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Biomedical subjects

F Kuipers

Publications and source records attributed to F Kuipers.

At least 91 records · Page 5Linked to original sources
PubMed1996

Bile secretion of cadmium, silver, zinc and copper in the rat. Involvement of various transport systems.

In the present study we compared, in vivo in rats, the hepatobiliary transport of monovalent (silver:Ag) and divalent metals (zinc:Zn; cadmium:Cd) with that of copper (Cu). Cu can have two oxidation states in vivo, i.e. Cu(I) and Cu(II). Studies were performed in normal Wistar (NW) rats and mutant GY Wistar rats. The latter express defective canalicular ATP-dependent glutathione-conjugate transport (cMOAT); reduced glutathione (GSH) is virtually absent in bile of these mutants. Cd (400 nmol/100g body wt, i.v.) was rapidly secreted into bile in NW rats concommitant with a 4-fold increase in biliary GSH secretion. In contrast, biliary Cd concentrations remained below detection limits in GY rats. Injection of Zn (1500 nmol/100g body wt) did not affect Zn secretion in GY rats and resulted only in a very small increase in NW rats (recovery < 2%). The biliary secretion pattern of Ag (800 nmol/100g body wt, i.v.) was highly similar to that of Cu (260 nmol/100g body wt). A biphasic pattern composed of a rapid and slow phase was observed in NW rats for both metals with a recovery of 48.5 +/- 10.6% and 44.9 +/- 8.4% of the dose for Ag and Cu, respectively. In GY rats, the rapid phase of both Ag and Cu secretion was absent and recoveries were 23.2 +/- 3.6% and 19.7 +/- 3.2%, respectively. When Ag and Cu were administered simultaneously, the recoveries of Ag and Cu were decreased in NW and GY rats when compared to single administration. Our data indicate that divalent and monovalent metals are secreted into bile via different transport systems in the rat. The absence of Cd and Zn secretion into bile of GY rats after their i.v. administration suggest a role of cMOAT in their biliary elimination. Cu and Ag probably share common transport systems for hepatobiliary removal, being in part dependent on the presence of either GSH in bile or cMOAT activity or on both. The GSH-independent portion of transport, i.e. the slow phase, may be mediated by the newly identified Cu transporting P-type ATPase (cCOP).

Animals↗
PubMed1996

Relationship between biliary lipid and protoporphyrin secretion; potential role of mdr2 P-glycoprotein in hepatobiliary organic anion transport.

BACKGROUND/AIMS: Erythropoietic protoporphyria, caused by ferrochelatase deficiency, leads to protoporphyrin accumulation in the liver. Therapeutic attempts to increase the secretion of this hydrophobic organic anion into bile are hampered by a lack of understanding of the secretory mechanism(s) involved. We have investigated biliary secretion of protoporphyrin in rats and mice, primarily targeted on the role of biliary lipids in this process. METHODS: Gel permeation chromatography was applied to investigate the association of porphyrins with lipid fractions in bile. Secretion of endogenous porphyrins was studied in (GY mutant) rats and mdr2 P-glycoprotein deficient mice, under conditions of widely varying biliary lipid secretion rates. RESULTS: Gel permeation chromatography revealed that, in native human and rat bile, protoporphyrin associated with cholesterol/phospholipid vesicles upon elution with bile salt-free buffer. In contrast, the more hydrophilic coproporphyrin isomers I and III were found only in bile salt/organic anion hybrid particles and smaller aggregates. Interruption of the enterohepatic circulation in normal Wistar rat resulted in parallel decrease of endogenous protoporphyrin-, lipid-, and bile salt secretion, but did not alter the secretion of coproporphyrin I and III. Uncoupling of lipid- from bile salt secretion by sulfated taurolithocholate resulted in impaired secretion into bile of protoporphyrin only. Conversely, secretion of coproporphyrin I and III, but not that of protoporphyrin, was impaired in mutant Groningen Yellow rats with defective ATP-dependent hepatobiliary organic anion transport. In mice homozygous for a disruption of the mdr2 P-glycoprotein gene, resulting in complete absence of phospholipids in bile and strongly reduced cholesterol output, secretion of protoporphyrin was reduced by 90%, whereas that of coproporphyrin I and III was affected to a much lesser extent. CONCLUSIONS: Our data demonstrate a close association between protoporphyrin and lipid secretion into bile, indicating that these processes are, at least functioning coupled. This finding implicates a role of mdr2 P-glycoprotein activity in hepatobiliary removal of the hydrophobic organic anion protoporphyrin. Hence, it may be speculated that protoporphyrin secretion can be influenced by drugs, diet or other means that affect biliary lipid secretion.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1996

