Xiao-Chai-Hu-Tang (XCHT) Intervening Irinotecan's Disposition: The Potential of XCHT in Alleviating Irinotecan-Induced Diarrhea.

BACKGROUND: Diarrhea is a severe side effect of irinotecan, a pro-drug of SN-38 used for the treatment of many types of cancers. Pre-clinical and clinical studies showed that decreasing the colonic exposure of SN-38 can mitigate irinotecan-induced diarrhea. OBJECTIVE: The purpose of this study is to evaluate the anti-diarrhea potential of Xiao-Chai-Hu-Tang (XCHT), a traditional Chinese herbal formula, against irinotecan-induced diarrhea by determining if and how XCHT alters the disposition of SN-38. METHODS: LC-MS/MS was used to quantify the concentrations of irinotecan and its major metabolites (i.e., SN-38, SN-38G). An Intestinal perfusion model was used to determine the effect of XCHT on the biliary and intestinal secretions of irinotecan, SN-38, and SN-38G. Pharmacokinetic (PK) studies were performed to determine the impact of XCHT on the blood and fecal concentrations of irinotecan, SN-38, and SN-38G. RESULTS: The results showed that XCHT significantly inhibits both biliary and intestinal excretions of irinotecan, SN-38, and SN-38G (range: 35% to 95%). PK studies revealed that the fecal concentrations of irinotecan and SN-38 were significantly decreased from 818.35 ± 120.2 to 411.74 ± 138.83 µg/g or from 423.95 ± 76.44 to 245.63 ± 56.72 µg/g (p<0.05) by XCHT, respectively, suggesting the colonic exposure of SN-38 is significantly decreased by XCHT. PK studies also showed that the plasma concentrations of irinotecan, SN-38, and SN-38G were not affected by XCHT. CONCLUSION: In conclusion, XCHT significantly decreased the exposure of SN-38 in the gut without affecting its plasma level, thereby possessing the potential of alleviating irinotecan-induced diarrhea without negatively impacting its therapeutic efficacy.

Curcumin in Hepatobiliary Disease: Pharmacotherapeutic Properties and Emerging Potential Clinical Applications.

Curcumin, an aromatic phytoextract from the turmeric (Curcuma longa) rhizome, has been used for centuries for a variety of purposes, not the least of which is medicinal. A growing body of evidence suggests that curcumin has a broad range of potentially therapeutic pharmacological properties, including anti-inflammatory, anti-fibrotic, and anti-neoplastic effects, among others. Clinical applications of curcumin have been hampered by quality control concerns and limited oral bioavailability, although novel formulations appear to have largely overcome these issues. Recent in vitro and in vivo studies have found that curcumin's cytoprotective and other biological activities may play a role in an array of benign and malignant hepatobiliary conditions, including but not limited to non-alcoholic fatty liver disease, cholestatic liver disease (e.g. primary sclerosing cholangitis), and cholangiocarcinoma. Here we provide an overview of fundamental principles, recent discoveries, and potential clinical hepatobiliary applications of this pleiotropic phytocompound.

Huang Qi Decoction Prevents BDL-Induced Liver Fibrosis Through Inhibition of Notch Signaling Activation.

Notch signaling has been demonstrated to be involved in ductular reactions and fibrosis. Previous studies have shown that Huang Qi Decoction (HQD) can prevent the progression of cholestatic liver fibrosis (CLF). However, whether HQD affects the Notch signaling pathway is unclear. In this study, CLF was established by common bile duct ligation (BDL) in rats. At the end of the first week, the rats were randomly divided into a model group (i.e., BDL), an HQD group, and a sorafenib positive control group (SORA) and were treated for 3 weeks. Bile duct proliferation and liver fibrosis were determined by tissue staining. Activation of the Notch signaling pathway was evaluated by analyzing expressions of Notch-1, -2, -3, and -4, Jagged (JAG) 1, and Delta like (DLL)-1, -3, and -4. The results showed that HQD significantly reduced the deposition of collagen and the Hyp content of liver tissue and inhibited the activation of HSCs compared with the BDL group. In addition, HQD significantly decreased the protein and mRNA expressions of TGF-[Formula: see text]1 and [Formula: see text]-SMA. In contrast, HQD significantly enhanced expression of the Smad 7 protein. HQD also reduced biliary epithelial cell proliferation, and reduced the mRNA levels of CK7, CK8, CK18, SRY-related high mobility group-box gene (SOX) 9, epithelial cell adhesion molecule (EpCAM) and the positive areas of CK19 and OV6. In addition, the mRNA and protein expressions of Notch-3, -4, JAG1, and DLL-1, -3 were significantly reduced in the HQD compared to the BDL group. These results demonstrated that HQD may prevent biliary liver fibrosis through inhibition of the Notch signaling pathway, and it may be a potential treatment for cholestatic liver disease.

