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At least 307 records · Page 17Linked to original sources
PubMed1993

Polydeoxycholate in human and hamster feces: a major product of cholate metabolism.

Fecal bile acid excretion is one of the two major routes by which cholesterol is eliminated from the body, fecal cholesterol being the other. During their enterohepatic circulation, bile acids are secreted into the duodenum, pass down the jejunum and into the ileum where more than 95% is reabsorbed by the gut. Bile acids that escape reabsorption in the small intestine are metabolized by microorganisms in the large intestine. The major routes of metabolism are reported to be deconjugation, dehydroxylation, especially at the 7 alpha-hydroxy position, and dehydrogenation of the hydroxyl moieties. There are also some reports that saponifiable metabolites containing mostly deoxycholic acid form a major component of the bile acids found in human feces. We have identified a novel metabolite of cholic acid, 3 alpha-hydroxy polydeoxycholate, in both human and hamster feces that is the major constituent of these saponifiable metabolites. Furthermore, we have shown in hamsters that the animals that excreted more bile acid were excreting the additional bile acid as polydeoxycholate. As expected, there was a negative correlation between bile acid excretion in the feces and plasma cholesterol concentrations in these animals. We speculate that polydeoxycholate is formed in the lower gut of both humans and hamsters and that, by its formation, bile acid will be sequestered in an insoluble form, thus inhibiting its reabsorption by the gut. This process may help to reduce plasma cholesterol concentrations and coronary heart disease in humans.

Animals↗
PubMed1989

Effect of anions on adsorption of bile salts by colestipol hydrochloride.

The Langmuir affinity constant and adsorptive capacity for the adsorption of citrate anion or cholate anion by colestipol hydrochloride at pH 7.5, 37 degrees C, were similar. Prior exposure of colestipol hydrochloride to citrate anion caused the adsorption of cholate anion to decrease slightly in comparison to a control utilizing only cholate anion. The concentration of citrate anion was found to be directly related to the decrease in cholate anion adsorption. Simultaneous exposure of colestipol hydrochloride to citrate and cholate anions at pH 7.5, 37 degrees C, resulted in the same adsorption of cholate anion as sequential exposure to citrate anion followed by cholate anion. Sequential exposure of colestipol hydrochloride to simulated gastric fluid and simulated intestinal fluid containing cholate anion resulted in a small decrease in cholate adsorption which was attributed to competition with phosphate anion in simulated intestinal fluid. Pepsin in the simulated gastric fluid did not affect adsorption of cholate anion from simulated intestinal fluid. Preexposure to components of tomato juice and orange juice also slightly reduced the adsorption of cholate anion by colestipol hydrochloride.

Adsorption↗
PubMed1977

Possible explanations for the differences in secretory characteristics between conjugated and free bile acids.

1. The hepatic extraction fraction and maximum excretory rate of conjugated cholate are greater than those of free cholate (studied after acute taurine depletion); the possibility that this difference might be due to greater bile-to-blood back-diffusion of un-ionized cholic acid (pKa 5-5) compared to that of taurocholic acid (pKa 2) has been investigated by varying the pH of bile by secretin or acetazolamide administration in the anaesthetized dog. 2. The mean biliary pH during free cholate excretion in the control state in twenty-three experiments was 7-5 (at which approximately 1% of cholate is un-ionized). Three to fourfold changes in the hydrogen ion activity of bile (which resulted in changes of the same magnitude in the percentage of un-ionized cholic acid) had no significant effect on the total (mainly free) cholate maximum excretory rate. It is concluded that back-diffusion of un-ionized cholic acid in the bile ducts is not an important determinant of the secretory performance of free cholate. 3. The bile flow rate associated with mainly free cholate excretion is much higher than that associated with taurocholate excretion at the same rate; the extra bile flow appears to arise largely by means that are independent of the osmotic effect of cholate excretion, as the osmotic coefficient (osmolality/total solute concentration) of bile containing mainly free free cholate (calculated directly) was only slightly greater than that of bile containing mainly taurocholate (obtained by extrapolation) at the same total cholate concentration. 4. The peak hepatic excretory rate of taurocholate following the instillation of the entire contents of the gall-bladder of a fasted dog into the distal ileum was only about one fifth of the maximum rate attainable; at the peak rate taurocholate is almost completely removed in the first passage of blood through the liver.