Adenosine triphosphate-dependent copper transport in human liver.

BACKGROUND/AIM: The recent cloning and sequencing of the Wilson disease gene indicates that hepatic copper (Cu) transport is mediated by a P-type ATPase. The location of this Cu-transporting protein within the hepatocyte is not known; in view of its proposed function and current concepts of hepatic Cu transport, it may reside in intracellular membranes (endoplasmic reticulum (ER), lysosomes) and/or in the bile canalicular membrane. The objective of this study was to establish characteristics and localization of ATP-dependent Cu transport in human liver. METHODS: We have investigated Cu transport in vesicles of human liver plasma membranes showing a gradual increase in enrichment of canalicular domain markers: i.e. basolateral liver plasma membranes (blLPM), a mixed population of basolateral and canalicular (XLPM) and canalicular liver plasma membranes (cLPM). RESULTS: In the presence of ATP (4 mM) and an ATP-regenerating system, uptake of radiolabeled Cu (64Cu, 10 microM) into cLPM vesicles and, to a lesser extent, into blLPM and XLPM was clearly stimulated when compared to control AMP values. Initial uptake rates of ATP-dependent Cu transport were 5.6, 7.8 and 13.7 nmol.min-1.mg-1 protein for blLPM, XLPM and cLPM, respectively, and showed no relationship with marker enzyme activity of ER and lysosomes (glucose-6-phosphatase and acid-phosphatase, respectively). Leucine aminopeptidase activity, as a marker for the cLPM, significantly correlated with ATP-dependent uptake rates measured in different membrane preparations: r = 0.70 (n = 9, p < 0.05). Estimated K(m) and Vmax values of ATP-dependent Cu uptake were 49.5 microM and 36.9 nmol.min-1.mg-1 protein, respectively. CONCLUSION: This study provides biochemical evidence for the presence of an ATP-dependent Cu transport system in human liver (cCOP), mainly localized at the canalicular domain of the hepatocytic plasma membrane.

Adenosine Triphosphate↗
PubMed1995

Differential effects of eicosapentaenoic acid on glycerolipid and apolipoprotein B metabolism in primary human hepatocytes compared to HepG2 cells and primary rat hepatocytes.

We compared the effects of eicosapentaenoic acid (EPA) and oleic acid (OA) on glycerolipid and apolipoprotein B (apoB) metabolism in primary human hepatocytes, HepG2 cells and primary rat hepatocytes. Cells were incubated for 1 to 5 h with 0.25 mM bovine serum albumin in the absence (control) or presence of 1 mM of EPA or OA. Synthesis and secretion of [3H]glycerolipid were determined after 1 h incubation with [3H]glycerol. Cellular and medium apoB abundance was semi-quantitatively estimated in human cells by Western blotting. The following observations were made. (1) Compared to control, OA induced a 7-fold increase in [3H]triacylglycerol (TG) synthesis in human hepatocytes and a 4-fold increase in rat hepatocytes and HepG2 cells. EPA enhanced [3H]TG synthesis about 2-fold in all three cell types although it stimulated [3H]diacylglycerol (DG) synthesis to an extent (i.e., 2.5- to 5-fold) similar to OA. (2) In contrast to OA, which stimulated VLDL-associated [3H]TG secretion 2.5- to 3-fold in the three cell types relative to control, EPA did not alter [3H]TG secretion in HepG2 and rat hepatocytes and suppressed [3H]TG secretion by 75% in primary human hepatocytes. (3) In primary human hepatocytes, both OA and EPA did not alter cellular apoB abundance but EPA decreased apoB secretion by 44% as compared to control. In contrast, both EPA and OA increased cellular and medium apoB abundance 2- to 2.5-fold in HepG2 cells, although medium apoB tended to be lower in EPA-treated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Randomized, double-blinded, placebo-controlled intervention study with supplemental calcium in families with hereditary nonpolyposis colorectal cancer.