Antioxidant Effect of Ukrain Versus N-Acetylcysteine Against Acute Biliary Pancreatitis in An Experimental Rat Model.

Purpose/Aim: Oxidative stress plays an important role in the pathogenesis of acute pancreatitis (AP). We compared the therapeutic effects of Ukrain (NSC 631570) and N-acetylcysteine (NAC) in rats with AP. MATERIALS AND METHODS: Forty male Sprague Dawley rats were divided into four groups: controls; AP; AP with NAC; and AP with Ukrain. AP was induced via the ligation of the bile-pancreatic duct; drugs were administered intraperitoneally (i.p.) 30 min and 12 h after AP induction. Twenty-four hours after AP induction, animals were sacrificed and the pancreas was excised. Levels of malondialdehyde (MDA) and nitric oxide (NO), and activity levels of tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO) were measured in tissue samples. Total oxidant status (TOS), total antioxidant status (TAS), and total bilirubin, as well as activity levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase and lipase were measured in serum samples. Pancreatic tissue histopathology was also evaluated. RESULTS: Test drugs reduced levels of MDA, NO, TNF-α, total bilirubin, AST, ALT, TOS and MPO, amylase and lipase activities (P < 0.001), and increased TAS (P < 0.001). Rats treated with test drugs attenuated AP-induced morphologic changes and decreased pancreatic damage scores compared with the AP group (P < 0.05). Both test drugs attenuated pancreatic damage, but the therapeutic effect was more pronounced in rats that received Ukrain than in those receiving NAC. CONCLUSIONS: These results suggest that treatment with Ukrain or NAC can reduce pancreatic damage via anti-inflammatory and antioxidant effects.

Characterization of acute biliary hyperplasia in Fisher 344 rats administered the indole-3-carbinol analog, NSC-743380.

NSC-743380 (1-[(3-chlorophenyl)-methyl]-1H-indole-3-carbinol) is in early stages of development as an anticancer agent. Two metabolites reflect sequential conversion of the carbinol functionality to a carboxaldehyde and the major metabolite, 1-[(3-chlorophenyl)-methyl]-1H-indole-3-carboxylic acid. In an exploratory toxicity study in rats, NSC-743380 induced elevations in liver-associated serum enzymes and biliary hyperplasia. Biliary hyperplasia was observed 2 days after dosing orally for 2 consecutive days at 100mg/kg/day. Notably, hepatotoxicity and biliary hyperplasia were observed after oral administration of the parent compound, but not when major metabolites were administered. The toxicities of a structurally similar but pharmacologically inactive molecule and a structurally diverse molecule with a similar efficacy profile in killing cancer cells in vitro were compared to NSC-743380 to explore scaffold versus target-mediated toxicity. Following two oral doses of 100mg/kg/day given once daily on two consecutive days, the structurally unrelated active compound produced hepatic toxicity similar to NSC-743380. The structurally similar inactive compound did not, but, lower exposures were achieved. The weight of evidence implies that the hepatotoxicity associated with NSC-743380 is related to the anticancer activity of the parent molecule. Furthermore, because biliary hyperplasia represents an unmanageable and non-monitorable adverse effect in clinical settings, this model may provide an opportunity for investigators to use a short-duration study design to explore biomarkers of biliary hyperplasia.

