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PubMed1988

Intestinal absorption of bile acid glucuronides in rats.

While the intestinal absorption of taurine, glycine, and sulfate conjugates of bile acids has been studied extensively, nothing is known about the absorption of bile acid glucuronides. In the present study, the intestinal phase of the enterohepatic circulation of two bile acid glucuronides was examined. [3 beta-3H]cholic acid 3-O-beta-D-glucuronide or [3 beta-3H]lithocholic acid 3-O-beta-D-glucuronide was perfused through isolated segments of ileum or jejunum with intact blood supply in rats prepared with a biliary fistula. [14C]Taurocholic acid was perfused simultaneously with each glucuronide to compare glucuronide absorption with that of an actively transported bile acid. Intestinal absorption was determined by measuring the rate of secretion of labeled bile acid in bile. The absorption of [3H]cholic acid glucuronide by the ileum and jejunum was one fortieth and one eighth, respectively, that of [14C]taurocholic acid. Comparison of the two glucuronides show that [3H]lithocholic acid glucuronide absorption was 18 and 10 times greater than [3H]cholic acid glucuronide absorption from the jejunum and ileum, respectively. Collectively, the above observations suggest that glucuronidation of bile acids markedly reduces absorption from the small intestine.

Animals↗
PubMed1986

Bile acids regulate hepatic low density lipoprotein receptor activity in the hamster by altering cholesterol flux across the liver.

The effect of different bile acids on receptor-dependent and receptor-independent low density lipoprotein (LDL) uptake in the liver and intestine was investigated. When fed at the 0.1% level for three weeks, cholic acid and chenodeoxycholic acid suppressed hepatic cholesterol synthesis in the rat by 80% and 50%, respectively, while ursodeoxycholic acid had no effect. In contrast, hepatic cholesteryl ester levels, rates of hepatic LDL transport, and concentrations of plasma LDL-cholesterol were not affected by bile acid feeding in this species. Cholic acid and chenodeoxycholic acid also suppressed hepatic cholesterol synthesis in the hamster. However, since basal rates of hepatic cholesterol synthesis in this species, as in man, are very low, the absolute reduction in hepatic synthesis could not compensate for the change in hepatic sterol balance induced by bile acid feeding. Hence, in the hamster the feeding of cholic acid and chenodeoxycholic acid increased hepatic cholesteryl ester levels 660% and 39%, respectively, reduced hepatic receptor-dependent LDL uptake by 50% and 32%, respectively, and elevated plasma LDL-cholesterol levels by 160% and 50%, respectively. Ursodeoxycholic acid feeding did not alter any of these processes, and none of the bile acids changed the rate of hepatic receptor-independent LDL transport. In the intestine, none of the bile acids altered rates of cholesterol synthesis or LDL uptake. When cholic acids, chenodeoxycholic acid, or ursodeoxycholic acid was infused continuously for 8 hr in supranormal amounts into control hamsters or rats or into animals pretreated with cholestyramine, there were no changes in LDL transport or any other parameter of hepatic cholesterol metabolism. Thus, these studies indicated that cholic acid and chenodeoxycholic acid have no acute, direct effect on rates of receptor-dependent LDL transport or cholesterol synthesis but do alter these processes indirectly by inducing changes in cholesterol balance across the liver. Ursodeoxycholic acid, in contrast, does not affect these processes either directly or indirectly and so causes no change in plasma LDL levels.

Animals↗
PubMed1986

Dynamics of the conjugate pattern during the infusion of bile acids into isolated rat liver.

