ascorbic-acid and Cholestasis

Prevention and restoration of hepatic fibrosis from chronic liver injury is essential for the treatment of patients with chronic liver diseases. Vitamin C is known to have hepatoprotective effects, but their underlying mechanisms are unclear, especially those associated with hepatic fibrosis. Here, we analyzed the impact of vitamin C on bile acid induced hepatocyte apoptosis in vitro and lithocholic acid (LCA)-induced liver injury in vitamin C-insufficient Gulo(-/-) mice, which cannot synthesize vitamin C similarly to humans. When Huh-BAT cells were treated with bile acid, apoptosis was induced by endoplasmic reticulum stress-related JNK activation but vitamin C attenuated bile acid-induced hepatocyte apoptosis in vitro. In our in vivo experiments, LCA feeding increased plasma marker of cholestasis and resulted in more extensive liver damage and hepatic fibrosis by more prominent apoptotic cell death and recruiting more intrahepatic inflammatory CD11b(+) cells in the liver of vitamin C-insufficient Gulo(-/-) mice compared to wild type mice which have minimal hepatic fibrosis. However, when vitamin C was supplemented to vitamin C-insufficient Gulo(-/-) mice, hepatic fibrosis was significantly attenuated in the liver of vitamin C-sufficient Gulo(-/-) mice like in wild type mice and this hepatoprotective effect of vitamin C was thought to be associated with both decreased hepatic apoptosis and necrosis. These results suggested that vitamin C had hepatoprotective effect against cholestatic liver injury.

Topics: Animals; Ascorbic Acid; Cell Line; Cholestasis; Cytoprotection; Hepatocytes; Humans; Lithocholic Acid; Liver; Liver Cirrhosis; Male; Mice; Mice, Knockout; Reactive Oxygen Species

Owing to its ability to inactivate harmful radicals, vitamin C plays a key role in antioxidant defense. The bioavailability of this vitamin depends upon the nutritional intake and its uptake by cells, mainly through the sodium-dependent transporters SVCT1/Svct1 and SVCT2/Svct2 (human/rat). Here, we investigated the effect of liver metabolic/oxidative stress on the expression of these transporters in extrahepatic tissues.. In Zucker rats, used here as a model of liver steatosis, Svct1-2 mRNA levels were similar in obese and lean animals, except for lung tissue, where Svct2 was up-regulated. Diabetes mellitus, developed by streptozotocin administration, was accompanied by a down-regulation of Svct1 in liver and kidney, together with a down-regulation of Svct2 in kidney and brain. Complete obstructive cholestasis due to bile duct ligation for 1 week induced a significant down-regulation of both Svct1 and Svct2 in ileum, whereas Svct2 was up-regulated in liver, and no significant changes in the expression of either transporter were found in kidney, brain or lung. In rat hepatoma Can-10 cells, bile acids, but not the FXR agonist GW4064, induced an up-regulation of Svct1 and Svct2. In human hepatoma Alexander cells transfected with FXR/RXRα/OATP1B1, neither GW4064 nor unconjugated or glycine-/taurine-conjugated major bile acids were able to up-regulate either SVCT1 or SVCT2.. Pathological circumstances characterized by the presence of metabolic/oxidative stress in the liver induce different responses in the expression of ascorbic acid transporters in intrahepatic and extrahepatic tissues, which may affect the overall bioavailability and cellular uptake of this vitamin.

Topics: Animals; Ascorbic Acid; Bile Acids and Salts; Biological Availability; Carcinoma, Hepatocellular; Cell Line, Tumor; Cholestasis; Diabetes Mellitus, Experimental; Disease Models, Animal; Fatty Liver; Gene Expression; Humans; Kidney; Liver; Liver Neoplasms; Male; Obesity; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Zucker; RNA, Messenger; Sodium-Coupled Vitamin C Transporters; Stress, Physiological

