Sulfated and Nonsulfated Bile Acids in Urine, Serum, and Bile of Patients with Hepatobiliary Diseases

Makino, Isao; Hashimoto, Hirosuke; Shinozaki, Kenjiro; Yoshino, Koichi; Nakagawa, Shoichi

doi:10.1016/s0016-5085(75)80094-1

Cited by 232 publications

(75 citation statements)

References 19 publications

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“…Furthermore, during cholestatic liver disease in man, there is a significant increase in the excretion of bile acids in urine, in particular sulfated, glucuronidated, and 1-and 6-hydroxylated metabolites. [44][45] In the present study, 15 minutes after administration, there was no difference in either the percentage of LCA in the kidney or in the accumulation of LCA in the urine of the different experimental models, probably because of its lack of significant biotransformation in the short term. It would be expected, however, that effective hepatic modification of the circulating bile acid such as by sulfation, glucuronidation, and 6␤-hydroxylation would result in enhanced urinary excretion over the long term.…”

Section: Discussionmentioning

confidence: 58%

Extrahepatic deposition and cytotoxicity of lithocholic acid: Studies in two hamster models of hepatic failure and in cultured human fibroblasts

et al. 1998

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Effects of bile acids on tissues outside of the enterohepatic circulation may be of major pathophysiological significance under conditions of elevated serum bile acid concentrations, such as in hepatobiliary disease. Two hamster models of hepatic failure, namely functional hepatectomy (HepX), and 2-day bile duct ligation (BDL), as well as cultured human fibroblasts, were used to study the comparative tissue uptake, distribution, and cytotoxicity of lithocholic acid (LCA) in relation to various experimental conditions, such as binding of LCA to low-density lipoprotein (LDL) or albumin as protein carriers. Fifteen minutes after iv infusion of [24-14 C]LCA, the majority of LCA in shamoperated control animals was recovered in liver, bile, and small intestine. After hepatectomy, a significant increase in LCA was found in blood, muscle, heart, brain, adrenals, and thymus. In bile duct-ligated animals, significantly more LCA was associated with blood and skin, and a greater than twofold increase in LCA was observed in the colon. In the hepatectomized model, the administration of LCA bound to LDL resulted in a significantly higher uptake in the kidneys and skin.

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Section: Discussionmentioning

confidence: 58%

Extrahepatic deposition and cytotoxicity of lithocholic acid: Studies in two hamster models of hepatic failure and in cultured human fibroblasts

et al. 1998

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“…This does not exclude the possibility of secondary transformations of bile acids in organs other than the liver. Thus, the kidneys have been suggested as sites for bile acid sulphation [2,38,401. However, renal sulphation of bile acids appears to be of minor importance in the hamster [41].…”

Section: Discussionmentioning

confidence: 99%

Bile acid profiles in urine of patients with liver diseases

Bremmelgaard

Sjövall

1979

Eur J Clin Investigation

148

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Abstract. Quantitative gas chromatography‐mass spectrometry was used to study the metabolic profiles of unconjugated, conjugated and sulphated bile acids in urine of patients with intermittent intrahepatic cholestasis of unknown aetiology, cirrhosis of the liver, primary biliary cirrhosis, viral and toxic hepatitis and extrahepatic cholestasis. A large number of bile acids was present which can broadly be classified into four groups: cholic and chenodeoxycholic acids constituted between 49·4% and 77·9% of the total bile acids (mean values of the groups); deoxycholic and other 3,12‐disubstituted bile acids between 1·3% and 12·3%, monohydroxy bile acids between 6·7% and 14·4% and bile acids hydroxylated at C‐1 or C‐6 between 4·6% and 14·6%. The high proportion of bile acids from the latter group, and the presence of tetrahydroxylated bile acids, clearly distinguished hepatic disease from the normal state. The metabolic profiles were very variable and there were few consistent differences between the groups of diseases studied. Norcholic acid constituted a significantly higher percentage of the total bile acids in cirrhotic patients (6·2 ± 6·8%) than in non‐cirrhotic patients (1·3±1·8%, P<0·001). With this exception, no profile was specific for any type of intra‐ or extra‐hepatic cholestasis. The excretion rates of the major l‐hydroxylated bile acids were positively correlated to each other. The same was true for the major 6‐hydroxylated bile acids. This may indicate that cholic, chenodeoxycholic and deoxycholic acids act as substrates for common 1‐ and 6‐hydroxylating enzymes. Possibly the taurine conjugates are preferred substrates since 1‐hydroxylated bile acids and hyocholic acid were found mainly in this fraction. A positive correlation between the excretion of sulphated 3β‐hydroxy‐5‐cholenoic acid and 3β,12α‐dihydroxy‐5‐cholenoic acid indicates a direct metabolic relationship between these compounds. Confirming previous data, a high proportion of bile acids was sulphated. The degree of sulphation increased with decreasing number of hydroxyl groups, reaching 100% for the monohydroxy and most of the dihydroxy acids. Tetrahydroxycholanoates were not sulphated, and sulphation of trihydroxycholanoates was positively correlated to the renal bile acid excretion rate. Bile from patients with intermittent intrahepatic cholestasis did not contain the tetrahydroxylated bile acids present in urine. Hyocholic acid was a very minor, mainly taurine conjugated, bile acid. Monohydroxy bile acids were usually below the detection limit. These data do not support the hypothesis that lithocholic acid participates in the initiation or perpetuation of intermittent intrahepatic cholestasis of unknown aetiology.

