Increased Bile Flow Research Articles

Effect of HDL1 infusion on biliary secretion in perfused rat liver.

The effects of HDL1 lipoprotein infusion on biliary lipid secretion were studied in the in vitro model of rat perfused liver. A strong increase in bile flow was observed during and after lipoprotein infusion. This caused a significant rise in cholesterol, phospholipid and bile salt secretions. However, only the percentage of cholesterol increased with respect to the other bile lipids. The changes observed in the cholesterol/phospholipid molar ratio values of liver membrane subfractions (i.e., liver plasma membrane, mitochondria plus lysosomes and microsomes) isolated from the perfused rat liver after HDL1 administration were not significant.

Papaverine inhibits transcytotic vesicle transport and lipid excretion into bile in isolated perfused rat liver.

Papaverine is a nonspecific smooth muscle relaxant and a phosphodiesterase inhibitor. Its effects on biliary excretion of lipids and horseradish peroxidase were investigated in a single-pass isolated perfused rat liver model. A constant infusion of papaverine (1.6 mumol/min; 40 mumol/L) significantly increased bile flow (microliters per minute per gram of liver) before (2.03 +/- 0.09 vs. 1.0 +/- 0.06) and after sodium taurocholate infusion (2.77 +/- 0.10 vs. 1.88 +/- 0.11). However, papaverine significantly and reversibly reduced biliary excretion of phospholipids and cholesterol (nanomoles per minute per gram of liver) after a 1.0 mumol/min sodium taurocholate infusion, from 7.45 +/- 0.83 and 1.42 +/- 0.15 to 1.75 +/- 0.18 and 0.39 +/- 0.06, respectively (p less than 0.01), whereas secretion of bile acids was unaffected. When a 1-min pulse of horseradish peroxidase (25 mg) was infused in isolated perfused rat liver after a continuous infusion of N6,O-2'-dibutyryladenosine 3',5'-cyclic monophosphate (0.25 mumol/min; 6.25 mumol/L), horseradish peroxidase appeared in bile in an early (4 to 6 min) and late (20 to 25 min) peak. Papaverine significantly reduced the late peak, from 1.211 +/- 0.264 to 0.498 +/- 0.107 (p less than 0.01). Papaverine had no significant effects on either cyclic AMP or cyclic GMP in the liver and bile, although it has been reported that papaverine is a phosphodiesterase inhibitor. These findings indicate that papaverine inhibits biliary excretion of lipids but not bile acids, and they suggest that papaverine has an inhibitory effect on transcytotic vesicle transport independent of an increase of cyclic nucleotides in hepatocytes.

Alterations induced by fascioliasis and cirrhosis on the biliary excretion of cefmetazole in Wistar rats.

1. Alterations induced by fascioliasis and cirrhosis on the biliary excretion of cefmetazole have been studied in Wistar rats. 2. Both infestation with Fasciola hepatica and experimental cirrhosis originated a significant decrease in the biliary excretion and in bile flow increase induced by the drug. 3. Administration of the beta-lactam antibiotic induced a lower degree of uncoupling of biliary lipid secretion in the cirrhotic and fasciolotic animals, but the effect was evident in all experimental groups.

Regulatory volume decrease stimulates bile flow, bile acid excretion, and exocytosis in isolated perfused rat liver.

