Effect of tritoqualine (TRQ) on bile secretion in rats

An accelerating effect by TRQ-consecutive administration perorally on bile secretion in rats was investigated in comparison with phenobarbital (PB)-administered rats. The bile secretion velocity was increased significantly by administration of TRQ (25, 50, 100 mg/kg/day) or PB (50 mg/kg/day) compared to the control group. A 24% increase in the ratio of the liver weight to body weight was observed in the PB-administered group, but in the TRQ-administered group, a slight increase (5%) was seen compared with the control group. The concentration of excreted bile acid in the bile of rats to which TRQ and PB were administered were lower than that of the control group. However, when excreted bile acid content was represented in terms of wet liver weight, no difference was seen in the TRQ-administered group, but a 17% decrease was observed in the PB-administered group compared with the control group; and also, almost the same results were obtained with regards to the cholesterol and phospholipid in the bile. Though there was no difference of Na+, K+, or Cl- concentration in bile between the TRQ or PB-administered group and the control group, more Na+, K+ or Cl-/g wet liver was excreted in TRQ-treated group than the PB-administered group. TRQ was excreted through the bile duct promptly after an i.v. injection without an increase in the bile secretion, suggesting that the excretion of TRQ and its metabolites were not accompanied by the increase in bile secretion. These results indicate that the accelerating effect of TRQ on bile secretion was presumably derived from bile acid non-dependent bile secretion such as PB; however, a different pharmacological mechanism between TRQ and PB was presumed from the discrepancy of the decomposition in the secreted bile and of drug-metabolizing enzyme induction. Thus, it was suggested that there was a possibility that the accelerating action of bile secretion by TRQ was attributed to the activating effect of TRQ on the hepatocytes.     

Effect of cysteamine on bile secretion in the rat

The effect of cysteamine, a specific somatostatin depletor, on biliary secretion was studied in urethane-anesthetized rats. Different groups of rats received ip cysteamine at 25, 100 or 340 mg/kg just before bile collection commenced. Other groups of rats were pretreated with cysteamine (340 mg/kg ip) at 4 or 24 h prior to bile duct cannulation and bile collection. Bile secretions were collected at 30-min intervals for 4 h after bile duct cannulation. Total proteins, cholesterol, total lipids, glucose and several hepatic enzymes were assessed in bile. Results indicated that basal bile secretion was only slightly reduced and tended to decrease after drug administration (13% decrease after 340 mg/kg). Cysteamine induced dose-dependent decrease in protein secretion, and the maximum effect was reached at a dose of 340 mg/kg. The effect of cysteamine on protein secretion was prolonged, since it was still observed 24 h after the treatment with cysteamine. Cholesterol and lipid secretion was inhibited by 52.5 and 42.5%, respectively, by the drug, with the latter effect being evident 24 h after drug administration. In addition, the drug inhibited biliary glucose and aspartate aminotransferase concentrations, but increased that of alkaline phosphatase. The results suggest that acute administration of cysteamine inhibits protein, cholesterol and lipid secretion into bile.     

Effect of capsaicin on bile secretion in the rat

Capsaicin is a popular food ingredient. This study aimed to determine if capsaicin can affect bile flow and bile protein secretion, and the extent to which capsaicin can reach bile in the rat. The effect of capsaicin was studied in anesthetized rats equipped with cannulas inserted into the common bile duct. Capsaicin was administered by intragastric, intraduodenal (4-400 microg/ml; 10-1,000 microg/kg), intravenous (10 microg/kg) routes or applied on the serosal surface of the duodenum at 4 microg/ml. The administration of capsaicin decreased bile flow in comparison to the corresponding basal values, the maximum effect being reached at a concentration of 400 microg/ml of intragastric capsaicin (30.2%; p < 0.01), and 40 microg/ml (30.8%; p < 0.01) of intraduodenal capsaicin, 75 min after drug administration. Meanwhile, a decrease of 24.7 and 40% was observed 60 min after serosal and intravenous capsaicin administration, respectively. Biliary protein secretion was also reduced following capsaicin administration. High-performance liquid chromatography (HPLC) analysis showed that capsaicin was readily excreted into bile, peak levels were reached 75 or 60 min following its intragastric or intraduodenal administration, respectively (range 100-248 and 144-698.6 ng/ml after intragastric or intraduodenal capsaicin at 4-400 microg/ml, respectively). Capsaicin concentrations of 86 and 75 ng/ml could be detected in bile 15 min after intravenous administration or serosal application of the agent, respectively. Results suggest that capsaicin is readily absorbed after its intragastric or intraduodenal administration and goes through hepatobiliary excretion. Results also indicate that administration of capsaicin reduces bile flow and biliary proteins in the rat.     