The conjugate pattern of biliary [14C]bile acids was investigated in isolated perfused rat livers, which were infused with either [24-14C]cholic acid or [24-14C]chenodeoxycholic acid (40 mumol/h) together with or without taurine or cysteine (80 mumol/h). [14C]Bile acids were chromatographed on a thin-layer plate and the distribution of radioactivity on the plate was measured by radioscanning. The biliary excretion of [14C]bile acids was greater in the infusion with [14C]cholic acid than in the infusion with [14C]chenodeoxycholic acid. Biliary unconjugated [14C]bile acids amounted to about 50% of the total after the infusion with [14C]cholic acid, while only about 10% with [14C]chenodeoxycholic acid. In the initial period of infusion, biliary conjugated [14C]bile acids consisted mostly of the taurine conjugate, which decreased with time and the glycine conjugate increased complementarily. When taurine was simultaneously infused, the decrease in the taurine conjugate was suppressed to some extent. Cysteine infused in place of taurine had a similar influence but was less effective than taurine. The taurine content of liver after the infusion with either of the [14C]bile acids decreased greatly compared with that before the infusion, even when taurine or cysteine was infused simultaneously. The glycine content also decreased after the infusion, but the decrease in glycine was smaller than that in taurine. The results suggest that the conjugate pattern of biliary bile acids in rats depends mainly on the amount of taurine which is supplied to hepatic cells either exogenously from plasma or endogenously within themselves.

Animals↗
PubMedDate not supplied

Phospholipids and bile acids as diffusional carriers of Na+ across nonpolar media.

Phospholipids and bile acids, by virtue of their amphiphilic properties, can interact in nonpolar media forming "inverted" structures (micelles) which presumably have an hydrophilic core and might act as diffusional carriers (ionophores) of electrolytes across low dielectric constant media or lipid membranes. The Na+ ionophoretic capability of various purified phospholipids and the modulating effects of bile acids and phosphatidylcholine was examined by: (a) measurement of 22Na+ partition into the organic phase (chloroform) of a two-phase system and (b) direct measurement of the translocation of 22Na+ across a bulk chloroform phase separating two aqueous phases in a Pressman cell. All phospholipids tested, except for phosphatidylcholine, showed ionophoretic capability for Na+ at micromolar concentrations. Cardiolipin and phosphatidylserine were the most efficient Na+ carriers, comparable with monensin, an established Na+ ionophore. In contrast, cholic acid as well as other bile acids demonstrated only marginal or no Na+ ionophoretic capability. However, hydroxylated bile acids (particularly cholic acid), sodium dodecyl sulfate and Triton X-100, which can induce and stabilize inverted structures in lipid membranes, were able to increase 5- to 8-fold the phospholipid-mediated Na+ transport. Interaction of cardiolipin with Na+ in the chloroform phase followed a rectangular hyperbolic function with an apparent Kd within the physiological Na+ concentration range (16.9 +/- 5.1 mM). Addition of cholic acid to the cardiolipin-containing organic phase resulted in a 10-fold increase of maximal Na+ uptake and no change in apparent Kd. The effect of cholic acid on both cardiolipin-mediated Na+ partition and Na+ translocation across the chloroform phase showed a marked dependence on pH, being greater at pH 7.4.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Complex genetic control of HDL levels in mice in response to an atherogenic diet. Coordinate regulation of HDL levels and bile acid metabolism.