To study the effect of volume regulation on bile secretory function, isolated perfused rat livers (IPRL) were exposed to hypotonic stress (45 mM NaCl) while bile flow and the biliary excretion of bile acids and horseradish peroxidase (HRP) were assessed. Hypotonic stress induced a biphasic increase in bile flow, which rose in the first minute from 1.1 +/- 0.2 to 1.7 +/- 0.1 microliter.min-1.g liver-1 (P less than 0.01), an effect attributed to rapid osmotic equilibration of water, then increased further between 3 and 5 min to 1.6 +/- 0.1 microliter.min-1.g liver-1 (P less than 0.01, followed by a subsequent return to baseline. HRP excretion in bile increased during the second peak of bile flow from 0.9 +/- 0.2 to 1.1 +/- 0.2 ng.min-1.g liver-1, P less than 0.01. Pretreatment with colchicine but not lumicolchicine completely abolished the latter increase in bile flow and HRP excretion as did BaCl2 (1 mM), an inhibitor of both K+ channels and regulatory volume decrease (RVD) in hepatocytes. When sodium taurocholate was infused (1 mumol/min), hypotonic stress induced an even larger increase in the second peak of bile flow (5.1 +/- 0.7 microliters/g liver, P less than 0.01) and higher rates of bile acid excretion than in control perfusions with bile acid (126.2 +/- 21.0 vs. 99.0 +/- 17.1 nmol.min-1.g liver-1, P less than 0.05). These data suggest that both bile flow and bile acid excretion are stimulated during RVD by mechanisms that involve both K+ channels and microtubule-dependent exocytosis at the canalicular (apical) membrane domain.

Tauro-β-muricholate preserves choleresis and prevents taurocholate-induced cholestasis in colchicine-treated rat liver

In recent clinical and animal experimental studies, ursodeoxycholic acid (UDCA) has been noted to have marked choleretic and cytoprotective actions. To define the mechanism and determine whether such favorable influence is specific to UDCA, the choleretic action of β-muricholic acid (β-MCA), which has a similar chemical structure, was studied using an isolated rat-liver-perfusion system. As a result, β-MCA and taurine-conjugated β-MCA (Tβ-MCA) stimulated bile flow accompanied by elevation of bile acid output and phospholipid output, and β-MCA caused an elevation in biliary HCO3− concentration in normal rat livers. After colchicine treatment, taurocholic acid (TCA) administration was associated with marked cholestasis while both β-MCA and Tβ-MCA still increased bile flow under the same conditions. Furthermore, simultaneous administration of β-MCA or, more markedly, Tβ-MCA reversed the effects of TCA alone in colchicine-treated rat liver; significant preventive effects against the cholestasis could be shown. These data suggest that β-MCA and especially Tβ-MCA can support choleresis even under conditions of colchicine-dependent microtubule dysfunction. The effects of Tβ-MCA on organelle lipids and their intracellular transport may differ from those of TCA, presumably because of the anticholestatic and cytoprotective effects of Tβ-MCA.

Bromosulfophthalein disposition in chronically bile duct obstructed rats

The disposition of bromosulfophthalein was studied in chronically bile duct obstructed rats. In this model a catheter was inserted into the common bile duct and the distal tip was sealed. Resumption of bile flow was achieved with great ease. Obstruction of bile duct for 18 days in rats resulted in elevated bilirubin, ALT, AST, and alkaline phosphatase levels. Portal hypertension developed within this period (11.6 ± 0.5 in obstructed rats vs. 8.6 ± 0.6 mm Hg in sham-operated group). After the bile duct obstruction was opened, the half-life time for elimination of bromosulfophthalein (42.30 ± 6.47 min) was longer than in sham-operated rats (21.23 ± 3.34 min). Plasma clearance was reduced by 70% in bile duct obstructed rats. In spite of increased bile flow rate, biliary excretion of the dye was reduced by 40% in chronically bile duct obstructed rats. Hepatic glutathione levels were significantly reduced by 20% in this model. The specific activity of glutathione 5-transferase with chlorodinitrobenzene and styrene oxide, as substrates, was reduced by 50% and 30%, respectively. However, the percent of conjugated bromosulfophthalein in bile was similar to that of sham-operated rats.

