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PubMedDate not supplied

Determination of related impurities of bile acids in bulk drugs by cyclodextrin-modified micellar electrokinetic chromatography.

A cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC) method has been developed and validated for purity determination of two bile acids, ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA). Quantitation of related impurities such as lithocholic acid (LCA), chenodeoxycholic acid (CDCA), cholic acid (CA), and DCA in UDCA and CA in DCA was performed. A running buffer containing 20 mM borate-phosphate, 50 mM sodium dodecyl sulfate (SDS), 2.0 mM beta-cyclodextrin, and acetonitrile was used. Modifiers were added to improve resolution and selectivity. The applied voltage was 25 kV and detection was performed at 185 nm. Validation parameters such as selectivity, linearity, repeatability, intermediate precision, limit of detection, limit of quantitation, and robustness were evaluated. The method was simple and proved to be useful for the purity testing of bile acids in bulk drugs. Good results were obtained for related impurities at concentration levels from 0.05 to 1.5% with respect to the main component, according to international requirements.

Chromatography, Micellar Electrokinetic Capillary↗

PubMed1992

Hepatic ultrastructure in children with protein-energy malnutrition.

Samples of liver from eight children who died from malnutrition with its complications were studied by electron microscopy. Specimens were taken within one hour of death. These tissues had changes consistent with severe terminal illness, including mitochondrial swelling, with loss of matrix granules, disorganization of cristae, and evidence of calcium influx. Glycogen tended to be scanty. Lipid droplets were frequent. Endoplasmic membranes were depleted, and focal cytoplasmic degradation was frequent. Intracanalicular cholestasis was striking in four cases with loss of microvilli. Peroxisomes were depleted. This may be significant as peroxisomes are pivotal in the processing of very long-chain fatty acids, in cholic acid metabolism and in elimination of free radicals. The observations were compared with previous reports in the literature, and with seven biopsies taken in 1970 from malnourished children who recovered. One, obtained on the fourth day, from a child with marasmus, showed atrophy of cellular organelles. The other samples were biopsied during the recovery phase, and displayed considerable restoration to normal morphology. Mitochondria had prominent matrix granules. Peroxisomes were frequently seen. There was no evidence of cholestasis.

Biopsy↗

PubMed1990

Studies on the bile acids of the gall bladder bile of a mud-puppy, Salamander necturus.

The major bile acids of gall bladder bile of salamander necturus have been reported and shown to be taurine conjugates. The bile acid conjugates were hydrolysed and the free bile acids were separated by thin layer chromatography and identified through gas liquid chromatography and mass spectrometry (GC-MS) as methyl esters and methyl-ester trimethyl silyl ethers. About 56.3% of the total bus acid was present as allocholic acid whereas 3alpha, 7alpha, l2alpha-dihydroxy-5alpha-cholestanoic acid and cholic acid represented 30.4 and 12.3% respectively. Dihydroxy bile acids such as deoxycholic, allodeoxycholic and allochenodeoxycholic were present in less than 0.5% of the total bile acids.

Journal Article↗

PubMed1990

Identification of short side chain bile acids in urine of patients with cerebrotendinous xanthomatosis.

Urine from patients with cerebrotendinous xanthomatosis (CTX) was found to contain a number of minor bile acids along with three major bile acids, 7-epicholic acid, norcholic acid, and cholic acid. The following minor bile acids were identified by combined gas-liquid chromatography-mass spectrometry: 7-ketobisnordeoxycholic acid; 12-ketobisnorchenodeoxycholic acid; 7-ketonordeoxycholic acid; 12-ketochenodeoxycholic acid; 7-ketodeoxycholic acid; 12-ketochendeoxycholic acid; bisnorcholic acid; allonorcholic acid; allocholic acid; 1 beta-hydroxybisnorcholic acid; 1 beta-hydroxynorcholic acid; 1 beta-hydroxycholic acid; 2 beta-hydroxybisnorcholic acid; 2 beta-hydroxy-norcholic acid; 2 beta-hydroxycholic acid. The presence of C22 and C23 bile acids in urine of the CTX patients suggests that bile alcohols having a hydroxyl group at C22 or C23 in the side chain may be further degraded to these bile acids.