Inbred strains of mice differ in susceptibility to atherogenesis when challenged with a high fat, high cholesterol diet containing 0.5% cholic acid. Studies of recombinant inbred (RI) strains derived from the susceptible strain C57BL/6J (B6) and the resistant strains C3H/HeJ (C3H) and BALB/cJ have revealed an association between fatty streak lesion size and a decrease in high density lipoprotein (HDL) levels on the diet. To better understand the genetic factors contributing to HDL metabolism and atherogenesis in response to the diet, we studied mice derived from an intercross between B6 and C3H using a complete linkage map approach. A total of 185 female progeny were typed for 134 genetic markers spanning the mouse genome, resulting in an average interval of about 10 cM between markers. A locus on distal chromosome 1 containing the apolipoprotein AII gene was linked to HDL-cholesterol levels on both the chow and the atherogenic diets, but this locus did not contribute to the decrease in HDL-cholesterol in response to the diet. At least three distinct genetic loci, on chromosomes 3, 5, and 11, exhibited evidence of linkage to a decrease in HDL-cholesterol after a dietary challenge. Since a bile acid (cholic acid) is required for the diet induced changes in HDL levels and for atherogenesis in these strains, we examined cholesterol-7-alpha hydroxylase (C7AH) expression. Whereas B6 mice exhibited a large decrease in C7AH mRNA levels in response to the diet, C3H showed an increase. Among the intercross mice, multiple loci contributed to the regulation of C7AH mRNA levels in response to the diet, the most notable of which coincided with the loci on chromosomes 3, 5, and 11 controlling HDL levels in response to the diet. None of these loci were linked to the C7AH structural gene which we mapped to proximal chromosome 4. These studies reveal coordinate regulation of C7AH expression and HDL levels, and they indicate that the genetic factors controlling HDL levels are more complex than previously suggested by studies of RI strains. Furthermore, we observed that two of the loci for C7AH expression contributed to differences in gallstone formation between these strains.

Animals↗
PubMed1984

Phenolic 9,10-secosteroids as products of the catabolism of bile acids by a Pseudomonas sp.

The obligate aerobe, Pseudomonas putida ATCC 31752, efficiently utilises bile acids as a source of carbon and energy for growth and maintenance. When aeration is considerably restricted, a consequence to the catabolism of the bile acids in a fermentor is an accumulation of certain steroidal catabolites. Evidence is presented to show that among these are hydroxy-9,10-seco-1,3,5 (10)-androstratriene-9, 17-diones and those from four of the common bile acids, cholic, chenodeoxycholic, hyodeoxycholic and deoxycholic acids have been isolated and their structures determined. The product of catabolism of hyodeoxycholic acid appears to exist in a hemi-acetal form which readily forms an acetal during isolation procedures. All but one of these are described for the first time.

Bile Acids and Salts↗
PubMed1987

3 alpha-hydroxysteroid dehydrogenase activity of the Y' bile acid binders in rat liver cytosol. Identification, kinetics, and physiologic significance.

Rat Y' bile acid binders (33 kD) have been previously recognized as cytosolic bile acid binding proteins (Sugiyama, Y., T. Yamada, and N. Kaplowitz, 1983, J. Biol. Chem., 258:3602-3607). We have now determined that these Y' binders are 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSD), bile acid-metabolizing enzymes. 3 alpha-HSD activity copurified with lithocholic acid-binding activity after sequential gel filtration, chromatofocusing, and affinity chromatography. Three peaks of 3 alpha-HSD activity (I, II, III) were observed in chromatofocusing and all were identified on Western blot by a specific Y' binder antiserum. 3 alpha-HSD-I, the predominant form, was purified and functioned best as a reductase at pH 7.0 with a marked preference for NADPH. Michaelis constant values for mono- and dihydroxy bile acids were 1-2 microM, and cholic acid competitively inhibited the reduction of 3-oxo-cholic acid. Under normal redox conditions, partially purified 3 alpha-HSD-I and freshly isolated hepatocytes catalyzed the rapid reduction of 3-oxo-cholic to cholic acid without formation of isocholic acid, whereas the reverse reaction was negligible. The Y' bile acid binders are therefore 3 alpha-HSD, which preferentially and stereospecifically catalyze the reduction of 3-oxo-bile acids to 3 alpha-hydroxy bile acids.

3-Hydroxysteroid Dehydrogenases↗
PubMed1985

Synthesis of potential cholelitholytic agents: 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid, 3 alpha,7 beta,12 alpha-trihydroxy-7 alpha-methyl-5 beta-cholanoic acid, and 3 alpha,12 alpha-dihydroxy-7 xi-methyl-5 beta-cholanoic acid.