Effects of ursodeoxycholate, its glucuronide and disulfate and β-muricholate on biliary bicarbonate concentration and biliary lipid excretion

We previously reported that high-dose ursodeoxycholate (UDC) infusion in rats resulted in extensive glucuronidation of UDC, and speculated that the glucuronidation causes bicarbonate-rich hypercholeresis induced by UDC (Takikawa, H., Sano, N., Narita, T. and Yamanaka, M. Hepatology 1990; 11: 743–749). To test this hypothesis, UDC, UDC-3- O-glucuronide, UDC-3,7-disulfate and β-muricholate were separately and intravenously infused into rats (1 μmol/min per 100 g), and biliary bicarbonate concentration was measured. The effects of these bile acids on biliary lipid secretion were also studied. All four bile acids increased bile flow and biliary bile acid excretion. UDC and β-muricholate significantly increased biliary bicarbonate concentration, whereas UDC glucuronide and disulfate did not. Independence of UDC glucuronide excretion and biliary bicarbonate concentration was also confirmed in EHBR, a hyperbilirubinemic mutant Sprague-Dawiey rat. In this case biliary bicarbonate concentration also increased in spite of the absence of UDC glucuronide in the bile after UDC infusion. Biliary phospholipid secretion was increased with UDC, unchanged with β-muricholate, and decreased with UDC glucuronide and disulfate. Biliary cholesterol secretion was increased with UDC, unchanged with β-muricholate and UDC glucuronide, and decreased with UDC disulfate. These data indicate that glucuronidation is not the cause of bicarbonate-rich hypercholeresis induced by UDC but that glucuronidation and sulfation change the effect of UDC on biliary lipid secretion.

Choleretic effect of andrographolide in rats and guinea pigs.

Andrographolide from the herb Andrographis paniculata (whole plant) per se produces a significant dose (1.5-12 mg/kg) dependent choleretic effect (4.8-73%) as evidenced by increase in bile flow, bile salt, and bile acids in conscious rats and anaesthetized guinea pigs. The paracetamol induced decrease in volume and contents of bile was prevented significantly by andrographolide pretreatment. It was found to be more potent than silymarin, a clinically used hepatoprotective agent.

Effect of complete sulfation of bile acids on bile formation: role of conjugation and number of sulfate groups.

The effect of complete sulfation of conjugated cholic, chenodeoxycholic and deoxycholic acids on bile formation was investigated in rats. The sulfated bile acids were infused intravenously in stepwise increasing doses (1, 2, 3 and 4 mumol/min/100 gm body wt) in rats after 90 min of bile acid pool depletion. The effects of these bile acids on bile flow, bile salt, biliary phospholipid and cholesterol secretion rates were determined. In addition, their choleretic activity and their effect on biliary lipid secretion were calculated. Appropriate controls infused with nonsulfated bile were also performed. The sulfated bile acids increased bile flow with increasing the infusion doses, and the maximum bile flow was significantly higher than nonsulfated bile acids. Although cholestasis was developed during the infusion of nonsulfated bile acids, no cholestatic effect was observed for sulfated bile acids. With the exception of cholic acid, sulfation significantly increased the bile acid secretory rate maximum. The sulfates of chenodeoxycholic and deoxycholic acids were further hydroxylated. The choleretic activities for all the sulfated bile acids were significantly higher than the nonsulfated bile acids. All the sulfated bile acids significantly reduced the biliary lipid secretion, and a significant correlation was found between the choleretic activity and the phospholipid-dependent bile acid secretion. The data also showed that infusion of sulfated taurine-conjugated bile acids produced higher bile flow and bile acid secretion rate and was less effective when biliary lipid secretion rates were reduced compared with glycine conjugates. It is concluded that sulfated conjugated bile acids may have a role in protection during cholestasis either by stimulation of bile flow or by reduction of biliary lipid secretion, thus protecting cell membranes from the detergent properties of high concentrations of nonsulfated bile acids.

Cell swelling increases bile flow and taurocholate excretion into bile in isolated perfused rat liver.