Effect of 4-hydroxyandrost-4-ene-3,17-dione (formestane) on the bile secretion and metabolism of 4-(14)C-cholesterol to bile acids

4-Hydroxyandrost-4-ene-3,17-dione (formestane) is a selective aromatase inhibitor. It is indicated for postmenopausal patients with advanced breast cancer. The aim of the present study was to investigate the effect of 4-hydroxyandrost-4-ene-3,17-dione on the bile secretion and metabolism of 4-(14)C-cholesterol to bile acid. The experiments were carried out in the ovariectomized and sham-operated female Wistar rats. Formestane (20 mg/kg, i.m., daily) was administered to animals for 2 weeks. Twenty four hours after the last drug administration, rats were anesthetized with ethyl urethane. 4-(14)C-cholesterol (740 kBq/kg, s.a. 2.28 GBq/mmol) was infused for 1 min by catheter inserted into the jugular vein. Bile samples were assayed for total 14C radioactivity 14C-bile acids were determined in bile (after thin-layer chromatographic separation) by the use of isotopic technique with liquid scintillator. Previous studies showed that systemic adverse effects occurred in about 12% of patients following intramuscular drug administration. Many of them such as hot flushes, vaginal spotting and emotional lability were related to the mechanism of action of formestane i.e. estrogen suppression. Lethargy, rash, nausea, dizziness, indigestion, ataxia, cramps and facial swelling have also been reported. The results of the present study have shown that formestane administered to the female ovariectomized rats decreased the bile secretion and diminished conversion of 4-(14)C-cholesterol to trihydroxy bile acids. The decreased synthesis of trihydroxy bile acids and increased concentrations of cholesterol and litocholic acid in bile may be associated with increased risk of gallstone formation.     

Effect of silymarin on biliary bile salt secretion in the rat

The effect of the hepatoprotector silymarin on bile secretion, with particular regard to bile salt secretion, was studied in Wistar rats. Silymarin (25, 50, 100, and 150 mg/kg/day, i.p., for 5 days) induced a dose-dependent increase in bile flow and bile salt secretion, the maximal effect being reached at a dose of 100 mg/kg/day (+17 and +49%, for bile flow and bile salt output, respectively; P < 0.05). Assessment of bile salt composition in bile revealed that stimulation of the bile salt secretion was accounted for mainly by an increase in the biliary secretion of beta-muricholate and, to a lesser extent, of alpha-muricholate, chenodeoxycholate, ursodeoxycholate, and deoxycholate. The maximum secretory rate (T(m)) of bile salts, as assessed by infusing the non-hepatotoxic bile salt tauroursodeoxycholate i.v. at stepwise-increasing rates, was not influenced by silymarin. The flavonolignan also increased the endogenous bile salt pool size (+53%, P < 0.05) and biliary bile acid excretion after bile acid pool depletion (+54%, P < 0.05), a measure of de novo bile salt synthesis. These results suggest that silymarin increases the biliary excretion and the endogenous pool of bile salts by stimulating the synthesis, among others, of hepatoprotective bile salts, such as beta-muricholate and ursodeoxycholate.     

Effect of epomediol on ethinyloestradiol-induced changes in bile acid and cholesterol metabolism in rats