Drug-induced liver injury (DILI) is one of the most common drug-induced adverse events (AEs) leading to life-threatening conditions such as acute liver failure. It has also been recognized as the single most common cause of safety-related post-market withdrawals or warnings. Efforts to develop new predictive methods to assess the likelihood of a drug being a hepatotoxicant have been challenging due to the complexity and idiosyncrasy of clinical manifestations of DILI. The FDA adverse event reporting system (AERS) contains post-market data that depict the morbidity of AEs. Here, we developed a scalable approach to construct a hepatotoxicity database using post-market data for the purpose of quantitative structure-activity relationship (QSAR) modeling. A set of 2029 unique and modelable drug entities with 13,555 drug-AE combinations was extracted from the AERS database using 37 hepatotoxicity-related query preferred terms (PTs). In order to determine the optimal classification scheme to partition positive from negative drugs, a manually-curated DILI calibration set composed of 105 negatives and 177 positives was developed based on the published literature. The final classification scheme combines hepatotoxicity-related PT data with supporting information that optimize the predictive performance across the calibration set. Data for other toxicological endpoints related to liver injury such as liver enzyme abnormalities, cholestasis, and bile duct disorders, were also extracted and classified. Collectively, these datasets can be used to generate a battery of QSAR models that assess a drug's potential to cause DILI.

Topics: Algorithms; Ampicillin; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Ascorbic Acid; Bile Duct Diseases; Calibration; Chemical and Drug Induced Liver Injury; Cholestasis; Data Mining; Databases, Factual; Drug Labeling; Endpoint Determination; Humans; Levofloxacin; Liver; Naproxen; Product Surveillance, Postmarketing; Quantitative Structure-Activity Relationship; Toxicity Tests; Vitamins

Maternal cholestasis causes oxidative damage to the placental-fetal unit that may challenge the outcome of pregnancy. This has been associated with the accumulation of biliary compounds able to induce oxidative stress. However, other cholephilic compounds such as ursodeoxycholic acid (UDCA) and bilirubin have direct anti-oxidant properties. In the present study we investigated whether these compounds exert a protective effect on cholestasis-induced oxidative stress in placenta as compared to maternal and fetal livers, and whether this is due in part to the activation of anti-oxidant mechanisms involving vitamin C uptake and biliverdin/bilirubin recycling. In human placenta (JAr) and liver (HepG2) cells, deoxycholic acid (DCA) similar rates of free radical generation. In JAr (not HepG2), the mitochondrial membrane potential and cell viability were impaired by low DCA concentrations; this was partly prevented by bilirubin and UDCA. In HepG2, taurocholic acid (TCA) and UDCA up-regulated biliverdin-IX alpha reductase (BVR alpha) and the vitamin C transporter SVCT2 (not SVCT1), whereas bilirubin up-regulated both SVCT1 and SVCT2. In JAr, TCA and UDCA up-regulated BVR alpha, SVCT1 and SVCT2, whereas bilirubin up-regulated only SVCT2. A differential response to these compounds of nuclear receptor expression (SXR, CAR, FXR and SHP) was found in both cell types. When cholestasis was induced in pregnant rats, BVR alpha, SVCT1 and SVCT2 expression in maternal and fetal livers was stimulated, and this was further enhanced by UDCA treatment. In placenta, only BVR alpha was up-regulated. In conclusion, bilirubin accumulation and UDCA administration may directly and indirectly protect the placental-fetal unit from maternal cholestasis-induced oxidative stress.

Topics: Animals; Antioxidants; Ascorbic Acid; Cell Line, Tumor; Cholestasis; Female; Humans; Male; Maternal-Fetal Exchange; Organic Anion Transporters, Sodium-Dependent; Oxidative Stress; Oxidoreductases Acting on CH-CH Group Donors; Pregnancy; Pregnancy Complications; Rats; Rats, Wistar; Reactive Oxygen Species; Ursodeoxycholic Acid