The effects of aniso-osmotically and amino-acid-induced cell-volume changes on bile flow and biliary taurocholate excretion were studied in isolated perfused rat liver. With taurocholate (100 microM) in the influent perfusate, hypo-osmotic exposure (225 mosmol/l) increased taurocholate excretion into bile and bile flow by 42 and 27% respectively, whereas inhibition by 32 and 47% respectively was observed after hyperosmotic (385 mosmol/l) exposure. The effects of aniso-moticity on taurocholate excretion into bile was observed throughout aniso-osmotic exposure, even after completion of volume-regulatory ion fluxes and were fully reversible upon re-exposure to normo-osmotic media. Hypo-osmotic cell swelling (225 mosmol/l) increased the Vmax. of taurocholate translocation from the sinusoidal compartment into bile about 2-fold. Also, cell swelling induced by glutamine and glycine stimulated both bile flow and biliary taurocholate excretion. There was a close relationship between the aniso-osmotically and amino-acid-induced change of cell volume and taurocholate excretion into bile. The data suggest that liver cell volume plays an important role in regulating bile-acid-dependent bile flow and biliary taurocholate excretion.

Concomitant stimulation by vasopressin of biliary and perfusate calcium fluxes in the perfused rat liver

Changes in perfusate Ca2+ (measured with a Ca(2+)-selective electrode) and changes in bile calcium (measured by atomic absorption spectroscopy) were continuously and simultaneously monitored after infusion of (a) vasopressin, (b) glucagon and (c) both vasopressin and glucagon together to the perfused rat liver. Also monitored were perfusate glucose and oxygen concentrations and bile flow. Vasopressin induces a sharp, transient, pulse of increased bile flow and increased bile calcium within 1 min of infusion, concomitant with rapid changes in perfusate Ca2+ fluxes, glucose output and oxygen uptake. This is immediately followed by a decrease in both bile flow and bile calcium for as long as the hormone is administered. Changes induced by glucagon are a relatively slow onset of perfusate Ca2+ efflux and oxygen uptake, but rapid glucose output, and a small but significant and transient decrease in bile flow and bile calcium which, despite the continued infusion of the hormone, spontaneously and rapidly returns to normality. However, the greatest responses are observed after co-administration of both hormones. Coincident with the augmented perfusate Ca2+ fluxes (influx) seen in earlier work, there occurs within 1 min of vasopressin infusion a sharp increase in bile secretion and bile calcium greater in magnitude than that produced by vasopressin alone. Immediately thereafter bile secretion and bile calcium decline below basal values and remain there for as long as the hormones are administered. Glucagon and vasopressin therefore each have opposing effects on bile flow and bile calcium. However, the action of vasopressin is enhanced by the prior administration of glucagon. The data thus reveal features about the actions of glucagon and Ca(2+)-mobilizing hormones on bile flow and bile calcium not previously recorded and provide a novel framework around which the whole issue of hepato-biliary Ca2+ homoeostasis can be assessed in normal and diseased liver.

Effects of Bile Salt Infusion on Chlorpromazine-lnduced Cholestasis in the Isolated Perfused Rat Liver

The present study has demonstrated that tauroursodeoxycholate (TUDC), but not taurocholate, can reverse chlorpromazine (CPZ)-induced cholestasis in the isolated perfused rat liver. At an infusion rate of 1.5 mumol/min, TUDC led to restoration of bile flow in the perfused rat liver made cholestatic by the addition of 250 microM CPZ. This reversal was accompanied by an increased excretion of CPZ and its metabolites. A higher infusion rate of 5.0 mumols TUDC/min, however, led to only a transient increase in bile flow and to no increase in CPZ excretion. In contrast to the effects of TUDC, infusion of taurocholate led to an exacerbation of CPZ-induced cholestasis. The differences in the efficacy of the two bile salts may be due to their relative detergent (hydrophobic) properties.

Contribution of the biliary pathway to the homeostasis of vitamin D3 and of 1,25-dihydroxyvitamin D3.