The therapeutic activity of sulphate-bicarbonate-calcium-magnesiac mineral water in the functional disorders of the biliary tract.

BACKGROUND AND AIM: Functional disorders of the biliary tract involve gallbladder and sphincter of Oddi and cause pain and/or digestive troubles. In this context, in addition to pharmacological treatments, an important role is played by the use of sodium-sulphate and sulphate-bicarbonate mineral waters that, because of their composition into ions macro and trace elements, can stimulate the release or modulate the activity of some neurohumoral regulators of the digestive process. We want to do a study on the effects of hydropinotherapy with a sulphate-bicarbonate-calcium-magnesium mineral water in patients suffering from pain and other symptoms caused by biliary dyskinesias, biliary sand (without gallstones), or following a cholecystectomy (post-cholecystectomy syndromes). MATERIALS AND METHODS: We enrolled 43 patients suffering from those affections; all the patients did two cycles in one year of hydropinotherapy with Acqua Santa at Italy's Chianciano Spa; 20 of these patients did a third cycle of hydropinotherapy in the second year of the study. At the end of the second and of the third cycle we compared the frequency of eleven main symptoms in both groups and we also performed an longitudinal-observational study on the frequency of those symptoms before the beginning of the first cycle of the therapy and at the end of the second and of the third cycle. Statistical analyses were based on the use of Pearson's χ2 test. RESULTS: The frequency of the symptoms observed at the end of second and third cicle of hydropinotherapy was significantly lower than that considered before starting therapy. The differences were statistically significant. CONCLUSIONS: The results of our research regarding the hydropinotherapy by sulphate-bicarbonate-calcium-magnesium mineral water show a significant improvement of symptoms in patients suffering from disturbances of biliary tract.

Copper metabolism and pediatric cholestasis.

PURPOSE OF REVIEW: Copper is an essential trace mineral but both deficiency and toxicity need to be avoided. Copper is regulated via excretion by the biliary system and caution was recommended when administered in patients with cholestasis. Recent clinical reports indicate that despite the cholestasis, copper should not be withheld from parenteral nutrition. RECENT FINDINGS: Transporters involved in regulating copper levels have been identified. This explains the processes that regulate copper levels and the diseases that result from transporter defects. Monitoring copper ideally requires a liver biopsy but there are reports that in infants serum copper levels correlate with the liver copper. The published cautions about copper in cholestatic patients on parenteral nutrition led to the removal of copper from the solutions. Subsequently, multiple reports of clinical copper deficiency developing in these patients including infants were published. Newer literature indicates no elevation in infant copper levels despite normal copper parenteral nutrition supplementation in the presence of cholestasis. SUMMARY: Copper is essential and levels are regulated in response to an individual's needs. The liver excretion of copper is the primary regulating method but clinically cholestasis does not result in elevated levels in infants. The best clinical approach to parenteral nutrition copper is careful monitoring even in the presence of cholestasis.

Evaluation of Lysimachia christinae Hance extracts as anticholecystitis and cholagogic agents in animals.

ETHNOPHARMACOLOGICAL RELEVANCE: Lysimachia christinae Hance is one of the herbs commonly used in traditional Chinese medicine for the treatment of cholecystitis and cholagogic efficiency. AIMS OF THE STUDY: The water extract of Lysimachia christinae Hance was investigated to see if it possesses cholecystitis and cholagogic effects through traditional pathways. MATERIALS AND METHODS: Lithocholic acid (LCA) and Escherichia coli were used to induce cholecystitis in adult guinea pigs. The present study evaluated the cholagogic effects of LCHE treatment on bile secretion and bile emptying in Sprague-Dawley rats and male Kunming mice. RESULTS: The results showed that LCHE not only produced excellent anticholecystitis effects but also improved lesion severity in gallbladders induced by LCA. Similarly, LCHE administered to animals in the high-dose group exhibited an antibacterial effect in acute cholecystitis, and treatment with a mid-range or a high dose of LCHE resulted in an antipyretic effect, however, three doses of LCHE treatment groups had no effect on pathological change induced by Escherichia coli in gallbladder. Treatment with a high dose of LCHE significantly promoted bile secretion (0-90min, P<0.01), and treatment with a mid-range dose also significantly promoted bile secretion (30-60min P<0.05). Furthermore, treatment with a high dose of LCHE significantly promoted bile emptying (P<0.01). CONCLUSIONS: Our results demonstrate that LCHE exhibits a marked anticholecystitis and cholagogic activity in animals, which supports previous claims of its use in traditional Chinese medicine.