BACKGROUND: A high-fat diet has been recognized for some time as a major risk factor for colorectal cancer. It is thought that fat promotes this disease by increasing the levels of fatty and bile acids within the colon. These acids irritate and damage the epithelial cells of the colon. As a result of this cellular destruction, an increase in the rate of cellular proliferation occurs. Oral calcium supplementation has been proposed as a dietary intervention for individuals at high risk of colorectal cancer because of its ability to reduce rectal epithelial cell proliferation through the binding of fatty and bile acids. Placebo-controlled studies, however, have yielded varying results. PURPOSE: We conducted a randomized, double-blinded, placebo-controlled trial to test oral calcium supplementation in patients at high risk of developing hereditary nonpolyposis colorectal cancer. METHODS: Thirty subjects at risk for this cancer, with an increased epithelial cell proliferation along the colon and rectum, were randomly assigned to either a placebo group (n = 15) or a treatment group (n = 15). They received either oral calcium carbonate (CaCO3) supplements (1.5 g) or placebo (cellulose and starch) three times a day during a 12-week period. Colonic biopsy specimens (rectal, sigmoidal, and descending) were obtained prior to and after the intervention trial, during endoscopy, for determination of labeling index (LI) of whole crypts and crypt compartments by 5-bromo-2'-deoxyuridine incorporation and immunohistochemistry. Proportional bile acid compositions in duodenal bile and cytolytic activity of fecal water were also determined. All P values represent two-tailed tests of statistical significance. RESULTS: Statistically significant reductions, comparing before with after intervention, in rectal whole-crypt LI after receiving either calcium supplements (from 10.9% +/- 5.2% [mean +/- SD] to 6.2% +/- 1.5%; P < .02) or placebo (from 11.7% +/- 4.7% to 8.2% +/- 3.1%; P < .05) were observed. In the three bowel segments, no statistically significant differences were observed between the supplemental calcium and placebo groups. A statistically significant reduction in cytolytic activity was determined during calcium supplementation (from 57% +/- 41% to 32% +/- 30%; P < .05), whereas in the placebo group, it did not change (from 42% +/- 41% to 36% +/- 27%; P > .10). CONCLUSIONS: Oral calcium supplementation was shown to cause only a minor nonstatistically significant reduction of epithelial cell proliferation in the rectum, compared with placebo, and to have no effect on the same parameter in the sigmoid and descending colon in first-degree relatives of hereditary nonpolyposis colorectal cancer patients. IMPLICATION: These results cast doubt on the value of calcium supplementation in the prevention of colorectal cancer, especially in individuals already consuming an adequate amount of dietary calcium.

Adolescent↗
PubMed1995

Differences in propionate-induced inhibition of cholesterol and triacylglycerol synthesis between human and rat hepatocytes in primary culture.

Propionate is a short-chain fatty acid formed in the colon and supposedly involved in the cholesterol-lowering effect of soluble fibre. To explore the underlying mechanism(s) of this fibre action, we have used human hepatocytes in primary culture to study the effects of propionate on hepatic lipid synthesis. Initial experiments with mevalonate and mevinolin, a competitive inhibitor of hydroxymethylglutaryl (HMG)-CoA reductase (EC 1.1.1.88) were performed to evaluate basic regulatory mechanisms in these cells; results were compared with those obtained with rat hepatocytes. Incubation for 24 h with mevalonate caused a similar, concentration-dependent inhibition of [14C]acetate incorporation into cholesterol in human and rat hepatocytes. Likewise, mevinolin (100 mumol/l) inhibited the formation of cholesterol from radiolabelled acetate by about 80% in cells from both species. Propionate inhibited cholesterol as well as triacylglycerol synthesis from [14C]acetate with a similar concentration-dependency in rat hepatocytes. Fifty percent inhibition was obtained at a propionate concentration of only 0.1 mmol/l. This propionate-induced inhibition was not affected by a 100-fold excess of unlabelled acetate. Human hepatocytes were much less susceptible in this respect: propionate concentrations of 10-20 mmol/l were required to obtain similar inhibitory effects in these cells, i.e. values greatly exceeding reported portal propionate concentrations in humans. The results suggest the existence of differences in the regulation of hepatic cholesterol (and triacylglycerol) synthesis between human and rat liver cells. These results do not support the hypothesis that the fibre-induced decrease in plasma cholesterol concentration in man is mediated by a direct effect of propionate on hepatic cholesterol synthesis.