This report describes the chemical synthesis of six new bile acid analogs, namely, 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid (7 beta-methyl-cholic acid), 3 alpha,7 beta,12 alpha-trihydroxy-7 alpha-methyl-5 beta-cholanoic acid (7 alpha-methyl-ursocholic acid), 3 alpha,12 alpha-dihydroxy-7 xi-methyl-5 beta-cholanoic acid (7 xi-methyl-deoxycholic acid), 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-7-en-24-oic acid, 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-6-en-24-oic acid, and 3 alpha,12 alpha-dihydroxy-7-methylene-5 beta-cholan-24-oic acid. The carboxyl group of the starting material 3 alpha,12 alpha-dihydroxy-7-oxo-5 beta-cholanoic acid was protected by conversion to its oxazoline derivative. A Grignard reaction of the bile acid oxazoline with CH3MgI followed by acid hydrolysis gave two epimeric trihydroxy-7-methyl-cholanoic acids and three dehydration products. The latter were purified by silica gel column chromatography and silica gel-AgNO3 column chromatography of their methyl ester derivatives. Catalytic hydrogenation of 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-6-en-24-oic acid and 3 alpha,12 alpha-dihydroxy-7-methylene-5 beta-cholan-24-oic acid gave 3 alpha,12 alpha-dihydroxy-7 xi-methyl-5 beta-cholanoic acid. The configuration of the 7-methyl groups and the position of the double bonds were assigned by proton nuclear magnetic resonance spectroscopy and the chromatographic and mass spectrometric properties of the new compounds. These compounds were synthesized for the purpose of exploring new and potentially more effective cholelitholytic agents. The hydrophilic bile acids 7 beta-methyl-cholic acid and 7 alpha-methyl-ursocholic acid are of particular interest because they should be resistant to bacterial 7-dehydroxylation.

Cholelithiasis↗
PubMed1988

Contraceptive steroids alter the steady-state kinetics of bile acids.

Contraceptive steroids increase the ratio of cholic acid to chenodeoxycholic acid in bile. This alteration may contribute to the development of cholesterol gallstones. The objective of this study was to measure the effects of contraceptive steroids on bile acid kinetics and to relate them to changes in cholesterol metabolism. Steady-state kinetics of bile acids were measured in 15 healthy women, on and off contraceptive steroids. Cholic acid synthesis increased 30.3% (P less than 0.025) and its pool increased by 37.4% (P less than 0.025). Chenodeoxycholic acid synthesis decreased 6.4% (P = 0.08) and its pool decreased by 11.8% (P less than 0.05) during use of contraceptive steroids. The fractional turnover rates of both primary bile acids did not change. The changes in kinetics of the primary bile acids were related to alterations in biliary lipid and cholesterol metabolism, separately reported. (J. Lipid Res. 1987. 28: 828-839). During use of contraceptive steroids, total bile acid pool and total bile acid synthesis correlated directly with cholesterol synthesis, assayed in mononuclear leukocytes (r = 0.50 and r = 0.54, respectively) but not with the plasma clearance of chylomicron remnants, measured with retinyl palmitate. The data indicate that contraceptive steroids directly alter the hepatic synthesis of bile acids and suggest that newly synthesized cholesterol may be a preferred substrate for bile acid synthesis during use of contraceptive steroids.

Adult↗
PubMed1996

Increasing hepatic cholesterol 7alpha-hydroxylase reduces plasma cholesterol concentrations in normocholesterolemic and hypercholesterolemic rabbits.