The role of the biliary pathway in the homeostasis of the vitamin D3 (D3) group of compounds is poorly understood. The purpose of the studies was to investigate the biliary excretion pattern of materials derived from the parent compound D3 and from the hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) during constant iv infusion, and to probe the influence of 1,25(OH)2D3 pretreatment on the excretion into the bile of D3-derived materials. Under anesthesia, the bile duct, duodenum (for bile replacement), and jugular veins were cannulated. The experiments were then carried out in fully awake rats with access to food and water ad libitum during a period of 6 h. Data indicate that before steady state was reached, biliary excretion of 1,25(OH)2[3H]D3 was much more important than that of [14C]D3 with bile/plasma concentration ratios above 1 in 1,25(OH)2[3H]D3-infused animals from the 15th-60th min of infusion compared to ratios between 0.12-0.40 in [14C]D3-infused rats (P less than 0.0001); this led to a cumulative excretion 6.3-fold higher after 1,25(OH)2[3H]D3 than after [14C]D3 administration, with 3.9 +/- 0.4% and 0.6 +/- 0.1% of the dose being recovered into the bile during the first hour of excretion. However, once stable plasma concentrations were reached, the rate of excretion of the two compounds became similar, with bile/plasma concentration ratios of 0.64 +/- 0.02 and 0.70 +/- 0.02 (P greater than 0.05), and plasma bile clearance of 26.4 +/- 1.0 and 25.7 +/- 1.7 microliters/min.kg for 1,25(OH)2[3H]D3 and [14C]D3, respectively (P greater than 0.05). During that period, the MCR of 1,25(OH)2D3 was estimated to be 118.3 +/- 10.5 microliters/min.kg. On the other hand, 1,25(OH)2D3 pretreatment as constant ip infusion (14 pmol/24 h for 6 days) significantly increased bile flow [1,25(OH)2D3 treated, 44.9 +/- 1.6 microliters/min.kg; untreated, 36.6 +/- 0.5 microliters/min.kg, P less than 0.01)], leading to significant increases in the plasma bile clearance of [14C]D3-derived compounds early in the course of the study (P less than 0.004) in the presence of similar bile/plasma concentration ratios in the two groups. During the steady state phase of investigation, however, bile/plasma concentration ratios became lower in 1,25(OH)2D3-than in placebo-treated animals (P less than 0.05), but due to the 1,25(OH)2D3-mediated increase in bile flow, similar plasma bile clearances were observed in both groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Hepatic disposition of organic anions in rats infested with Fasciola hepatica

This study was undertaken to investigate the effects of subclinical fascioliasis at various stages of its development (3, 6, and 11 weeks after infestation with an oral dose of 20 metacercariae of Fasciola hepatica) on the hepatobiliary transport of organic anions in rats. Basal bile acid secretion was not significantly modified in infested rats as compared to the controls but there was a significantly increased bile flow in the 11-week group. In all infested rats, maximal biliary excretion and cumulative excretion of bromosulphthalein was significantly reduced, although there was a tendence to recovery in the 11-week infested group. Decreased biliary secretion was accompanied by increased plasma and liver concentrations of bromosulphthalein. Glutathione S-transferase activity was significantly reduced by Weeks 3 and 6 postinfestation. Liver glutathione concentration was significantly reduced in all infested rats. Maximal excretion of dibromosulphthalein, a compound not biotransformed in the liver, fell by Week 6 postinfestation and recovered a normal value thereafter. These results indicate that effects of experimentally induced fascioliasis on hepatic disposition of organic anions depend upon the stage of its development and that are a consequence of both metabolism and transport related factors.

Effect of cyclosporine and steroids on canine bile flow

Cyclosporine and hydrocortisone are the main immunosuppressants used in transplant surgery. The purpose of this study was to determine the effect of intravenous administration of cyclosporine and hydrocortisone on bile flow in dogs. Cyclosporine in doses of 0.5, 1.0 and 1.5 mg.kg-1.hr-1 were administered along with 18 mumol/min intravenous sodium taurocholate to dogs with chronic biliary and gastric fistulas. Bile volume and bile chloride concentration and output were increased by cyclosporine in a dose-related manner, whereas bile salt concentration decreased and bile salt output was unchanged. Hydrocortisone produced small but significant increases in bile flow only at the highest dose of hydrocortisone administered. Subsequently, experiments were performed when sodium taurocholate was administered in progressively increasing doses (9, 18 and 36 mumol/min), with the dose changed every hour. Bile volume, [14C]erythritol clearance in bile and bile salt concentrations were measured with and without cyclosporine and hydrocortisone administration. Cyclosporine increased the bile salt-independent fraction of canalicular bile flow and ductular bile flow. Experiments evaluating the role of the cyclosporine carrier polyoxyethylated castor oil (Cremophor EL) demonstrated that this substance had no independent choleretic activity, whereas cyclosporine dissolved in ethanol and administered without Cremophor EL significantly increased bile flow. The results of this study indicate that cyclosporine stimulates chloride-rich choleresis independent of bile salt secretion.