Acetates↗
PubMed1995

Adenosine triphosphate-dependent copper transport in isolated rat liver plasma membranes.

The process of hepatobiliary copper (Cu) secretion is still poorly understood: Cu secretion as a complex with glutathione and transport via a lysosomal pathway have been proposed. The recent cloning and sequencing of the gene for Wilson disease indicates that Cu transport in liver cells may be mediated by a Cu transporting P-type ATPase. Biochemical evidence for ATP-dependent Cu transport in mammalian systems, however, has not been reported so far. We have investigated Cu transport in rat liver plasma membrane vesicles enriched in canalicular or basolateral membranes in the presence and absence of ATP (4 mM) and an ATP-regenerating system. The presence of ATP clearly stimulated uptake of radiolabeled Cu (64Cu, 10 microM) into canalicular plasma membrane vesicles and, to a lesser extent, also into basolateral plasma membrane vesicles. ATP-dependent Cu transport was dose-dependently inhibited by the P-type ATPase inhibitor vanadate, and showed saturation kinetics with an estimated Km of 8.6 microM and a Vmax of 6.9 nmol/min/mg protein. ATP-stimulated Cu uptake was similar in canalicular membrane vesicles of normal Wistar rats and those of mutant GY rats, expressing a congenital defect in the activity of the ATP-dependent canalicular glutathione-conjugate transporter (cMOAT). These studies demonstrate the presence of an ATP-dependent Cu transporting system in isolated plasma membrane fractions of rat liver distinct from cMOAT.

ATP-Binding Cassette Transporters↗
PubMed1995

Evaluation and clinical application of the Enterotest for the determination of human biliary porphyrin composition.

The Enterotest string test is an easy and non-invasive method for sampling duodenal fluid, which has been successfully used for the analysis of duodenal microflora, as well as biliary bile acid and lipid composition. The method was evaluated for determination of porphyrins in duodenal bile in normal subjects and subjects with porphyria, following cholecystokinin induced gall bladder contraction; it is known that analysis of biliary porphyrins is more discriminatory for the diagnosis of asymptomatic porphyria than their analysis in faeces or urine. Moreover, serial analysis of bile from patients with erythropoietic protoporphyria may help in establishing their ability to secrete protoporphyrin in bile and to assess effects of treatment. The binding of various porphyrins to Enterotest strings was investigated by incubating pieces of the string in different human bile samples with low to very high porphyrin concentrations, followed by HPLC analysis of porphyrins both in the native bile and in extracts obtained from the strings. No differences between porphyrin composition in native bile and extracts were observed. Duodenal fluid obtained by means of the Enterotest from volunteers not receiving cholecystokinin showed large variations in porphyrin patterns not resembling those of native bile. Mesoporphyrin, a secondary porphyrin derived from protoporphyrin by bacteria, was often detectable. These data indicate that the duodenal content without cholecystokinin injection does not reflect biliary porphyrin composition. The presence of mesoporphyrin in the whole intestinal tract, but not in serum and bile, suggests that there is no enterohepatic circulation of secondary porphyrins. There was close agreement between the porphyrin ratios found with the standard duodenal intubation technique and the Enterotest, performed simultaneously in one healthy volunteer after induction of gall bladder contraction by cholecystokinin. From these experiments, it was concluded that fluid adsorbed to the Enterotest string after gall-bladder contraction can be used to determine biliary porphyrin composition. Since duodenal bile is diluted gall bladder bile, variable porphyrin concentrations were found when applying the Enterotest in combination with cholecystokinin in the same subject on successive days. However, porphyrin ratios, such as the protoporphyrin to coproporphyrin I ratio, were relatively constant. In subjects with symptomatic variegate porphyria, the Enterotest showed highly aberrant porphyrin patterns, with increased protoporphyrin to coproporphyrin I ratios and, in addition, the presence of some unknown porphyrins. A deviating biliary protoporphyrin/coproporphyrin I ratio in one patient appeared to be a useful diagnostic index for the presence of latent variegate porphyria (or variegate porphyria in remission).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