Toxicogenomics applied to cultures of human hepatocytes enabled an identification of novel petasites hybridus extracts for the treatment of migraine with improved hepatobiliary safety.

Butterbur extracts (Petasites hybridus) are recommended for the prevention of migraine, but pharmacovigilance reports may be suggestive of rare hepatobiliary toxicity. To evaluate its hepatotoxic potential, a series of in vivo and in vitro studies were carried out. Essentially, there were no signs of hepatocellular toxicity at estimated therapeutic C(max) levels of 60 ng/ml. Nonetheless, in a 28-day toxicity study at approximately 200-fold of therapeutic doses, induced liver transaminases and bilirubin elevations were observed. In a subsequent 6-month chronic toxicity study, the initial hepatobiliary effects were reproduced, but at the end of the study, liver function recovered and returned to normal as evidenced by clinical chemistry measurements. To identify possible mechanisms of hepatotoxicity, we investigated liver function in vitro at > 170-fold of therapeutic C(max) levels, including cytotoxicity (lactate dehydrogenase, MTT, and ATP), transaminase activities (alanine aminotransferase and aspartate aminotransferase), albumin synthesis, urea and testosterone metabolism to assay for cytochrome P450 monooxygenase activity. Only with extracts rich in petasin (37% petasin) and at high and well above therapeutic doses, liver toxicity was observed. A toxicogenomic approach applied to hepatocyte cultures enabled hypothesis generation and was highly suggestive for extracts high in petasin content to impair bile acid transport and lipid and protein metabolism. Importantly, neither chronic rat in vivo nor rat in vitro studies predicted reliably hepatotoxicity, therefore reemphasizing the utility of human-based in vitro investigations for the development of safe medicinal products. Finally, toxicogenomics enabled the characterization of a novel butterbur extract with no signals for hepatotoxicity.

Metabolism of echinacoside, a good antioxidant, in rats: isolation and identification of its biliary metabolites.

Echinacoside (ECH) is one of the major active phenylethanoid glycosides (PEGs) in famous traditional Chinese medicine, Herba Cistanches. Although it has various bioactivities, such as antioxidation, neuroprotection, and hepatoprotection, knowledge about its metabolic fate is scant. In the present study, eight phase II metabolites, 3,4 -O-dimethyl-ECH-3 -O-beta-d-glucuronide (M1); 4,4 -O-dimethyl-ECH-3 -O-beta-d-glucuronide (M2); 3,4 -O-dimethyl-ECH-4-O-sulfate ester (M3); 4,4 -O-dimethyl-ECH-3-O-sulfate ester (M4); 3,3 -O-dimethyl-ECH (M5); 3,4 -O-dimethyl-ECH (M6); 4,3 -O-dimethyl-ECH (M7); and 4,4 -O-dimethyl-ECH (M8), were isolated from rat bile sample after intravenous administration of ECH and identified by mass spectra and NMR spectroscopy, including (1)H NMR, (13)C NMR, nuclear Overhauser effect difference spectroscopy, and two-dimensional NMR (heteronuclear single quantum correlation, heteronuclear multiple-bond correlation spectroscopy, gradient-selected correlation spectroscopy, and nuclear Overhauser effect spectroscopy). Among them, M5 to M8 were O-di-methylated conjugates; M1 and M2 and M3 and M4 were O-dimethyl glucuronides and O-dimethyl sulfates, respectively. In the three types of metabolites of rat, the major metabolites were the methyl ethers and the glucuronides, whereas the sulfates were minor. The regioselectivity of conjugation for ECH and metabolic pathway of ECH were proposed, which gave insight into the mechanism of ECH for its bioactivities in vivo.