To investigate whether antioxidants vitamin E and C can retard development of hepatic fibrosis in the biliary-obstructed rats.. Fifty Wistar albino rats were randomly assigned to 5 groups (10 rats in each). Bile duct was ligated in 40 rats and they were treated as follows: group vitC, vitamin C 10 mg/kg sc daily; group vitE, vitamin E 15 mg/kg sc daily; group vitEC, both of the vitamins; bile duct-ligated (BDL, control) group, physiological saline sc. The fifth group was assigned to sham operation. At the end of fourth week, the rats were decapitated, and hepatic tissue biochemical collagen content and collagen surface area were measured. Hepatic tissue specimens were histopathologically evaluated according to Scheuer system. Serum hyaluronate levels were measured by ELISA method.. Despite being higher than sham group, hepatic collagen level was significantly decreased in each of the vitC, vitE and vitEC groups (32.7 +/- 1.2, 33.8 +/- 2.9, 36.7 +/- 0.5 mug collagen/mg protein, respectively) compared to BDL (48.3 +/- 0.6 mg collagen/g protein) (P < 0.001 for each vitamin group). Each isolated vitamin C, isolated vitamin E and combined vitamin E/C supplementation prevented the increase in hepatic collagen surface density (7.0% +/- 1.1%, 6.2% +/- 1.7%, 12.3% +/- 2.0%, respectively) compared to BDL (17.4% +/- 5.6%) (P < 0.05 for each). The same beneficial effect of vitamin C, vitamin E and combined vitamin E/C treatment was also observed on the decrease of serum hyaluronate levels compared to BDL group (P < 0.001). The relative liver and spleen weights, serum transaminases, cholestatic enzymes, bilirubins and histopathological inflammation scores were not different between the antioxidant treatment groups and the control. However, fibrosis staging scores were obviously reduced only in the vitamin E/C combination group (vit EC: 2.4 +/- 0.8 vs BDL: 3.1 +/- 0.7; P < 0.05).. Each antioxidant vitamin E, vitamin C and their combination retard hepatic fibrosis in biliary-obstructed rats. Oxidative stress may play a role in the pathogenesis of hepatic fibrosis in secondary biliary cirrhosis.

Topics: Animals; Antioxidants; Ascorbic Acid; Cholestasis; Collagen; Drug Synergism; Female; Hyaluronic Acid; Ligation; Liver Cirrhosis; Liver Cirrhosis, Biliary; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Vitamin E

Primary biliary cirrhosis (PBC) is a chronic cholestatic disorder characterised by an immunological, and often granulomatous, attack on bile ducts leading to fibrosis, cirrhosis, liver failure and death. Animal and human studies suggest that oxidant stress plays a key role in progression of other liver diseases, but no comprehensive investigation has been performed previously in PBC. A wide range of lipid peroxidation and antioxidant markers were measured in the blood and urine of 41 patients with histologically confirmed PBC. Lipid peroxidation markers were significantly elevated [plasma and urinary 8-isoprostane, P<0.001; plasma malondialdehyde (MDA), P=0.007] compared to age- and sex-matched controls. The most striking antioxidant depletion occurred with plasma total glutathione where levels were significantly reduced (30% of controls). Total serum antioxidant levels were decreased (P=0.013) and serum selenium and vitamin A were also lower (both P<0.001); vitamins C and E were normal. Most patients had early disease biochemically and were Child-Pugh grade A. Urinary 8-isoprostane correlated positively with Ludwig stage and markers of hepatic injury and cholestasis. This study clearly demonstrates that oxidant stress, as reflected in a comprehensive spectrum of lipid peroxidation and antioxidant markers, is a significant feature of early-stage PBC.

Topics: Antioxidants; Ascorbic Acid; Biomarkers; Cholestasis; Dinoprost; F2-Isoprostanes; Glutathione; Humans; Lipid Peroxidation; Liver; Liver Cirrhosis, Biliary; Malondialdehyde; Oxidants; Oxidative Stress; Selenium; Vitamin A; Vitamin E

In rats with chronic portal hypertension (PH) and common bile duct ligation (CBDL), significant ileal bacterial overgrowth, translocation of indigenous intestinal bacteria, a decrease in hepatic and ileal reduced glutathione (GSH) and an increase in ileal mucosal lipid peroxidation occur. alpha-Tocopherol (vitamin E) and ascorbic acid (vitamin C) treatment attenuated the incidence of bacterial translocation, improved hepatic and ileal GSH levels and decreased ileal mucosal lipid peroxidation. These results suggest that in chronic PH and CBDL oxidative processes in the liver and intestine play an important role for bacterial translocation.