Effect of cyclosporine and steroids on canine bile flow

Cyclosporine and hydrocortisone are the main immunosuppressants used in transplant surgery. The purpose of this study was to determine the effect of intravenous administration of cyclosporine and hydrocortisone on bile flow in dogs. Cyclosporine in doses of 0.5, 1.0 and 1.5 mg · kg−1 · hr−1 and hydrocortisone in doses of 1.25, 2.5 and 5 mg · kg−1 · hr−1 were administered along with 18 μmol/min intravenous sodium taurocholate to dogs with chronic biliary and gastric fistulas. Bile volume and bile chloride concentration and output were increased by cyclosporine in a dose-related manner, whereas bile salt concentration decreased and bile salt output was unchanged. Hydrocortisone produced small but significant increases in bile flow only at the highest dose of hydrocortisone administered. Subsequently, experiments were performed when sodium taurocholate was administered in progressively increasing doses (9, 18 and 36 μmol/min), with the dose changed every hour. Bile volume, [14C]erythritol clearance in bile and bile salt concentrations were measured with and without cyclosporine and hydrocortisone administration. Cyclosporine increased the bile salt-independent fraction of canalicular bile flow and ductular bile flow. Experiments evaluating the role of the cyclosporine carrier polyoxyethylated castor oil (Cremophor EL) demonstrated that this substance had no independent choleretic activity, whereas cyclosporine dissolved in ethanol and administered without Cremophor EL significantly increased bile flow. The results of this study indicate that cyclosporine stimulates chloride-rich choleresis independent of bile salt secretion.

Biliary excretion of bile acid conjugates in a hyperbilirubinemic mutant sprague-dawley rat

The hepatic transport of bile acid conjugates was studied in the Eisai hyperbilirubinuria rat, a Sprague-Dawley mutant rat with conjugated hyperbilirubinemia. Serum bile acid levels were increased, bile acid-independent bile flow was decreased and biliary glutathione concentrations were markedly decreased in the Eisai hyperbilirubinuria rat. Biliary excretion of sulfobromophthalein was markedly impaired and almost no glutathione conjugate was excreted in the bile of the Eisai hyperbilirubinuria rat. Biliary excretion of lithocholate-3-O-glucuronide and lithocholate-3-sulfate in the Eisai hyperbilirubinuria rat was markedly delayed, whereas that of lithocholate was only slightly delayed. After [14C]chenodeoxycholate infusion (1 mumol/min/100 gm for 60 min), the increases in bile flow and biliary excretion of isotope in the Eisai hyperbilirubinuria rat were not so prominent as those observed in control rats, and the glucuronide of chenodeoxycholate, which constituted about 15% of biliary chenodeoxycholate in control rats, was not observed in the Eisai hyperbilirubinuria rat. Initial uptake of lithocholate and its glucuronide and sulfate by isolated hepatocytes was not impaired in the Eisai hyperbilirubinuria rat; the profiles of cytosolic bile acid binding proteins in Eisai hyperbilirubinuria rat liver were identical to those in control liver. These data indicate that the Eisai hyperbilirubinuria rat has excretory impairment of organic anions, bile acid glucuronide and sulfate and that it has characteristics very similar to those of the hyperbilirubinemic mutant Wistar rats TR- and GY.

Choleretic action of andrographolide obtained from Andrographis paniculata in rats

AbstractAndrographolide, a diterpene, isolated from Andrographis paniculata exhibited a strong choleratic action when administered intraperitoneally (i.p.) to albino rats. This substance induced an increase in bile flow together with a change in the physical properties of the bile secretion.