Bile Acids and Salts↗

PubMed1990

Bile salts in submicellar concentrations promote bidirectional cholesterol transfer (exchange) as a function of their hydrophobicity.

Cholesterol, despite its poor solubility in aqueous solutions, exchanges efficiently between membranes. Movement of cholesterol between different subcellular membranes in the hepatocyte is necessary for assembly of lipoproteins, biliary cholesterol secretion, and bile acid synthesis. Factors which initiate and facilitate transfer of cholesterol between different membranes in the hepatocyte are incompletely understood. It is known that cholesterol secretion into the bile is linked to bile salt secretion. In the present study, we investigated the effects of bile salts of different physicochemical properties at submicellar concentrations (150- 600 microM) on the transfer of [14C]cholesterol from hepatocytes, or crude hepatocellular membranes (donors), to rat high density lipoproteins (acceptor). Bile salts included taurine conjugates of ursodeoxycholic acid (TUDCA), hyodeoxycholic acid (THDCA), cholic acid (TCA), chenodeoxycholic acid (TCDCA), and deoxycholic acid (TDCA). High density lipoprotein (HDL) was separated from hepatocellular membranes and the transfer of [14C]cholesterol from the membranes to HDL was quantitatively determined. In the absence of HDL, [14C]cholesterol remained confined to the membrane fraction. Following addition of HDL, [4-14C]cholesterol in the HDL fraction increased linearly over time. Addition of hydrophilic bile salts (TUDCA and THDCA) increased transfer of [4-14C]cholesterol to HDL only minimally. By contrast, more hydrophobic bile salts stimulated transfer of labeled cholesterol to HDL, and their potency increased in order of increasing hydrophobicity (TCA less than TCDCA less than TDCA). Both for single bile salts and mixtures of bile salts at a total bile salt concentration of 0.30 mM, the rate of cholesterol transfer exhibited a strong linear correlation with a bile salt monomeric hydrophobicity index (r = 0.95; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Promotive effect of primary and secondary bile acids on the induction of gamma-glutamyl transpeptidase-positive liver cell foci as a possible endogenous factor for hepatocarcinogenesis in rats.

The promoting effects of 5 bile acids on liver carcinogenesis were investigated in male Fischer rats initially treated with diethylnitrosamine (DEN). Two weeks after a single dose of DEN (200 mg/kg, intraperitoneally), rats were given bile acids for 8 weeks. At 3 weeks following DEN administration, all rats were subjected to partial hepatectomy. Among the bile acids tested, cholic acid (CA) and deoxycholic acid (DCA) exerted promoting activity as evidenced by significantly increased values of gamma-glutamyl transpeptidase-positive (gamma-GT+) foci as compared with the corresponding controls given DEN alone. In contrast, the other 3 bile acids tested, chenodeoxycholic acid (CDCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA), did not significantly increase the level of gamma-GT+ foci over that induced by DEN alone. It is noteworthy that only bile acids of the same metabolic pathway, CA as a primary bile acid and DCA as a secondary bile acid, showed promoting effects whereas CDCA and its metabolic derivatives, LCA and UDCA, were inactive. The results indicate that CA and DCA might act as endogenous promoters of hepatocarcinogenesis in pathological conditions with increased levels of serum bile acids.

Animals↗

PubMed1984

Bile salts of the coelacanth, Latimeria chalumnae.