Animals↗
PubMed1989

Mediation of cellular anion detoxification in leukemic cells by unidirectional efflux pumps.

Methotrexate influx in L1210 cells is mediated almost entirely by a single system, whereas efflux occurs via three routes, the influx carrier functioning in reverse and two additional systems which are operationally unidirectional. The two unidirectional routes show considerable similarities in energy-dependence and inhibitor sensitivities but can be separated by their differential inhibition by bromosulfophthalein (BSP), probenecid, and vincristine. The predominant route is inhibited by BSP and vincristine, whereas the other route is sensitive to probenecid. A search for additional anion substrates for the unidirectional efflux systems for methotrexate led to the finding that cholate exits L1210 cells via the same two unidirectional efflux systems as methotrexate. Cholate efflux is carrier-mediated, energy-dependent, and unidirectional, and it can be inhibited by several compounds which inhibit the efflux of methotrexate. Moreover, the same concentration of each compound which produced a half-maximal inhibition of methotrexate efflux also inhibited the efflux of cholate by 50%. Cholate efflux occurred predominantly (85%) via the BSP-sensitive route. The observation that methotrexate and cholate share the same efflux systems in L1210 cells suggest that perhaps other large anions are also accommodated by these systems since methotrexate and cholate differ in net negative charge and have few common structural features. The hypothesis advanced from these studies has been that the function of the unidirectional efflux systems is to extrude various organic anion catabolites which might otherwise become toxic if allowed to accumulate within cells. Possible intracellular anions in this latter category include sulfonated or carboxylated steroids, bilirubin, and products of vitamin D and prostaglandin catabolism. Unidirectional efflux pumps have been identified for other anionic compounds including cyclic AMP and oxidized glutathione, and in both cases similarities were apparent with the efflux of methotrexate and cholate. The most compelling comparison was with prostaglandin A1 which inhibited the efflux of cyclic AMP, methotrexate, and cholate half-maximally at the same low concentration of 0.1 microM. Energy-dependent unidirectional efflux pumps for large neutral or cationic drugs have also been identified in cells with acquired multidrug resistance. The latter efflux activity is thought to be mediated by a membrane glycoprotein (p170) which is also sensitive to several of the various inhibitors (reserpine, verapamil, and quinidine) which reduce the efflux of methotrexate and cholate.

Animals↗
PubMed2003

Enterohepatic circulation of bile salts in farnesoid X receptor-deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid-binding protein.

The bile salt-activated farnesoid X receptor (FXR; NR1H4) controls expression of several genes considered crucial in maintenance of bile salt homeostasis. We evaluated the physiological consequences of FXR deficiency on bile formation and on the kinetics of the enterohepatic circulation of cholate, the major bile salt species in mice. The pool size, fractional turnover rate, synthesis rate, and intestinal absorption of cholate were determined by stable isotope dilution and were related to expression of relevant transporters in the livers and intestines of FXR-deficient (Fxr-/-) mice. Fxr-/- mice showed only mildly elevated plasma bile salt concentrations associated with a 2.4-fold higher biliary bile salt output, whereas hepatic mRNA levels of the bile salt export pump were decreased. Cholate pool size and total bile salt pool size were increased by 67 and 39%, respectively, in Fxr-/- mice compared with wild-type mice. The cholate synthesis rate was increased by 85% in Fxr-/- mice, coinciding with a 2.5-fold increase in cholesterol 7alpha-hydroxylase (Cyp7a1) and unchanged sterol 12alpha-hydroxylase (Cyp8b1) expression in the liver. Despite a complete absence of ileal bile acid-binding protein mRNA and protein, the fractional turnover rate and cycling time of the cholate pool were not affected. The calculated amount of cholate reabsorbed from the intestine per day was approximately 2-fold higher in Fxr-/- mice than in wild-type mice. Thus, the absence of FXR in mice is associated with defective feedback inhibition of hepatic cholate synthesis, which leads to enlargement of the circulating cholate pool with an unaltered fractional turnover rate. The absence of ileal bile acid-binding protein does not negatively interfere with the enterohepatic circulation of cholate in mice.

