangements are in agreement with published crystallographic studies.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acid; Cholic Acids; Deoxycholic Acid; Lithocholic Acid; Mammals; Models, Molecular; Molecular Conformation; Solvents; Spectrophotometry, Infrared; Spectrum Analysis, Raman; Structure-Activity Relationship; Ursodeoxycholic Acid

Rifampin was shown to relieve pruritus in cholestatic liver diseases. There has been much speculation about the origin of pruritus, but it has not yet been comprehensively explained. The role of bile acids in producing pruritus is obscure and still under debate. Since rifampin both inhibits the uptake of bile acids into the hepatocyte and strongly induces mixed-function oxidases in the liver, the beneficial effects of this drug might be a consequence of altered bile acid metabolism.. We investigated the influence of rifampin on urinary bile acid excretion with special respect to glucuronide and sulphate conjugates in 14 healthy volunteers before and after administration of rifampin, 600 mg x 7 days, using each subject as his or her own control.. Bile acid glucuronide excretion increased from 0.55 to 1.19 mumol/24 h. This was in particular due to a significant increase of the urinary excretion of the 6 alpha-hydroxylated hyocholic and hyodeoxycholic acids, the relative amounts of which accounted for about two thirds of the urinary bile acid excretion. Excretion of sulphates, however, decreased from 1.40 to 0.86 mumol/24 h due to a significantly reduced excretion of lithocholic acid sulphate. No changes in the excretion rates of other primary and secondary bile acids and no changes in their conjugation patterns were observed.. The results provide evidence that rifampin induces 6 alpha-hydroxylation of bile acids. The products are subsequently glucuronidated at the 6 alpha-hydroxy group, thus stimulating renal excretion of potentially toxic bile acids.

Topics: Adult; Antibiotics, Antitubercular; Bile Acids and Salts; Cholic Acids; Deoxycholic Acid; Female; Gas Chromatography-Mass Spectrometry; Glucuronates; Humans; Hydrocortisone; Hydroxylation; Male; Mixed Function Oxygenases; Rifampin; Sulfates

The effects of hyodeoxycholic (HDCA) and alpha-hyocholic acids (alpha-HCA), on cholesterol, bile acid and lipoprotein metabolism, were studied in hamsters. The animals were fed a low cholesterol control diet supplemented with 0.1% HDCA or alpha-HCA for 3 weeks. In both treated groups, the LDL-cholesterol concentration was significantly lowered and was associated with a global hypocholesterolemic effect. Moreover, hepatic cholesterol ester storage was reduced and HMGCoA reductase activity was respectively enhanced 13.5-times and 7.7-times in HDCA and alpha-HCA groups compared to controls. In contrast, cholesterol 7 alpha-hydroxylase activity and LDL-receptor activity and mass were not modified. In bile, the cholesterol saturation index was increased 5-fold (HDCA group) and 2-fold (alpha-HCA group) as a consequence of an enlarged proportion of biliary cholesterol. The two 6-hydroxylated bile acids induced an enhanced fecal excretion of neutral sterols (HDCA group: 11.6-times, alpha-HCA group: 3.2-times versus controls) which was consistent with a 59% decrease in intestinal cholesterol absorption in the HDCA group. The major effects due to bile acid treatments were a decrease in LDL-cholesterol concentration, a strong stimulation of hepatic cholesterol biosynthesis and an excessive loss of cholesterol in feces. These perturbations might be the result of the enrichment of bile with hydrophilic bile acids, leading to a limited return of endogenous cholesterol from the intestine to the liver.