The effect of bile acid depletion and replacement with glycodeoxycholic acid on plasma cholesterol concentrations, hepatic low-density lipoprotein (LDL) receptor binding and messenger RNA (mRNA) levels, and hepatic activities and mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7alpha-hydroxylase was investigated in 19 New Zealand white (NZW) and 15 Watanabe heritable hyperlipidemic (WHHL) rabbits. Bile acid depletion was produced by external bile drainage for 5 days, which maximized cholic acid synthesis. Replacement was achieved by infusing glycodeoxycholic acid intraduodenally for 24 hours so that the hepatic bile acid flux reached prefistula levels. Plasma and liver cholesterol concentrations were 13 times and 50% greater, respectively, hepatic LDL receptor-mediated binding was 26% less, and cholesterol 7alpha-hydroxylase activity and mRNA levels were 62% and 86% less in WHHL than NZW rabbits. After bile drainage, plasma cholesterol concentrations decreased 29% in NZW rabbits and 40% in WHHL rabbits and were associated with a 2.1-fold increase in hepatic LDL receptor-mediated binding in the NZW rabbits, but there was no change in the WHHL rabbits. Cholesterol 7alpha-hydroxylase activity and mRNA levels increased three and four times in NZW and WHHL rabbits, respectively, although liver cholesterol levels remained unchanged. Replacement with exogenous glycodeoxycholic acid increased plasma cholesterol concentrations 1.7 times in NZW rabbits and decreased enhanced cholesterol 7alpha-hydroxylase activity 54%, mRNA levels 86%, cholic acid synthesis 38%, and hepatic LDL receptor-mediated binding 57% in NZW rabbits. Bile acid depletion stimulated cholic acid synthesis by up-regulating cholesterol 7alpha-hydroxylase to use cholesterol and reduce plasma concentrations substantially in both NZW and WHHL rabbits, although LDL receptors did not function in WHHL rabbits. Glycodeoxycholic acid replacement inhibited elevated cholesterol 7alpha-hydroxylase, cholic acid synthesis, and hepatic LDL receptor binding to reestablish baseline plasma cholesterol levels in NZW rabbits. Hypercholesterolemia in WHHL rabbits was related to the combination of dysfunctional LDL receptors and inhibited cholesterol 7alpha-hydroxylase. Plasma cholesterol concentrations were reduced significantly when cholesterol 7alpha-hydroxylase was stimulated even in the absence of LDL receptor function.

Animals↗
PubMed1991

Importance of bile acid structure in amelioration of griseofulvin-induced murine protoporphyric hepatopathy.

This study investigated the effects of bile acid structure on griseofulvin-induced murine hepatopathy and explored the mechanism(s) of cholestasis in this model of protoporphyria. Mice were fed pulverized chow with cholate, chenodeoxycholate, or ursodeoxycholate, with or without griseofulvin. After 1 to 4 weeks, bile flow, bile acid excretion and composition, biliary protoporphyrin excretion, hepatic protoporphyrin contents, liver histology, and griseofulvin plasma concentrations were determined. Additionally, bile acid absorption was measured. Griseofulvin induced a progressive increase in liver weight, hepatic protoporphyrin content, and histopathologic evidence of cholestasis. Biliary protoporphyrin excretion increased and pigmented gallbladder microliths developed. Bile flow and bile acid excretion fell in relation to liver weight but not in relation to body weight. Cholic acid augmented biliary protoporphyrin excretion, markedly reduced hepatic protoporphyrin content, and obviated the development of intrahepatic biliary thrombi. Ursodeoxycholate and chenodeoxycholate both reduced biliary protoporphyrin excretion. This was associated with bile acid compositional changes, particularly a fall in cholic acid. Although histopathologic abnormalities were not altered, these bile acids reduced hepatic protoporphyrin contents. Bile acid treatments with griseofulvin all increased bile flow and bile acid excretion relative to controls, but differences in the relationship of bile flow to bile acid structure on protoporphyrin disposition. They document biliary excretion as the principal mode of cholic acid amelioration of griseofulvin-induced hepatopathy. They also suggest distinctive roles for griseofulvin and protoporphyrin in the generation of the cholestasis.

Absorption↗
PubMed1993

Importance of high-density lipoprotein-phosphatidylcholine in secretion of phospholipid and cholesterol in bile.