Characterization of human liver microsomal UDP-glycosyltransferases using photoaffinity analogs.

The photoaffinity analogs [beta-32P]5-azido-UDP-glucuronic acid ([32P]5N3UDP-GlcUA) and [beta-32P]5-azido-UDP-glucose ([32P]5N3UDP-Glc) were used to characterize UDP-glycosyltransferases of microsomes prepared from human liver. Photoincorporation of both probes into proteins in the 50- to 56-kdalton range, known to contain UDP-glucuronosyl transferases (UGTs), was concentration dependent, and photolabeled proteins were susceptible to trypsin digestion only in the presence of detergent. The latter was demonstrated by the appearance on Western blots of the trypsin-treated, detergent-disrupted microsomes of a protein band of slightly lower molecular mass than, and presumably derived from, the UGTs. However, a labeled cleavage product was found only in samples photolabeled with [32P]5N3UDP-GlcUA and not in those labeled with [32P]5N3UDP-Glc. In detergent-treated microsomes, all of the nucleotide sugars that were tested protected better against photoinsertion of [32P]5N3UDP-GlcUA than of [32P]5N3UDP-Glc, with UDP-glucose being the most effective, followed by UDP-GlcUA and UDP-galactose. The pattern of inhibition of a series of uridinyl analogs toward photolabeling by the two probes was quite different: one inhibitor that was ineffective in blocking photoincorporation of [32P]5N3UDP-GlcUA (L-DPASiU) was one of the most potent inhibitors of photolabeling with [32P]5N3UDP-Glc. A similar dichotomy was seen with several inhibitors in enzymatic assays measuring hyodeoxycholic acid 6-O glucuronidation and glucosidation activities; the most potent inhibitors of HDCA glucosidation were not as effective against glucuronidation. The results indicate a lumenal orientation for human microsomal UGTs and provide substantial evidence that two distinct enzyme systems are involved in 6-O glucuronidation and 6-O glucosidation of HDCA.

Affinity Labels↗
PubMed1994

Dietary fish oil potentiates bile acid-induced cholesterol secretion into bile in rats.

Recently we demonstrated that dietary fish oil (FO) causes changes in intrahepatic cholesterol transport and hypersecretion of cholesterol into bile in rats (J. Clin. Invest. 88: 943-951, 1991). We have now investigated in more detail the relationship between cholesterol and bile acid secretion in rats with chronic bile diversion fed purified diets supplemented (9% wt/wt) with either FO or corn oil (CO) for 2 weeks. Effects of FO on biliary cholesterol secretion (+ 400% as compared to CO after 14 days) were much more pronounced than previously observed in rats with intact enterohepatic circulation (+50%). Biliary bile acid (+30%) and phospholipid (+120%) secretion were increased to a much lesser extent than that of cholesterol resulting in the formation of bile supersaturated with cholesterol. The biliary cholesterol/bile acid molar ratio was 0.069 and 0.032 in FO- and CO-fed rats, respectively, at noon of day 14. This ratio increased to 0.108 in FO-fed rats at midnight, when bile acid output was maximal, but remained unchanged in CO-fed rats during the day-night cycle. Intravenous administration of taurochenodeoxycholic acid (15 mumol/kg) resulted in a 2-fold increase in bile acid output and a simultaneous 1.6-fold stimulation of cholesterol secretion in both groups, implying that administration of the bile acid induced the secretion of 2-3 times as much cholesterol in FO- than in CO-fed rats. Likewise, administration of bilirubin ditaurate (30 mumol/kg), an inhibitor of bile acid-induced biliary lipid secretion, reduced cholesterol output in both groups by about 50% while bile acid output remained unchanged. It is concluded that, in rats, dietary fish oil increases the disposition of cholesterol into bile by potentiating bile acid-dependent cholesterol secretion, presumably by facilitating the recruitment of bile-destined cholesterol.