Topics: Animals; Bile; Bile Acids and Salts; Cholesterol; Cholic Acids; Cricetinae; Deoxycholic Acid; Diet; Intestinal Absorption; Lipoproteins; Liver; Mesocricetus; Receptors, LDL

Two independent methods have been developed and compared to determine the lipophilicity of a representative series of naturally occurring bile acids (BA) in relation to their structure. The BA included cholic acid (CA), chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA), deoxycholic acid (DCA), hyodeoxycholic acid (HDCA), ursocholic acid (UCA), hyocholic acid (HCA), as well as their glycine and taurine amidates. Lipophilicity was determined using a 1-octanol/water shake-flask procedure and the experiments were performed at different pH and ionic strengths and at initial BA concentrations below their critical micellar concentrations (CMC) and the water solubility of the protonated form. The experimental data show that both the protonated (HA) and ionized (A-) forms of BA can distribute in 1-octanol, and consequently a partition coefficient for HA (logP' HA) and for A- (logP' A-) must be defined. An equation to predict a weighted apparent distribution coefficient (D) value as a function of pH and pKa has been developed and fits well with the experimental data. Differences between logP for protonated and ionized species for unconjugated BA were in the order of 1 log unit, which increased to 2 for glycine-amidate BA. The partition coefficient of the A- form increased with Na+ concentration and total ionic strength, suggesting an ion-pair mechanism for its partition into 1-octanol. Lipophilicity was also assessed using reverse phase chromatography (C-18-HPLC), and a capacity factor (K') for ionized species was determined. Despite a broad correlation with the logP data, some BA behaved differently. The logP values showed that the order of lipophilicity was DCA greater than CDCA greater than UDCA greater than HDCA greater than HCA greater than CA greater than UCA for both the protonated and ionized unconjugated and glycine-amidate BA, while the K' data showed an inversion for some BA, i.e., DCA greater than CDCA greater than CA greater than HCA greater than UDCA greater than HDCA greater than UCA. The logP data fitted well with other indirect measurements of BA monomeric lipophilicity such as albumin binding or accessible total hydrophobic surface area data calculated by energy minimization and molecular computer graphics. Differences between unconjugated and amidated BA are consistent with the presence of an amide bond and a lower pKa when pH dependence was studied. Capacity factors, on the other hand, were related to properties of BA micelles such as ch

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acid; Cholic Acids; Chromatography, High Pressure Liquid; Deoxycholic Acid; Hydrogen-Ion Concentration; Lipids; Octanols; Structure-Activity Relationship; Ursodeoxycholic Acid

Changes in the composition of serum bile acids were investigated after orthotopic liver transplantation in piglets. Serum levels of all bile acid components rapidly increased during the anhepatic phase and then quickly decreased, returning to the preoperative state within 6 h of revascularization of the allograft. In the animals in which extrahepatic biliary stenosis was a complication, serum total bile acids (TBA) increased remarkably. A marked increase of hyocholic acid and marked decrease of hyodeoxycholic acid were noted; as percentages of TBA, the average levels per day were 91.3 +/- 1.3 and 5.0 +/- 1.3%, respectively. No change in chenodeoxycholic acid (CDCA) was observed. In the animals suffering acute rejection without extrahepatic biliary stenosis, serum TBA increased slightly and the percentage of CDCA rose, the average level being 29.6 +/- 1.5%. These results suggest that the measurement of the composition of serum bile acids may serve as a useful means of assessing allograft function after liver transplantation.

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acids; Deoxycholic Acid; Female; Liver Transplantation; Male; Swine

Bile acids may damage the gastric mucosa, and they are cocarcinogenic in experimental colonic and gastric cancer. Chronic atrophic gastritis (CAG) and chronic atrophic gastritis with intestinal metaplasia (CAGIM) are associated with gastric carcinoma. We, therefore, analysed bile acids in the antral mucosa in controls (n = 10), in patients with CAG (n = 12) and CAGIM (n = 20). In both forms of chronic antral gastritis, total mucosal bile acid concentrations drop, caused mainly by lower primary bile acids. The proportions of secondary bile acids rise, in particular of toxic lithocholic acid. This is probably caused by bacterial activity in the stomach. Whether secondary bile acids, especially lithocholic acid, alone or in combination with other bacterial degradation products, influence gastric carcinogenesis remains to be elucidated in further studies.