The purpose of this work was to evaluate biliary phosphatidylcholine (PC) secretion after intravenous infusion of high density lipoprotein (HDL)-[3H]phosphatidylcholine (HDL-[3H]PC) in rats and to study the effect of infusion of dehydrocholic and cholic acids, which, respectively, inhibit and stimulate biliary secretion of PC. The data obtained in this study showed that, in the basal state, HDL-PC accounted for 38% of biliary PC. Dehydrocholic acid infusion caused only a "residual" secretion of HDL-PC in the bile; however, cholic acid infusion stimulated the secretion of HDL-PC as well as PC from intrahepatic microsomes. The low level of radioactivity of HDL-PC in intrahepatic compartments suggests that HDL-PC taken up by the liver is predestined for the bile secretion. The correlation between the kinetics of bile secretion of HDL-cholesterol and HDL-[3H]PC suggests the importance of HDL-PC in reverse transport of cholesterol to the liver and its transport to the bile. The differences between the effects of dehydrocholic acid and cholic acid infusions can be explained by the differences in bile salts binding to the surface of HDL.

Animals↗
PubMed1983

The minor bile acids of the toad, Bufo vulgaris formosus.

Bile from the toad, Bufo vulgaris formosus, was found to contain a number of minor bile acids along with two major bile acids, 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholest-22-ene-24-carboxylic acid and 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholest-23-en-26-oic acid. The following minor bile acids were identified by combined gas-liquid chromatography-mass spectrometry: cholic acid, allocholic acid, 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-26-oic acid, 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 alpha-cholestan-26-oic acid, 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 alpha-cholest-22-ene-24-carboxylic acid, 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 alpha-cholest-23-en-26-oic acid, varanic acid, and 3 alpha, 7 alpha, 12 alpha, 24-tetrahydroxy-24-methyl-5 beta-cholestan-26-oic acid. The fact that the toad bile contains not only cholic acid but also 3 alpha, 7 alpha, 12 alpha-trihydroxy- and 3 alpha, 7 alpha, 12 alpha,24-tetrahydroxy-5 beta-cholestan-26-oic acids, which have been recognized as biosynthetic intermediates of cholic acid in mammals, suggests that the toad is capable of synthesizing cholic acid by the same pathway as that for the biosynthesis of the C24 bile acid in mammals.

Animals↗
PubMed1976

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

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

Adult↗
PubMed1994

Pathogenic factors in early recurrence of cholesterol gallstones.

BACKGROUND/AIMS: Supersaturation of bile with cholesterol, rapid nucleation of cholesterol crystals, and/or incomplete emptying of the gallbladder are believed to be required for gallstone formation. The importance of these factors for the recurrence of gallbladder stones was studied. METHODS: Twenty patients, untreated after successful shock wave therapy, were studied in a matched case-control design for bile acid turnover, composition of duodenal bile, and gallbladder emptying. In 10 of them, gallstones had recurred within 12 +/- 2 months (X +/- SEM); the other 10 had been free of stones since 22 +/- 3 months. RESULTS: In each group, duodenal bile was supersaturated with cholesterol in 8 of 10 patients and showed abnormal nucleation time of cholesterol crystals in half of the patients. Patients with recurrent stones had smaller pool sizes of cholic acid (-43%) and enhanced conversion of cholic acid to deoxycholic acid. The odds for stone recurrence were ninefold increased in the presence of excessive deoxycholic acid (exceeding cholic acid) in the bile acid pool or incomplete emptying of the gallbladder (residual volume > 5 mL) in response to cholecystokinin. The odds ratio was over 20-fold increased when incomplete emptying of the gallbladder coincided with supersaturated bile or with excessive deoxycholic acid. CONCLUSIONS: Enhanced conversion of cholic acid to deoxycholic acid and incomplete emptying of the gallbladder could be important cofactors for the recurrence of gallstones.

Bile↗
PubMed2002

Changes in the pattern of bile acids in the nuclei of rat liver cells during hepatocarcinogenesis.