Natural heme oxygenase-1 inducers in hepatobiliary function.

Many physiological effects of natural antioxidants, their extracts or their major active components, have been reported in recent decades. Most of these compounds are characterized by a phenolic structure, similar to that of alpha-tocopherol, and present antioxidant properties that have been demonstrated both in vitro and in vivo. Polyphenols may increase the capacity of endogenous antioxidant defences and modulate the cellular redox state. Changes in the cellular redox state may have wide-ranging consequences for cellular growth and differentiation. The majority of in vitro and in vivo studies conducted so far have attributed the protective effect of bioactive polyphenols to their chemical reactivity toward free radicals and their capacity to prevent the oxidation of important intracellular components. However, in recent years a possible novel aspect in the mode of action of these compounds has been suggested; that is, the ultimate stimulation of the heme oxygenase-1 (HO-1) pathway is likely to account for the established and powerful antioxidant/anti-inflammatory properties of these polyphenols. The products of the HO-catalyzed reaction, particularly carbon monoxide (CO) and biliverdin/bilirubin have been shown to exert protective effects in several organs against oxidative and other noxious stimuli. In this context, it is interesting to note that induction of HO-1 expression by means of natural compounds contributes to protection against liver damage in various experimental models. The focus of this review is on the significance of targeted induction of HO-1 as a potential therapeutic strategy to protect the liver against various stressors in several pathological conditions.

Comparison of soybean oil- and olive oil-based lipid emulsions on hepatobiliary function and serum triacylglycerols level during realimentation.

This study compared the effects of soybean oil- versus olive oil-based lipid emulsions on hepatobiliary function and serum triacylglycerols in patients who required transient parenteral nutrition support for significant weight loss. Patients who received a parenteral ready-to-use industry admixture including either soybean oil- (n = 10) or olive oil-based lipid emulsion (n = 11) for 2 weeks were retrospectively analysed. Cholestatic and cytolytic enzymes, conjugated bilirubin and serum triacylglycerols were sampled before and 1 day after completing parenteral nutrition support. Significant deterioration of cholestatic enzymes occurred in five patients in the soybean oil group and in one in the olive oil group. Serum triacylglycerols significantly deteriorated in seven patients in the soybean oil group and in one patient in the olive oil group. No differences were recorded for cytolytic enzyme abnormalities. In conclusion, the olive oil-based emulsion induced abnormalities of cholestatic enzymes and serum triacylglycerols significantly less frequently than the soybean oil-based emulsion.

Acceleration of hepatobiliary excretion by lemon juice on 99mTc-tetrofosmin cardiac SPECT.

BACKGROUND: We sought to determine whether drinking lemon juice reduces extra-cardiac activity and improves image quality on (99m)Tc-tetrafosmin myocardial single photon emission computed tomography (SPECT). METHODS: Eighty male patients were enrolled in this study and divided into four groups with 20 patients in each group. Each patient received 259-333 MBq tetrofosmin. Ten minutes after injection no action was taken for group 1 (G1), patients in group 2 (G2) each drank 250 ml of water, patients in group 3 (G3) each drank 250 ml of whole milk, and patients in group 4 (G4) each drank 250 ml diluted lemon juice. Myocardial perfusion imaging without attenuation correction was performed after a 1 day rest-stress protocol. Both rest and stress images were aligned at corresponding slices for comparison. Interfering activity was determined visually on reconstructed images, and the heart-to-liver (H/L) ratios were calculated with planar images at 25-30 min and at 45-50 min. RESULTS: Interfering activity was seen in 80% of G1, 70% of G2, 60% of G3, and 35% of G4 (G4 vs. G1, P=0.006) on rest images, and in 70% of G1, 60% of G2, 55% of G3, and 30% of G4 (G4 vs. G1, P=0.014) on stress images at 25-30 min. It was also observed in 60% of G1, 50% of G2, 45% of G3, and 15% of G4 (G4 vs. G1, P=0.006) on rest images, and in 50% of G1, 45% of G2, 40% of G3, and 10% of G4 (G4 vs. G1, P=0.011) on stress images at 45-50 min. The mean H/L ratios of rest images were 0.47+/-0.13 for G1, 0.71+/-0.17 for G2, 0.65+/-0.12 for G3, and 0.93+/-0.23 for G4 at 25-30 min, and 0.63+/-0.14 for G1, 0.73+/-0.14 for G2, 0.85+/-0.25 for G3, and 1.15+/-0.25 for G4 at 45-50 min. On stress images, they were 0.49+/-0.11 for G1, 0.74+/-0.16 for G2, 0.69+/-0.11 for G3, and 0.98+/-0.22 for G4 at 25-30 min, and 0.66+/-0.15 for G1, 0.77+/-0.11 for G2, 0.89+/-0.26 for G3, and 1.21+/-0.19 for G4 at 45-50 min. CONCLUSION: Drinking 250 ml of diluted lemon juice accelerates the transit of tetrofosmin through the liver parenchyma and improves image quality on (99m)Tc-tetrafosmin myocardial SPECT.