Biliary secretion of trace elements and minerals in the rat: Effects of bile flow variation and diurnal rhythms

Effects of bile flow variations on bile secretion of trace elements were systematically evaluated by Proton-Induced X-ray Emission (PIXE) in the unanesthetized rat: (i) longitudinally for a 9 day-period of bile drainage, (ii) continuously for a period of 24 h, to include circadian rhythm and (iii) during exogenous bile salt administration. Potassium and Ca were determined for comparative purposes. In rat bile, six trace elements could always be detected by PIXE (Fe, Zn, Cu, Mo, Mn, Br); occasionally some V, Cr, Sr and Pb was found. Se could not be detected in bile. Bile-plasma concentration ratios of the elements could arbitrarily be divided into three groups: Fe, Zn and Se < 1; Ca, K, Cu, Mo and Br approx. 1 and Mn ⪢1. After interruption of the enterohepatic circulation, bile flow and bile salt concentration dropped sharply within 4 h to 36% and 4% of their initial values, respectively. Output rates of K, Ca, Mo, Br, Zn and Fe closely followed the decrease in bile flow; bile secretion of Mn and Cu, on the other hand, was minimally affected. A circadian rhythm was observed for all detectable elements; during the night period, secretion rates of Zn, Fe, Ca and K increased maximally by 60–80% and that of Mn, Mo, Br and Cu by 30–50%. Bile salt output and bile flow increased maximally by 70% and 50%, respectively, in the same time interval. Infusion (106 μmol/h) of taurocholate (TC), a micelle forming bile salt or dehydrocholate (DHC), a non-micellar bile salt, caused a maximal increase in bile flow by 67% and 93%, respectively. Under these conditions, biliary secretion of K, Ca, Mo, Br and Fe were stimulated by both types of bile salts, almost to a similar extent as bile flow. In contrast, the secretion of Zn, Cu and Mn was not affected or even reduced. This study shows that most detectable endogenous trace elements show a strong bile flow-dependency in their biliary secretion, except Zn, Cu and Mn. The elimination of Cu and Mn via bile, which represents the main route for their removal from the body, is largely independent of acute changes in bile flow, but does show a marked circadian rhythm.

Mirex inhibits bile acid secretory function in vivo and in the isolated perfused rat liver

The insecticides mirex and chlordecone suppress the biliary excretion of a wide variety of non-bile acid organic anions in vivo in the rat, and mirex inhibits the uptake of taurocholate (TC), a common bile acid, in isolated rat hepatocytes. We have therefore investigated the effects of mirex and chlordecone on bile acid secretory function (bile flow, bile acid concentration, bile acid secretory rate) in vivo and in the single-pass isolated perfused liver. Male Sprague-Dawley rats were orally dosed with corn oil, mirex (50 mg/kg), or chlordecone (18.75 mg/kg; in vivo studies only) for 3 consecutive days and experiments performed on Day 6. Mirex significantly increased liver weight from 12.2 ± 0.8 to 20.8 ± 1.3 g with no change in body weight whereas chlordecone had no significant effect on liver weight (11.9 ± 0.7 g) or body weight. Mirex significantly decreased while chlordecone increased bile flow per gram liver in vivo; both compounds, however, increased bile flow when expressed per kilogram of body weight. Mirex and chlordecone significantly decreased the bile acid concentration in bile and the bile acid secretory rate (nmol/min/g liver and μmol/min/kg body weight). Studies in the isolated perfused liver were designed to determine the effect of mirex on the ability of the liver to extract increasing concentrations of [ 3H]TC from the perfusate and excrete it in the bile. Mirex treatment significantly decreased the TC extraction ratio by 40–89% and the hepatic intrinsic clearance by 85–95%. Mirex also significantly decreased the TC-induced choleresis, the concentration of TC in the bile, and the TC secretory rate. The data indicate that mirex treatment markedly inhibits the ability of the liver to extract TC from the blood/perfusate and concentrate it in the bile.