Topics: Adult; Aged; Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acid; Cholic Acids; Deoxycholic Acid; Female; Gastric Mucosa; Gastritis; Gastritis, Atrophic; Humans; Intestines; Lithocholic Acid; Male; Metaplasia; Middle Aged; Pyloric Antrum; Stomach Neoplasms; Ursodeoxycholic Acid

The glucuronidation of 6-hydroxylated bile acids by human liver microsomes has been studied in vitro; for comparison, several major bile acids lacking a 6-hydroxyl group were also investigated. Glucuronidation rates for 6 alpha-hydroxylated bile acids were 10-20 times higher than those of substrates lacking a hydroxyl group in position 6. The highest rates measured were for hyodeoxy- and hyocholic acids, and kinetic analyses were carried out using these substrates. Rigorous product identification by high-field proton nuclear magnetic resonance and by electron impact mass spectrometry of methyl ester/peracetate derivatives revealed that 6-O-beta-D-glucuronides were the exclusive products formed in these enzymatic reactions. These results, together with literature data, indicate that 6 alpha-hydroxylation followed by 6-O-glucuronidation constitutes an alternative route of excretion of toxic hydrophobic bile acids.

Topics: Adult; Aged; Bile Acids and Salts; Child, Preschool; Cholic Acids; Deoxycholic Acid; Female; Glucuronates; Glucuronosyltransferase; Humans; Kinetics; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Microsomes, Liver; Substrate Specificity

Topics: Anaerobiosis; Animals; Cholic Acids; Clostridium; Deoxycholic Acid; Feces; Germ-Free Life; Rats

The effect of various dietary additions such as cholesterol, beta-sitosterol, bile acids, and bile acid analogs on gallstone formation was studied in the hamster. Gallstones were formed in 50% of the animals fed a high glucose, fat-free diet. Administration of 0.2% cholesterol or 1% beta-sitosterol had no effect on the incidence of gallstones. Ursodeoxycholic acid (0.5%) and its analog ursodeoxy-oxazoline [2-(3 alpha, 7 beta-dihydroxy-24-nor-5 beta-cholanyl)-4,4-dimethyl-2- oxazoline] were ineffective in preventing gallstones. Hyodeoxycholic acid and hyodeoxy-oxazoline [2-(3 alpha,6 alpha-dihydroxy-24-nor-5 beta-cholanyl)-4,4-dimethyl-2- oxazoline] at the same dosage effectively prevented gallstones, while the trihydroxy bile acid, hyocholic acid, was not effective. Of all the dietary regimens tested, only hyodeoxycholic acid significantly lowered serum cholesterol. The lithogenic diet produced a five-fold increase in hepatic HMG-CoA reductase activity; this activity was not affected by dietary cholesterol or beta-sitosterol. Hyodeoxycholic acid and hyocholic acid feeding increased the reductase activity by an additional 50% while the other bile acids had no effect. beta-Sitosterol doubled the cholesterol 7 alpha-hydroxylase activity whereas hyodeoxy-oxazoline lowered it. Hyodeoxycholic acid-fed animals had significantly lower cholesterol absorption than the animals on the lithogenic diet alone. Biliary cholesterol content increased dramatically in the animals fed the lithogenic diet and was increased still further by ursodeoxycholic acid, hyodeoxycholic acid, and hyodeoxy-oxazoline. These data show that hyodeoxycholic acid and hyodeoxy-oxazoline do not prevent gallstones by inhibiting hepatic cholesterol synthesis or biliary cholesterol secretion.

Topics: Animals; Bile; Bile Acids and Salts; Cholanes; Cholelithiasis; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholic Acids; Cricetinae; Deoxycholic Acid; Diet; Hydroxymethylglutaryl CoA Reductases; Liver; Male; Mesocricetus; Phospholipids; Sitosterols; Sterols; Ursodeoxycholic Acid

Germfree rats biosynthetize cholic and beta-muricholic acids. The latter does not exist in humans. Germfree rats were given human fecal suspensions. These rats degraded cholic acid into deoxycholic acid but failed to metabolize beta-muricholic acid.

Topics: Animals; Bacteria; Biotransformation; Cholic Acid; Cholic Acids; Chromatography, Gas; Deoxycholic Acid; Digestive System; Feces; Female; Germ-Free Life; Humans; Male; Rats