Topics: Animals; Ascorbic Acid; Bacterial Translocation; Biomarkers; Cholestasis; Common Bile Duct; Glutathione; Hypertension, Portal; Ileum; Intestinal Mucosa; Lipid Peroxidation; Liver; Male; Rats; Rats, Sprague-Dawley; Vitamin E

Operative stenosis of common bile duct (CBD) (S group) induced pigment gallstones in 14 of 16 guinea pigs one week after operation. If Vit E and Vit C were given intraperitoneally 10 mg/kg daily from 3 days before to one week after the operation (S+V group), the gallstone incidence decreased to 5/14 (P < 0.01). In comparison with control group (C), unconjugated bilirubin (UCB) and Ca2+ concentration in gallbladder bile of S group increased significantly (P < 0.05 and P < 0.01 respectively), while the scavenge rate (SR) of superoxide radical (O2-.) in bile decreased significantly (P < 0.05). Comparing S+V group with S group showed that the differences of UCB and Ca2+ concentration were not significant (P < 0.05 both); only the SR rose significantly (P < 0.05) and reached the level of C group. It is suggested that besides the increase of UCB and Ca2+ concentration, the participation of oxygen radicals may be needed in formation of pigment gallstones induced by bile duct obstruction.

Topics: Animals; Ascorbic Acid; Bile; Bile Pigments; Bilirubin; Cholelithiasis; Cholestasis; Free Radical Scavengers; Guinea Pigs; Male; Oxygen; Vitamin E

The blood flow in the portal vein and hepatic artery was studied by means of ultrasonic Doppler flow measurement to investigate organic and regional hemodynamics of the liver in purulent cholangitis. The blood flow in the portal vein was found to be significantly diminished in patients with acute cholangitis and hepatic failure. Hepatic microcirculation was studied on a experimental model of obstructive jaundice and obstructive purulent cholangitis in rats by polarographic measurement of hydrogen clearance. Considerable reduction of the volume rate of the local blood flow was noted, and the degree of the reduction was related to the severity and duration of the disease. Decompression of the biliary tract by external drainage improved the local blood flow rate which, however, diminished again in prolonged external drainage. The use of pharmacological agents for correction of microcirculation in decompression of the biliary tract led to total and rapid correction of the volume rate of the local blood flow.

Topics: Acute Disease; Animals; Aprotinin; Ascorbic Acid; Aspirin; Cholangitis; Cholestasis; Dextrans; Dipyridamole; Drainage; Drug Combinations; Heparin; Humans; Liver Circulation; Male; Microcirculation; Pentoxifylline; Pyridinolcarbamate; Rats; Rutin; Suppuration; Ultrasonography; Xanthinol Niacinate

Hypercholesterolemia was induced in rats by experimental cholestasis and aminonucleoside nephrosis. After ascorbic acid administration the hypercholesterolemia was significantly decreased in both cases. In the case of cholestasis serum choelsterol was normal and in the case of nephrosis serum cholesterol remained above normal.

Topics: Animals; Ascorbic Acid; Cholestasis; Cholesterol; Hypercholesterolemia; Male; Nephrosis; Nucleosides; Rats

Topics: Age Factors; Aminopyrine; Animals; Animals, Newborn; Ascorbic Acid; Cholestasis; Endoplasmic Reticulum; Enzyme Induction; Female; Fetus; Hexobarbital; Liver; Lysosomes; Male; Methylcholanthrene; Microscopy, Electron; Mitochondria, Liver; Phenylbutazone; Pregnancy; Rats

Topics: Adolescent; Adult; Ascorbic Acid; Child; Child, Preschool; Cholestasis; Hepatitis A; Humans; Infant; Prednisone; Sorbitol; Vitamin B Complex

Topics: Acute Disease; Ascorbic Acid; Bilirubin; Cholestasis; Cholesterol; Chronic Disease; Coenzymes; Exchange Transfusion, Whole Blood; gamma-Globulins; Glucocorticoids; Hepatitis A; Humans; Hyperbaric Oxygenation; Liver Cirrhosis; Liver Function Tests; Oxygen Inhalation Therapy; Sulfobromophthalein; Transaminases; Vitamin B Complex