Animals↗
PubMed1995

Identification and characterization of a basolateral dicarboxylate/cholate antiport system in rat hepatocytes.

The mechanisms and driving forces for the uptake of the unconjugated bile acid cholate were investigated both in cultured rat hepatocytes and in rat liver basolateral (sinusoidal) plasma membrane (BLPM) vesicles. Determination of initial uptake rates of [3H]cholate (0.1 microM) into cultured hepatocytes confirmed that the majority (75%) of the transmembrane transport was mediated by Na(+)-independent mechanisms. This portion of cholate uptake consisted of a pH-sensitive moiety representing nonionic diffusion, which may become quantitatively important at low pH and high cholate concentrations, as well as of a saturable (Michaelis constant 7.4 microM), 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS)-sensitive transport moiety, suggesting the involvement of a carrier. This latter transport system was functionally characterized by 1) inhibition of cellular cholate uptake in the absence of extracellular sodium by the dicarboxylic acid alpha-ketoglutarate (alpha-KG; 1 mM) and by the organic anion p-aminohippurate (PAH; 1 mM); 2) stimulation of cellular cholate uptake by alpha-KG (10 microM) or PAH (1 mM) in the presence of an inwardly directed sodium gradient; 3) lack of sensitivity toward lithium in BLPM vesicles; 4) trans-stimulation of vesicular cholate uptake by alpha-KG or PAH, but not by benzoate; and 5) cis-inhibition of alpha-KG/alpha-KG self-exchange by extravesicular cholate (400 microM), PAH (5 mM), probenecid, or DIDS. Collectively, these data indicate the presence of a Na(+)-dicarboxylate cotransport-coupled organic anion exchanger in the hepatocyte basolateral plasma membrane that may be involved in cholate uptake in the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

An evaluation of methods for the reconstitution of cytochromes P450 and NADPH P450 reductase into lipid vesicles.

Two methods (cholate dialysis and cholate gel filtration) used to incorporate cytochromes P450 (P450s) and reductase into unilamellar phospholipid vesicles were compared with a standard reconstituted system (SRS) in which the proteins were reconstituted with preformed liposomes. Both cholate dialysis and gel filtration methods were comparable in their ability to physically incorporate reductase and either CYP2B4 or CYP1A2 into phospholipid, as determined by the elution of enzymes in the void volume using size exclusion chromatography (mol. wt. cutoff -5,000,000). Incorporation of these proteins was more efficient with both cholate methods than when reductase and P450 were mixed with preformed vesicles (SRS). Using either cholate method, more than 85% of the P450 was physically incorporated into the phospholipid vesicles, whereas less than 40% of the P450 was physically incorporated into the phospholipid vesicles using the SRS. Catalytic activities of the vesicular preparations of reductase and either CYP1A2 or CYP2B4 also were significantly higher than those resulting from the SRS using dilaurylphosphatidylcholine. Although both cholate dialysis and gel filtration methods improved protein incorporation when compared with preincubation of proteins with preformed liposomes, reductase incorporation was dependent on the relative amount of reductase used. Reductase incorporation was complete at a 0.2:1 reductase/P450 ratio; however, the efficiency of incorporation decreased to less than 50% at equimolar reductase/P450. Interestingly, reductase incorporation was higher in the presence of CYP1A2 than with CYP2B4. Both cholate methods resulted in the loss of a proportion of spectrally detectable carbon monoxyferrous P450, resulting from incubation of the proteins with detergent.

Animals↗