Spray-dried milk supplemented with alpha-linolenic acid or eicosapentaenoic acid and docosahexaenoic acid decreases HMG Co A reductase activity and increases biliary secretion of lipids in rats.

In our earlier study, we have shown that rats fed spray-dried milk containing alpha-linolenic acid (LNA 18:3 n-3) or eicosapentaenoic acid (EPA 20:5 n-3) and docosahexaenoic acid (DHA 22:6 n-3) had significantly lower amounts of serum and liver cholesterol. To evaluate the mechanism for hypocholesterolemic effect of n-3 fatty acids containing milk formulation, we fed male Wistar rats with spray-dried milk containing linseed oil (LSO) (source of LNA) or fish oil (FO) (source of EPA+DHA) for 8 weeks. Feeding n-3 fatty acid containing milk formulation lowered the hepatic 3-hydroxy-methylglutaryl coenzyme A (HMG Co A) activity by 17-22% compared to rats given control diet devoid of n-3 fatty acids. The cholesterol level in liver microsomes was found to be decreased by 16% and 20%, respectively, in LSO and FO containing formulation fed rats. The bile flow was enhanced to an extent of 19-23% in experimental groups compared to control animals. The biliary cholesterol and phospholipid secretion was increased to an extent of 49-55% and 140-146%, respectively, in rats fed n-3 fatty acid containing formulation. The increase in the total bile acids secretion in bile was mainly reflected on an increase in the levels of taurine conjugated bile acids. These results indicated that n-3 fatty acid containing spray-dried milk formulation would bring about the hypocholesterolemic effect by lowering HMG Co A reductase activity in liver and by increasing the secretion of bile constituents.

Is coffee a functional food?

Definitions of functional food vary but are essentially based on foods' ability to enhance the quality of life, or physical and mental performance, of regular consumers. The worldwide use of coffee for social engagement, leisure, enhancement of work performance and well-being is widely recognised. Depending on the quantities consumed, it can affect the intake of some minerals (K, Mg, Mn, Cr), niacin and antioxidant substances. Epidemiological and experimental studies have shown positive effects of regular coffee-drinking on various aspects of health, such as psychoactive responses (alertness, mood change), neurological (infant hyperactivity, Alzheimer's and Parkinson's diseases) and metabolic disorders (diabetes, gallstones, liver cirrhosis), and gonad and liver function. Despite this, most reviews do not mention coffee as fulfilling the criteria for a functional food. Unlike other functional foods that act on a defined population with a special effect, the wide use of coffee-drinking impacts a broad demographic (from children to the elderly), with a wide spectrum of health benefits. The present paper discusses coffee-drinking and health benefits that support the concept of coffee as a functional food.

Effect of the type of dietary fat on biliary lipid composition and bile lithogenicity in humans with cholesterol gallstone disease.