Bile salts of the coelacanth, Latimeria chalumnae, Smith, have been analyzed and shown to have three bile alcohols, latimerol, 5 alpha-cyprinol, and 5 alpha-cholestane-3 beta, 7 alpha,-12 alpha,25,26-pentol, two C24 bile acids, chenodeoxycholic acid and cholic acid, one C26 bile acid, probably 3 beta, 7 alpha, 12 alpha-trihydroxy-27-nor-5 alpha-cholestan-26-oic acid, and two C27 bile acids, 3 alpha,7 alpha,12 alpha-trihydroxy-5 alpha-cholestan-26-oic acid and 3 beta,7 alpha,12 alpha-trihydroxy-5 alpha-cholestan-26-oic acid as determined by gas-liquid chromatography and gas-liquid chromatography-mass spectrometry.

Animals↗

PubMed1984

Prediction of fatality in fulminant hepatic failure.

Thirty-three consecutive patients admitted to the intensive care liver unit of Rigshospitalet with acute hepatic encephalopathy induced by viral hepatitis, drugs, or pregnancy were studied. All were treated with a standard anticoma regime. The 20 patients (61%) who died had a higher bilirubin level and lower total cholic acid conjugation and glycine cholic acid conjugation (p less than 0.05) than the surviving patients. Antipyrin clearance and galactose elimination capacity tended to be lower in the non-survival group than in the survival group (p = 0.09 and 0.11, respectively). Of single variables a bilirubin level of greater than 384 mumol/l gave the best prediction of non-survival (sensitivity, 0.80; specificity, 0.69; PVpos, 0.80; PVneg, 0.69; kappa, 0.49). However, a discriminant score based on combination of variables distinguished completely between non-survivors and survivors when validated by an unbiased method in which each patient is classified on the basis of the other patients' data. It is suggested that the discriminant score is used to select patients with very low probability of survival for liver transplantation or liver assistance procedures of unknown value.

Adult↗

PubMed1981

Epimerization of the 7-hydroxy group of bile acids by the combination of two kinds of microorganisms with 7 alpha- and 7 beta-hydroxysteroid dehydrogenase activity, respectively.

An unidentified gram-positive anaeroic organism capable of dehydrogenating the 7 beta-hydroxy group of ursodeoxycholic acid was recovered from human feces. By combined action of this organism with the ordinary 7 alpha-dehydrogenating bacteria, chenodeoxycholic acid and cholic acid alike were readily converted into their respective 7 beta-epimers and the reverse reactions were also carried out. The estimated levels of these 7 alpha- and 7 beta-dehydrogenating organisms among the intestinal microflora give a satisfactory explanation for the frequent appearance of the 7 beta-hydroxylated bile acids in vivo.

Anaerobiosis↗

PubMed1982

Hepatic extraction of bile acids in rats.

The hepatic extraction ratio (Eh) of five common bile acids was determined by comparison of the area under the plasma concentration time curve (AUC) after administration into the femoral and portal veins of rats. Taurocholic acid (TCA), glycocholic acid (GCA), cholic acid (CA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) were studied. Using equimolar doses of the bile acids (9.3mumoles), the effects of both conjugation and the number and position of hydroxyl groups on Eh were compared. TCA had the highest Eh (about 80 per cent) followed in order by GCA (65 per cent), CA (55 per cent) and CDCA (55 per cent, with DCA exhibiting the lowest Eh (40 per cent). This suggests that conjugation has a more important effect on hepatic extraction of bile acids than the number of hydroxyl groups.

Animals↗

PubMed1982

Tissue bile acids in patients with colon cancer and colonic polyps.

The purpose of this study was to determine whether in man unusual types of concentrations or bile acids were present in colonic polyps, colon carcinomas, or the adjacent, apparently normal tissue. Methods for the determination of soluble and tissue-bound bile acids were validated. Of 14 polyps analyzed, eight contained detectable levels of bile acid, predominantly chenodeoxycholic acid; no lithocholic acid was observed in either the tissue-bound or soluble bile acid fractions. Bile acids were found in four of nine samples of colon carcinoma; in one tumor, tissue-bound lithocholic acid was present. Bile acids were similarly found in seven of 10 samples of normal bowel taken adjacent to the carcinoma. In the soluble bile acid fraction, cholic acid was more abundant than chenodeoxycholic acid. There was no correlation between tissue histology and bile acid composition or concentration. Under the conditions used, this study did not disclose a relationship between tissue bile acids and colorectal histology.