Animals↗
PubMed1994

Effects of dietary corn and olive oil versus coconut fat on biliary cholesterol secretion in rats.

We have studied the effects of dietary corn and olive oil versus coconut fat on bile formation and fluidity of hepatic plasma membranes in rats. After 4 weeks of feeding the purified diets containing 9% (w/w) of the test fats, there was no difference in plasma cholesterol concentration between the dietary groups. The amount of free and esterified cholesterol in the liver was significantly higher in rats fed either corn oil or olive oil as compared with coconut fat. In the rats fed olive oil, but not in those fed corn oil this was associated with lower rates of biliary phospholipid excretion. Bile flow was not differently influenced by the three dietary fats. Hepatic plasma membranes of the rats fed corn or olive oil contained more cholesterol and less phospholipids than those on coconut fat, which was, however, not accompanied by changes in fluidity of the membranes. These results indicate that in rats the type of dietary fat can induce considerable changes in hepatic cholesterol metabolism without affecting plasma cholesterol concentrations, and without consistent effects on biliary cholesterol secretion.

Animals↗
PubMed1993

Conversion of liposomal 5-fluoro-2'-deoxyuridine and its dipalmitoyl derivative to bile acid conjugates of alpha-fluoro-beta-alanine and their excretion into rat bile.

We studied the hepatic processing and biliary excretion of metabolites of the radiolabeled cytostatic agent 5-fluoro,-2'-deoxy[6-3H]uridine (FUdR) and its lipophilic derivative FUdR-dipalmitate incorporated in liposomes. After intracardial injection in rats, free FUdR was cleared from the circulation within minutes. When FUdR or FUdR-dipalmitate was encapsulated in multilamellar vesicles (MLVs) composed of distearoylphosphatidylcholine/dipalmitoylphosphatidylglycerol (DSPC/DPPG/CHOL, 10:1), as expected, the clearance of 3H label was substantially delayed; incorporation of 50 mol% cholesterol in the liposomal bilayer caused a 2-fold further reduction in elimination rate. Incorporation of FUdR-dipalmitate in small unilamellar vesicles (SUV) of similar composition produced a several-fold further decrease in elimination rate: more than 40% of the injected dose was still circulating after 6 h. The plasma concentration of free FUdR after administration of liposomal FUdR-dipalmitate was below the detection limit (5 x 10(-8) M) at any time. Although only about 9% of the administered radioactivity was excreted into the bile within 48 h after injection of [3H]FUdR, a rapid initial excretion rate was observed (4% of the injected dose in the first 2 h). The bile-associated radioactivity was identified mainly as the catabolite alpha-fluoro-beta-alanine (FBAL), conjugated with the three major bile acid species present in rat bile, i.e., muricholic acid, cholic acid and chenodeoxycholic acid in a ratio of 1:3:1. Liposome incorporation of FUdR or FUdR-dipalmitate did not affect the nature of the excretory products but caused a significant decrease in the initial rate at which label appeared in the bile (< 2% in 6 h).

Animals↗
PubMed1993

Dietary cholesterol-induced down-regulation of intestinal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity is diminished in rabbits with hyperresponse of serum cholesterol to dietary cholesterol.