OBJECTIVE: The effect of the type of dietary fat on bile lipids and lithogenicity is unclear. This study compared the effects of two dietary oils that differed in fatty acid profile on biliary lipid composition in humans. METHODS: Female patients who had cholesterol gallstones and were scheduled for elective cholecystectomy were studied. For 30 d before surgery, subjects were kept on diets that contained olive oil (olive oil group, n = 9) or sunflower oil (sunflower oil group, n = 9) as the main source of fat. Gallbladder bile and stones were sampled at surgery. After cholecystectomy, duodenal samples were collected by nasoduodenal intubation during fasting and after administration of mixed liquid meals that included the corresponding dietary oil. Duodenal and gallbladder bile samples were analyzed for cholesterol, phospholipids, and total bile acids by established methods. Individual bile acid conjugates in gallbladder bile were measured by high-performance liquid chromatography. Gallstones were analyzed by semiquantitative polarizing light microscopy. RESULTS: Despite marked differences in the absolute concentration of biliary lipids and total lipid content, manipulation of dietary fat ingestion did not influence the cholesterol saturation or the profile of individual bile acids in gallbladder bile obtained from patients who had gallstones. All but one subject had mixed cholesterol stones. A cholesterol saturation index of hepatic bile in fasted cholecystectomized patients was similar in both dietary groups and indicative of supersaturation. In response to the test meal, the cholesterol saturation index decreased significantly in patients given the olive oil diet, reaching values lower than one at 120 min postprandially. In contrast, hepatic bile secreted by patients who consumed sunflower oil appeared supersaturated (cholesterol saturation index >1.5) throughout the experiment. CONCLUSIONS: Our results suggest that the type of dietary fat habitually consumed can influence bile composition in humans. In gallbladder, this influence was noted in the presence of more concentrated bile in the olive oil group. However, this was not translated into a modification of cholesterol saturation, which is likely due to the fact that cholesterol gallstones were present by the time the dietary intervention started. The finding that a typical postprandial variation in hepatic bile lithogenicity occurred only in olive oil patients was revealing. While keeping in mind the methodologic limitations of this part of the study, some gastrointestinal and metabolic mechanisms for this effect are discussed.

[Effects of Gerbamarin T balms on functions of the cardiovascular and hepatobiliary systems]. / Vliianie bal'zamov "Gerbamarin" T na funktsional'noe sostoianie serdechno-sosudistoi i gepato-biliarnoi sistem.

The effects two balms of "Herbamarin" T series on some parameters of cardiovascular and hepatobiliary systems were studied in mice either kept on the cholesterol diet or treated with CCl4. The results allow to recommend these balms as additional components to the therapy of various cardiovascular and hepatic diseases.

[ELISA kit for detection of biliary vesicular protein and its preliminary clinical application].

OBJECTIVE: To establish a rapid and precise detective method of 33.5 kd vesicular protein and to screen an effective treatment of cholelithiasis. METHODS: Specific antibody of the biliary vesicular protein was obtained by immunizing rabbits and enzyme-linked immunosorbent assay (ELISA) kit was developed. The concentrations of 33.5 kd vesicular protein in serum and bile of gallstone patients and control were examined respectively. The effects of Cholagogue Dry Syrup and Eulektrol Capsule on decreasing 33.5 kd vesicular protein were also studied by ELISA kit. RESULTS: One-step ELISA equation was Y=0.035 X (r=0.99). The vesicular protein concentrations in serum and bile of cholesterol gallstone group [(179.8+/-97.9) mg/L and (213.4+/-70.1) mg/L respectively] were significantly (P<0.05) higher than in the pigment stone group and control. Data showed that, with 2-week administration, Cholagogue Dry Syrup significantly decreased both biliary and serum 33.5 kd vesicular protein of cholesterol gallstone patients, while Eulekrol Capsule and control groups didn't have the same results. CONCLUSION: The concentrations of 33.5 kd protein are different in cholesterol gallstone patients and healthy groups which might be related to cholesterol nucleation process. Cholagogue Dry Syrup is of cholagogic and litholytic effect by decreasing biliary lithogenesis.