Adenocarcinoma↗

PubMed1982

26-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol by isolated nonparenchymal cells and hepatocytes from rat liver.

The ability of isolated nonparenchymal and parenchymal rat liver cells to metabolize 5beta-cholestane-3alpha,7alpha,12alpha-triol and other bile acid intermediates has been investigated. Incubation of nonparenchymal cells with 5beta-cholestane-3alpha,7alpha,12alpha-triol resulted in the formation of one more polar product identified as 5beta-cholestane-3alpha,7alpha,12alpha,26-tetrol. The formation was linear with time up to 2 hr and with the number of cells, and showed saturation kinetics with respect to substrate concentration. The maximum rate of conversion was 90 pmol/10(6) cells per hr. Incubation of hepatocytes with the triol resulted in the formation of several more polar products. In addition to 5beta-cholestane-3alpha,7alpha,12alpha,26-tetrol, products with retention time on high pressure liquid chromatography identical with 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oic acid and cholic acid were observed. The identity of these products was verified by combined gas-liquid chromatography-mass spectrometry. The rate of conversion was linear with time for about 10 min and saturation with respect to substrate concentration was not attained. At identical substrate concentrations, the total rate of conversion (12.5 nmol/10(6) cells per hr) was at least two orders of magnitude higher than with the nonparenchymal cells. Similar differences in rates of conversion were observed with other C(27)-bile acid intermediates. It is concluded that the nonparenchymal cells do not play any significant role in the conversion of bile acid intermediates, either under physiological conditions or under experimental conditions where such steroids have been administered intravenously.-Dueland, S., J. I. Pedersen, C. A. Drevon, and I. Björkhem. 26-Hydroxylation of 5beta-cholestane-3alpha,7alpha,12alpha-triol by isolated nonparenchymal cells and hepatocytes from rat liver.

Animals↗

PubMed1982

Hepatic bile acid uptake: effect of conjugation, hydroxyl and keto groups, and albumin binding.

Hepatic extraction of trihydroxy (free, glyco- and tauro-conjugated) dihydroxy, and monohydroxy bile acids has been evaluated in single pass liver perfusion experiments in rats. The percentage of each bile acid bound to albumin was also evaluated by equilibrium dialysis. Conjugation increased bile acid liver extraction, without relevant differences in the percentage of bile acid bound to albumin. Among the free bile acids, trihydroxy bile acids were more efficiently cleared by the liver than the dihydroxy acids, and the latter more than monohydroxy bile acids. 7-Ketolithocholic acid uptake was slightly less than that of cholic acid. Conversely, among dihydroxy bile acids, the percentage of the bile acid bound to albumin decreased from lithocholic acid to cholic acid. Decreasing the albumin concentration in the medium, and hence the fraction of the bile acid bound to albumin, resulted in an increase in bile acid liver extraction. Therefore besides differences in the chemical structure of bile acids, the extent of bile acid-albumin binding may be a determinant in bile acid liver uptake.

Animals↗

PubMed1999

Contribution of organic anion transporting polypeptide to uptake of its possible substrates into rat hepatocytes.