Bile acids reach the nuclei of hepatocytes, where they may play an important role in controlling gene expression by binding to nuclear receptors. In previous studies, changes in the amounts of the different molecular species of bile acids in the hepatocyte nucleus during rat liver regeneration have been reported. The aim of the present work was to investigate whether this also occurs during rat hepatocarcinogenesis. Liver cell nuclei were isolated after homogenization of livers from healthy adult rats (controls) and from rats at different time points during chemically induced hepatocarcinogenesis, corresponding to the stages of foci (12 weeks), hepatoma (20 weeks) and carcinoma (32 weeks). Bile samples from the cannulated common bile duct were collected for 1h from different sets of animals undergoing hepatocarcinogenesis. Bile acids in bile, liver homogenates and isolated nuclei were measured by GC-MS. Because the yield of nuclei isolated changed during the course of hepatocarcinogenesis (control, 20.1%; 12 weeks, 23.6%; 20 weeks, 7.8%; 32 weeks, 5.1%), amounts of bile acids in nuclei were corrected for the amount of DNA in each preparation. During hepatocarcinogenesis, bile acid concentrations in liver homogenates were reduced to approximately half the values obtained in control livers, while the levels of bile acids in both isolated nuclei and bile were not decreased. Hepatocarcinogenesis induced changes in the composition of bile acid pools. These were manifest as an increase in the proportion of cholic acid and a decrease in that of ursodeoxycholic acid in both bile and liver. These modifications differed from the changes seen in the nuclear bile acid pool, where a decrease in the proportion of cholic acid together with an increase in that of ursodeoxycholic acid were the major changes observed during hepatocarcinogenesis. With regard to the 'flat' bile acids (allo-cholic acid plus Delta(5)- or Delta(4)-unsaturated bile acids), a marked hepatocarcinogenesis-induced increase in the output of these species in bile was found. However, these bile acids were only found in liver homogenates at the hepatoma stage, whereas they were not detected in isolated nuclei at any stage of hepatocarcinogenesis. In summary, these results support the existence of a bile acid pool in hepatocyte nuclei whose composition differs from that of the extranuclear bile acid pool. Moreover, they indicate that, during hepatocarcinogenesis, the composition of the nuclear pool undergoes important alterations.

Animals↗
PubMed1995

Mechanism of ketoconazole-induced elevation of individual serum bile acids in the rat: relationship to the effect of ketoconazole on bile acid uptake by isolated hepatocytes.

Ketoconazole, an imidazole derivative, has been implicated in a number of hepatic dysfunctions. The aim of the present study was to determine the effect of in vivo treatment of rats with ketoconazole on individual serum bile acid levels and the in vitro effects of ketoconazole on the hepatocellular uptake of two bile acids and two other model substrates transported by liver cells. Male Sprague-Dawley rats were treated i.p. with a single injection of ketoconazole of 25 mg/kg (n = 4) or 50 mg/kg (n = 4); the control group (n = 4) received the vehicle only at a dose of 1 ml/kg. Blood samples were collected at 4 hr after dosing. With high-performance liquid chromatography, the serum was assayed for individual serum bile acids. At the higher dose, ketoconazole produced a significant increase in serum levels of cholic acid, taurocholic acid, chenodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, deoxycholic acid and taurochenodeoxycholic acid compared with the control group (P < .05). Cholic acid, taurocholic acid and chenodeoxycholic acid levels were significantly raised in rats treated with the lower dose. In vitro, ketoconazole strongly inhibited the hepatocellular uptake of [14C]cholic acid, [14C]taurocholic acid and [3H]ouabain but not [14C]2-aminoisobutyric acid, which indicated that the effect is relatively specific. The kinetics of inhibition were competitive and the inhibition constants for taurocholate and ouabain were 6 and 1 microM, respectively. Ketoconazole inhibited by both Na(+)-dependent taurocholate uptake and stimulated bile acid countertransport of preloaded hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