Effect of intravenous bilirubin infusion on biliary phospholipid secretion, hepatic P-glycoprotein expression, and biliary cytotoxicity in pigs.

BACKGROUND: Infusion of large intravenous bilirubin loads in bile acid-depleted pigs reduces P-glycoprotein-dependent biliary phospholipid secretion and increases the cytotoxicity of bile. The reasons for the diminution of biliary phospholipid secretion and the increase in biliary cytotoxicity are not known. This study was undertaken to determine whether the bilirubin-induced lowering of biliary phospholipid secretion is associated with alterations in hepatic P-glycoprotein (P-gp) expression and to determine why bilirubin infusions increase biliary cytotoxicity. METHODS: Hepatic bile was collected from bile acid-depleted pigs before and during intravenous bilirubin infusion. Hepatic P-gp expression was measured with protein blot analysis, using the P-gp-specific antibody C219. Biliary cytotoxicity was assayed against erythrocytes. The biliary phospholipid fatty acid profile was determined by means of gas chromatography. RESULTS: Bilirubin infusions lowered biliary phospholipid secretion by 69% without changing hepatic P-gp expression, suggesting that bilirubin infusions have an inhibitory effect on hepatic P-gp activity. Bilirubin infusions did not cause P-gp losses into bile. An unequivocal, proportional relationship (r2 = 0.80) pertained between cytotoxicity and the bile acid to phospholipid ratio in bile secreted before and during bilirubin infusion and in phosphatidylcholine-supplemented bile. Unconjugated bilirubin in bile did not contribute to biliary cytotoxicity. Biliary phospholipids were always phosphatidylcholine >> phosphatidylethanolamine, mainly of C16:0, 18:2 and C16:0, 18:1 fatty acid configuration. CONCLUSIONS: Intravenous bilirubin loads reduce biliary phospholipid secretion without changing hepatic P-gp expression. Bilirubin infusions increase biliary cytotoxicity by augmenting the biliary bile acid to phospholipid ratio.

Role of glutathione and methylation in the biliary excretion of selenium. The paradoxical effect of sulfobromophthalein.

Biotransformation of selenite involves both reactions with GSH and methylations. Therefore, the role of GSH, methylation, and the hepatobiliary GSH transporter was investigated in the biliary excretion of selenium in rats injected with sodium [75Se]selenite (1-10 micromol/kg, i.v.). Biliary output of selenium exhibited an apparent capacity limitation with an approximately 3 nmol/kg x min maximal rate and a dose-related decline in the fractional excretion. HPLC analysis of bile indicated absence of selenite and presence of selenodiglutathione (GS-Se-SG) and/or its hydrolysis products as the major biliary selenite metabolites. Depletion of hepatic glutathione by D,L-buthionine-[S,R]-sulfoximine or diethyl maleate decreased selenium excretion into bile by 60 and 80%, respectively. In contrast, inhibitors of methylation, i.e. periodate-oxidised adenosine or ethionine doubled the rate of biliary selenium excretion. While indocyanine green--an inhibitor of hepatobiliary GSH transport--failed to influence biliary selenium output, sulfobromophthalein (BSP)--another inhibitor of this sort--dramatically enhanced it. This effect was found to be a function of the dose of both selenite and BSP. The degree of BSP-induced enhancement of the selenium excretion rate gradually increased with elevation of the selenite dose, approaching 20-fold at 10 micromol/kg selenite. In contrast, the stimulatory effect of BSP on biliary selenium output was maximal at 50-100 micromol/kg and gradually lessened with elevation of the BSP dose above 100 micromol/kg. In summary, this study revealed that the biliary excretion of selenium depended on availability of hepatic GSH, probably for formation of GS-Se-SG, the putative cholephilic selenite metabolite. Methylation counteracted selenium excretion into bile and thus may contribute to the apparent capacity limitation of biliary selenium excretion. Finally, selenium output into bile was insensitive to inhibitors of the hepatobiliary GSH transporter, and was enhanced, paradoxically, by BSP several-fold. The mechanism of this unexpected effect is explored in the adjoining article.