Organic anion transporting polypeptide (oatp1) has been cloned from rat liver as one of the transporters responsible for the hepatic uptake of ligands, and its substrate specificity has been determined. However, the contribution of oatp1 to the Na+-independent uptake of ligands into rat hepatocytes remains to be investigated. In the present study, we determined the contribution of oatp1 and examined the uptake of ligands into primary cultured hepatocytes (cultured for 4 h) and into COS-7 cells transiently expressing oatp1 and normalized using estradiol-17beta-D-glucuronide as a reference compound. Western blot analysis indicated that oatp1 was less extensively glycosylated in transfected COS-7 cells, and the expression level in transfectant was one-seventh that in rat liver. The Km values for the uptake of estradiol-17beta-D-glucuronide were similar for cultured hepatocytes and oatp1-transfected COS-7 cells (Km = 12.3 versus 20.4 microM), although the Vmax value for oatp1-transfected COS-7 cells was one-seventh that for cultured hepatocytes (Vmax = 1.30 versus 0.175 nmol/min/mg protein). The contribution of oatp1 to the Na+-independent uptake of taurocholic acid and cholic acid into rat hepatocytes was more than 50 to 60%, whereas the corresponding values for the sulfate-conjugates of estrone and 6-hydroxy-5, 7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole were 20 to 30%. In addition, the analysis indicated that the contribution of oatp1 to the Na+-independent uptake of several ligands [glucuronide-conjugate of 6-hydroxy-5, 7-dimethyl2-methylamino-4-(3-pyridylmethyl)benzothiazole, ibuprofen, pravastatin, ouabain, and 2,4-dinitrophenyl-S-glutathione] was minimal. Collectively, the transfected COS-7 cells may be used to quantitatively predict oatp1 activity in hepatocytes after correction of its expressed amount. It is also suggested that multiple transport mechanisms are responsible for the Na+-independent uptake of organic anions into hepatocytes.

Animals↗

PubMed1992

Enterohepatic circulation in hamsters with an extracorporeal bile duct.

The present study describes a novel technique for investigations of the enterohepatic circulation in the hamster with an extracorporeal bile duct that allows long-term bile collection in the free-moving animal. The animals recovered for 7 days after the operation before the external loop was cut and bile was collected over a period of 78 h. Under these optimal conditions, initial bile flow (651 +/- 89 microliters per 100 g.h-1) and the secretion rates of biliary lipids were several-fold higher than reported in an earlier study using the acute fistula hamster. Biliary cholesterol secretion amounted to 369 +/- 32 nmol per 100 g.h-1, phospholipid secretion was 2.6 +/- 0.3 mumol per 100 g.h-1, and total bile acid secretion was 31.9 +/- 2.2 mumol per 100 g.h-1. A clearcut diurnal rhythm was demonstrated for bile flow and all biliary constituents. After 9 h the depletion of the bile acid pool was complete and cholic acid synthesis derepressed 1.4-fold from a basal rate of 818 nmol per 100 g.h-1, whereas the derepression of chenodeoxycholic acid synthesis was even less pronounced. Biliary cholesterol output increased 2.2-fold, but the phospholipid secretion was constant during the full experiment. It may be concluded that the technique of an extracorporeal bile duct in the free-moving animal allows studies of bile secretion under optimal conditions. Most likely the bile secretion rates given above approach the physiological rates in the hamster.

Animals↗

PubMed1976

Metabolism of bile alcohols in the perfused rabbit liver.