1. Epomediol is a terpenoid compound that has been reported to stimulate bile acid synthesis and to reverse 17alpha- ethinyloestradiol-induced cholestasis. The aim of the present study was to investigate the contribution of changes in bile acid and cholesterol metabolism to the protective effects of epomediol in ethinyloestradiol-treated rats. Animals received epomediol for 5 days at 100 mg/kg daily, i.p., ethinyloestradiol for 5 days at 5 mg/kg, s.c., or a combination of both drugs. 2. When compared with control animals, epomediol treatment resulted in a significant increase in bile flow (+42%) and in the secretion of bile acids (+74%) and cholesterol (+42%). Ethinyloestradiol administration caused a significant decrease in bile flow (-43%), bile acid secretion (-37%) and cholesterol secretion (-45%). Bile flow, bile acid secretion and cholesterol secretion were significantly increased in animals receiving ethinyloestradiol plus epomediol compared with ethinyloestradiol-treated rats (+13, +29 and +31%, respectively). 3. Both cholesterol 7alpha-hydroxylase and hydroxy-3- methylglutaryl coenzyme A reductase activities were significantly increased in epomediol-treated rats (+30 and +96%, respectively). Cholesterol 7alpha-hydroxylase activity was significantly reduced by ethinyloestradiol (-22%) and did not differ from control values in animals receiving epomediol plus ethinyloestradiol. Levels of cholesterol 7alpha-hydroxylase mRNA were elevated (+41%) by epomediol, but were not significantly modified by ethinyloestradiol or ethinyloestradiol plus epomediol. 4. It is concluded that epomediol enhances bile acid secretion by increasing the expression of cholesterol 7alpha-hydroxylase. Changes in bile acid metabolism contribute to the effects of epomediol in rats with ethinyloestradiol-induced cholestasis.     

Effect of Larrea divaricata Cav. extract and nordihydroguaiaretic acid upon peroxidase secretion in rat submandibulary glands.

Free radicals are involved in several diseases, including cancer, central nervous system alterations and inflammatory pathologies. Peroxidase is an oral enzyme implicated in the defence of oral cavity. It has been determined that flavonoids and lignans possess antioxidant and free radical scavenging either directly or indirectly, usually by means of increasing the secretion of free radicals scavenger enzymes. Larrea divaricata Cav. is a plant used in folk Argentine medicine for the treatment of cancer and inflammatory ailments. In this study, we have determined the effect and mechanism of action of an aqueous extract of the leaves of L. divaricata and NDGA on peroxidase secretion in female rat submandibular glands. The extract significantly increased the secretion and total peroxidase. % of secreted peroxidase (X +/- S.E.M.): extract maximum response: 150 +/- 10; % of total peroxidase (X +/- S.E.M.): extract maximum response: 1000 +/- 90. The effect of the extract on peroxidase secretion was mediated by beta1 adrenoceptors (% of secreted peroxidase: extract + atenol maximum response: 50 +/- 4 ). Meanwhile, NDGA produced a decrease in peroxidase secretion (peroxidase secreted: basal: 0.44 +/- 0.03; NDGA 2.5 x 10(-6) M: 0.20 +/- 0.02; prostaglandins E2 (PGE2) 10(-7)M: 1.32 +/- 0.5; NDGA + PGE2: 0.46 +/- 0.035), an effect that was exerted by the inhibition on prostaglandins synthesis.     

茴三硫对胆道梗阻术后患者胆汁分泌及肝功能的影响

目的：观察胆道梗阻患者外科引流术后服用茴三硫（胆维他）对胆汁分泌和肝功能的影响。方法：随机选择胆道梗阻行外流术后患者30例，在术后d3起口服茴三硫25mg,tid，共服10d。分别在服药前2d，服药后d3,d6,d9测定当日胆汁引流量及肝功能情况，并观察不良反应。设立对照组进行比较。结果：观察组患者胆汁分泌和肝功能的恢复。     

Effect of SMP-500, a novel acyl-CoA:cholesterol acyltransferase inhibitor,on serum cholesterol level and LDL cholesterol clearance in hamsters with induced hyperlipidemia

The effect of SMP-500, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on serum cholesterol levels was investigated in hyperlipidemic hamsters whose condition had been preestablished by diet. SMP-500 reduced the total serum cholesterol level in a dose-dependent manner. SMP-500 also reduced the hepatic free cholesterol content and markedly reduced the esterified cholesterol content compared with the control group. Interestingly, SMP-500 at a dose of 30 mg/kg increased LDL clearance in vivo. As SMP-500 at this dose potently lowered the total serum cholesterol level, the increased LDL clearance was identified as another mechanism for the cholesterol-lowering effect of SMP-500. However, unlike HMG CoA reductase inhibitors, SMP-500 did not affect cholesterol biosynthesis in HepG2 cells. Therefore the etiology of the increased LDL clearance is not yet clear, but the reduced hepatic free cholesterol may play an important role in this process. These results suggest that the cholesterol-lowering effect of SMP-500 is due, not only to the inhibition of ACAT, but also to the increase in cholesterol clearance from the blood. This finding supports the therapeutic potential of SMP-500 for the treatment of human hypercholesterolemia.