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“…(i) Since urinary loss of bile acids is negligible in health [43,44], this was not considered in the model.…”

Section: General Features Of the Modelmentioning

confidence: 99%

Simulation of the metabolism and enterohepatic circulation of endogenous chenodeoxycholic acid in man using a physiological pharmacokinetic model

Molino

Hofmann

Cravetto

et al. 1986

Eur J Clin Investigation

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The metabolism and enterohepatic circulation of chenodeoxycholic acid (CDC), a major primary bile acid in man, has been stimulated using a multicompartmental physiological pharmacokinetic model which was previously reported and used to simulate the metabolism of cholic acid. The model features compartments and linear transfer coefficients. Compartments, which are defined as the pools of single chemical species in well defined anatomical volumes, are aggregated into nine 'spaces' based on anatomical and physiological considerations (liver, gall-bladder, bile ducts, duodeno-jejunum, ileum, colon, portal blood, sinusoidal blood, and general circulation). Each space contains several compartments which correspond to the compounds present in that space, for example, the compound in question and its biotransformation products. For CDC (as for cholic acid in the previous simulation) each space contains three compartments corresponding to the unconjugated bile acid, its glycine amidate, and its taurine amidate. Transfer coefficients, which denote the fractional amount of the compartment's contents exiting per unit time, are categorized according to function: flow, for example gall-bladder contraction (which involves transfer of all substances contained in the space at the same fractional rate); biotransformation (which transfers the substrate from one compartment to another within the same space); or transport (which denotes movements between contiguous compartments, belonging to different spaces across a diffusion membrane or a cellular barrier). The model is made time-dependent by incorporating meals which trigger gall-bladder emptying and modify intestinal flow. The transfer coefficients in the cholic acid model were modified for the CDC model since there is indirect evidence that CDC amidates (probably chenodeoxycholylglycine) are absorbed from the duodeno-jejunum and the first pass hepatic clearance of CDC species differs from that of cholyl species. The model was then used with all existing experimental data to simulate CDC metabolism in healthy humans over a 24-h period during which three meals were ingested. Satisfactory agreement was obtained between simulated and experimental data indicating that this model continues to be useful for describing the metabolism of bile acids and may also be of value for describing the metabolism of drugs whose metabolism is similar to that of bile acids.

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Sulfated and Nonsulfated Bile Acids in Urine, Serum, and Bile of Patients with Hepatobiliary Diseases

Cited by 232 publications

References 19 publications

Extrahepatic deposition and cytotoxicity of lithocholic acid: Studies in two hamster models of hepatic failure and in cultured human fibroblasts

Extrahepatic deposition and cytotoxicity of lithocholic acid: Studies in two hamster models of hepatic failure and in cultured human fibroblasts

Bile acid profiles in urine of patients with liver diseases

Simulation of the metabolism and enterohepatic circulation of endogenous chenodeoxycholic acid in man using a physiological pharmacokinetic model

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