The mechanism and sequence of side chain hydroxylation of cholesterol in bile acid synthesis was studied in the isolated perfused rabbit liver. A comparison was made between the importance of 26- and 25-hydroxylation in cholic acid biosynthesis in the rabbit. The formation of [G-3H]cholic acid was observed when the liver was perfused with 5beta-[G-3H]cholestane-3alpha, 7alpha-diol, 5beta-[G-3H]cholestane-3alpha, 7alpha-12alpha-triol, and 5beta-[G-3H]cholestane-3alpha, 7alpha, 26-triol. No [G-3H]chenodeoxycholic acid was detected in the bile. These findings indicate that potential precursors of chenodeoxycholic acid were hydroxylated at position 12alpha either subsequent to or before hydroxylation of the cholesterol side chain. In addition, no other intermediates (tetrahydroxy or pentahydroxy bile alcohols) were found in the bile when these compounds were perfused in the liver. Bile acid precursors were detected in bile when the rabbit liver was perfused with 5beta-[24-14C]cholestane-3alpha, 7alpha, 25-triol. The 5beta-[24-14C]cholestane-3alpha, 7alpha, 25-triol was hydroxylated in the liver at the 12alpha position to yield the corresponding 5beta-cholestane-3alpha, 7alpha, 12alpha, 25-tetrol. The tetrol was further metabolized to a series of pentols (5beta-cholestane-3alpha, 7alpha, 12alpha, 22, 25-pentol; 5beta-cholestane-3alpha, 7alpha, 12alpha, 23, 25-pentol; 5beta-cholestane-3alpha, 7alpha, 12alpha, 24, 25-pentol; and 5beta-cholestane-3alpha, 7alpha, 12alpha, 25, 26-pentol). The major bile acid obtained from the perfusion of the 5beta-cholestane-3alpha, 7alpha, 25-triol was cholic acid. The experiments indicated that in the rabbit liver 12alpha-hydroxylation can occur after hydroxylation of the cholesterol side chain at either C-25 (5 beta-cholestane-3alpha, 7alpha, 25-triol) or C-26 (5beta-cholestane-3alpha, 7alpha-26-triol). Apparently, the rabbit can form cholic acid via the classical 26-hydroxylation pathway as well as via 25-hydroxylated intermediates.

Animals↗

PubMed1987

Serum bile acid profile in thyroid dysfunction and effect of medical treatment.

1. Serum non-esterified bile acid profile was examined in patients with thyroid dysfunction. Sixteen hyperthyroid patients, six hypothyroid patients, nine patients taking thyroid or antithyroid drugs and 26 healthy controls were studied. The medicated patients were euthyroid when serum samples were collected. Bile acid concentration was determined by the simplified microassay method involving mass fragmentation spectrometry. 2. The sum of the concentrations of the individual bile acids was not significantly different among the four groups. However, the composition of bile acid reflected the thyroid function. The most prominent bile acid was deoxycholic acid in the hypothyroid patients and chenodeoxycholic acid in the hyperthyroid patients. The serum bile acid profile of medically treated patients was similar to that of normal controls. The ratio of the sum of deoxycholic and cholic acid to that of lithocholic and chenodeoxycholic acid was found to be a good indicator of thyroid function, while the ratio of cholic acid to chenodeoxycholic acid correlated poorly with it. 3. The characteristic effect of thyroid hormone on the serum bile acid composition in man was the shift from the 'family' of cholic acid to that of chenodeoxycholic acid. This is in agreement with experimental results in the rat, and suggests a specific action of thyroid hormone on the hydroxylating enzymes involved in the conversion of cholesterol into bile acids.

Adolescent↗

PubMed1983

Effect of feeding cholesterol and sitosterol on hepatic steroid 12 alpha-hydroxylase activity in female hamsters.

The effects of dietary cholesterol and sitosterol on the activity of the hepatic steroid 12 alpha-hydroxylase, gallbladder bile acid composition, and serum and liver cholesterol concentrations were studied in female hamsters. The 12 alpha-hydroxylase activity was inhibited by 63% in cholesterol-fed animals and by 30% in sitosterol-fed animals. Cholesterol feeding increased percentages of chenodeoxycholic and lithocholic acids in gallbladder bile with reciprocal decrease of cholic acid, while sitosterol feeding had no significant effect on bile acid composition. Cholesterol feeding increased levels of serum and liver cholesterol, on the contrary, sitosterol decreased both concentrations. A positive correlation between the 12 alpha-hydroxylase activity and the ratio of cholic acid plus its metabolites to chenodeoxycholic acid plus its metabolite was also observed. These results support the proposal that steroid 12 alpha-hydroxylase is a major factor in determining the relative proportion of cholic acid and chenodeoxycholic acid synthesized in the liver and indicate that cholesterol feeding increased percentage of chenodeoxycholic acid by inhibiting the activity of steroid 12 alpha-hydroxylase.

Animals↗