Key enzymes of cholesterol metabolism were studied in two inbred strains of rabbits with hyper- or hyporesponse of serum cholesterol to dietary cholesterol. Baseline 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity in liver was similar in hypo- and hyperresponders, but that in intestine was twofold higher in the hyporesponders. The addition of cholesterol (3 g/kg) to the diet caused similar depression of hepatic HMG-CoA reductase activity in the two strains, whereas intestinal HMG-CoA reductase activity was significantly reduced in hyporesponders but not in hyperresponders. Cholesterol feeding induced higher free cholesterol concentrations in hepatic and intestinal microsomes of both hypo- and hyperresponders and higher activity of hepatic acyl-CoA:cholesterol acyltransferase (ACAT). Hepatic ACAT activity was significantly lower in cholesterol-fed hyperresponders than in hyporesponders, which may have contributed to the observed higher free cholesterol concentrations in hepatic microsomes of cholesterol-fed hyperresponders. Intestinal ACAT activity was similar in hypo- and hyperresponders; cholesterol feeding tended (P = 0.11) to elevate the activity of this enzyme. Hepatic cholesterol 7 alpha-hydroxylase activity was significantly higher in cholesterol-fed hyperresponders than in hyporesponders; it was slightly depressed after cholesterol loading in both rabbit strains.

Animals↗
PubMed1993

Effects of oral calcium supplementation on intestinal bile acids and cytolytic activity of fecal water in patients with adenomatous polyps of the colon.

Calcium has been proposed to prevent colon cancer in subjects at risk for this tumour. This effect is supposed to be due at least in part to binding the bile acids to calcium, making them insoluble and harmless. To evaluate the effects of oral calcium supplementation on intestinal bile acids, 19 patients with adenomatous colonic polyps were supplemented with 35.5 mmol Ca2+ daily for 12 weeks. Duodenal bile, 24-h feces and 24-h urine were collected before and at the end of the 12-week period. In duodenal bile proportional concentration of cholic acid increased (38 +/- 4 vs. 51 +/- 3%, P < 0.001), whereas that of chenodeoxycholic acid decreased (35 +/- 3 vs. 25 +/- 2%, P < 0.01). Total fecal bile acid excretion increased (950 +/- 126 vs. 1218 +/- 137 mumol 24 h-1, P < 0.01), with proportional concentrations of the main primary and secondary bile acids remaining the same. Cytolytic activity of fecal water, measured by the degree of lysis of erythrocytes by the water, decreased (45 +/- 8 vs. 30 +/- 7%, P < 0.05). Total excretion of calcium increased as expected from the supplementary dose. It is concluded that calcium supplementation markedly affects intestinal bile acids and lytic activity of fecal water and that, in view of similar results during 1-week calcium supplementation in young healthy subjects, these effects remain constant over at least 3 months and occur both in healthy persons and in patients at increased risk for colon cancer.

Bile Acids and Salts↗
PubMed1993

Mechanism of bile acid-induced biliary lipid secretion in the rat: effect of conjugated bilirubin.

We have compared the effects of bilirubin and bilirubin ditaurate (BDT) on biliary phospholipid and cholesterol secretion in unanesthetized normal Wistar (NW) and Groningen Yellow (GY) Wistar rats under various experimental conditions. GY rats express a genetic defect in biliary secretion, but not in hepatic uptake, of various organic anions. Under physiological conditions, NW and GY rats showed similar biliary secretion rates of bile acids and of bilirubin, despite the fact that bilirubin concentrations in GY plasma were 25 times as high and in GY livers three times as high as in NW plasma and livers, respectively. Secretion of cholesterol and phospholipids was not impaired in GY rats under these conditions. Biliary secretion of intravenously injected BDT (3 mumol/100 g body wt) was delayed in eight-day bile-diverted GY rats and showed lower peak values when compared with NW rats. The inhibitory effects of BDT on phospholipid and cholesterol secretion paralleled these differences, being delayed and much less pronounced in GY rats. No overshoot in phospholipid or cholesterol secretion was observed when bilirubin output returned to preinjection values. Stimulation of [14C]choline-labeled phospholipid secretion after a bolus injection of taurochenodeoxycholic acid (1 mumol/100 g body wt) closely followed biliary bile acid concentration. Similarly, inhibition of labeled phospholipid secretion by BDT closely paralleled the biliary bilirubin concentration. Gel filtration studies (Sepharose 4B-CL) under micelle-preserving conditions demonstrated a specific interaction of BDT with biliary bile acids. The presented data indicate that conjugated bilirubin does not inhibit biliary lipid secretion via interaction with bile acids inside the hepatocyte.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