lignans and Carbon-Tetrachloride-Poisoning

Schisandrin B (Sch B) and miR-101 family members play critical roles in the pathogenesis of liver fibrosis. However, the relationship between them has not been reported yet. Thus, this study aims to fill this research gap. Results showed that Sch B significantly upregulated the expression of miR-101-5p in HSC-T6 cells. Sch B also increased the expression of miR-101-5p by combined administration of TGF-β1 and Sch B. Using miR-101-5p inhibitor, we demonstrated that Sch B can target miR-101-5p through the TGF-β signalling pathway to regulate the proliferation and activation of HSC-T6 cells. A rat model of carbon tetrachloride-induced liver fibrosis was established, and results indicated that Sch B can attenuate liver fibrosis by upregulating the expression of miR-101-5p. In conclusion, Sch B can directly target miR-101 to suppress liver fibrosis. Sch B or miR-101-5p may be used as a therapeutic approach for the prevention and treatment of liver fibrosis.

Topics: Animals; Carbon Tetrachloride Poisoning; Cyclooctanes; Humans; Lignans; Liver Cirrhosis; Male; MicroRNAs; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Signal Transduction; Transforming Growth Factor beta

Sesamin (Ses) from Sesamun indicum seeds has potent antioxidants and anti-inflammatory effects.. This study focused on the antioxidant and anti-inflammatory effects of Ses on Carbon tetrachloride (CCl4)-induced hepatic fibrosis in experimental rats and the potential mechanism underlying the activation of NF-kB pathway.. Hepatic fibrosis was induced by interaperitoneally (i.p.) administered with 20% CCl4 in corn oil (2 mL/kg for 8 weeks) in rats. After 8 weeks, activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were checked. The levels of protein carbonyls and antioxidant enzymes such as superoxide dismutase (SOD) and GSH-Px were determined after Ses administration. H&E and Masson's trichrome staining for histopathological changes of liver tissues were observed. Western blotting was used to detect expression of IL-6, cyclooxygenase-2 (COX-2), and NF-kB activation. Finally, the levels of hydroxyproline in liver tissues were also determined.. Ses decreased the release of liver enzymes - ALT, AST, and TBIL, reduced protein carbonyls, attenuated the reduction of SOD and GSH-Px activities induced by CCl4 in the liver tissue. It also significantly reduced the levels IL-6 and COX-2 in the liver caused by CCl4 by inhibition of NF-kB activation. Histological results indicated that Ses significantly improved the pathological lesions of liver fibrosis.. Ses exerted hepatoprotective effects possibly due to the antioxidant effect and suppressing the NF-kB activation.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Carbon Tetrachloride Poisoning; Dioxoles; Lignans; Liver Cirrhosis; Male; Rats; Rats, Sprague-Dawley

It is valuable to establish a chemical-pharmacokinetic (PK)-pharmacodynamics (PD) fingerprint of traditional Chinese medicine (TCM) for comprehensively understanding the TCM integrated conception and revealing the material foundation. The chemical, metabolic in vitro, and PK/PD in vivo fingerprints of Schisandra chinensis (SC) alcoholic extract were established and comparatively analyzed using HPLC-UV-MS method, rat liver microsomes in vitro and CCl4 intoxicated rats in vivo. Four known effective lignans, schisandrin, schisantherin A, deoxyschizandrin and gamma-schisandrin, were detected as the standard references in SC alcoholic extract with high concentration. SC alcoholic extract and four lignans when incubated with rat liver microsomes produced several metabolites in NAPDH-dependent manner. Chemical fingerprint of some components with bioactivities were also identified in PK and PD fingerprints in normal and ALI rats that explained the material foundation of SC alcoholic extract for multiple pharmacological effects. Schisandrin, schisantherin A, deoxyschizandrin and gamma-schisandrin could be considered as the "PK marker" of SC alcoholic extract or its relevant preparations, while two metabolites of the four lignans, 7, 8-dihydroxy-schizandrin and another one (M(W) 432), could be recognized as drug-metabolism (DM) Marker. This work provides experimental data for the further studies of metabolism or material foundation of SC components.

Topics: Alanine Transaminase; Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Cyclooctanes; Drugs, Chinese Herbal; Lignans; Male; Microsomes, Liver; Plants, Medicinal; Polycyclic Compounds; Random Allocation; Rats; Rats, Sprague-Dawley; Schisandra; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet

We investigated whether two naturally-occurring prooxidants, namely, schisandrin B (Sch B) and curcumin, and a synthetic prooxidant, menadione, can invariably elicit cyto/hepatoprotective responses against oxidant-induced injury. Results showed that (-)Sch B (a potent enantiomer of Sch B, 15 μM), curcumin (7.5 μM) and menadione (2 μM) induced a similar extent of reactive oxygen species production in AML12 cells. The relative potencies of cytoprotection in vitro were in a descending order of curcumin>menadione>(-)Sch B, which were parallel to the extent of stimulation in cellular reduced glutathione level. We further examined their hepatoprotection in vivo. Pretreatment with Sch B (800 mg/kg) and curcumin (737 mg/kg), but not menadione (344 mg/kg), protected against CCl(4) toxicity, with the degree of protection afforded by Sch B being much larger than that of curcumin. The attenuated hepatoprotection afforded by curcumin may be attributed to its low bioavailability in vivo. This postulation is supported by the findings that intraperitoneal injections of Sch B (400 mg/kg) and curcumin (368 mg/kg) and the long term, low dose treatment with Sch B (20 mg/kg/d×15) and curcumin (18 mg/kg/d×15) induced glutathione antioxidant response and hepatoprotection to similar extents in vivo. The inability of menadione to induce hepatoprotection may be related to its extensive intestinal metabolism and/or hepatotoxicity. Taken together, prooxidants can invariably induce the glutathione antioxidant response and confer cytoprotection in vitro. Whether or not the prooxidant can produce a similar response in vivo would depend on its bioavailability and potential toxic effect.

Topics: Animals; Antioxidants; Carbon Tetrachloride Poisoning; Cell Line; Curcumin; Cyclooctanes; Female; Glutathione; Lignans; Liver; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Microsomes, Liver; Polycyclic Compounds; Reactive Oxygen Species; Vitamin E; Vitamin K 3

Forsythiae Fructus is known to have diuretic, anti-bacterial, and anti-inflammatory activities. This study examined the hepatoprotective effects of pinoresinol, a lignan isolated from Forsythiae Fructus, against carbon tetrachloride (CCl(4))-induced liver injury. Mice were treated intraperitoneally with vehicle or pinoresinol (25, 50, 100, and 200 mg/kg) 30 min before and 2 h after CCl4 (20 microl/kg) injection. In the vehicle-treated CCl(4 )group, serum aminotransferase activities were significantly increased 24 h after CCl4 injection, and these increases were attenuated by pinoresinol at all doses. Hepatic glutathione contents were significantly decreased and lipid peroxidation was increased after CCl4 treatment. These changes were attenuated by 50 and 100 mg/kg of pinoresinol. The levels of protein and mRNA expression of inflammatory mediators, including tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2, were significantly increased after CCl4 injection; and these increases were attenuated by pinoresinol. Nuclear translocation of nuclear factor-kappaB (NF-kappaB) and phosphorylation of c-Jun, one of the components of activating protein 1 (AP-1), were inhibited by pinoresinol. Our results suggest that pinoresinol ameliorates CCl4)-induced acute liver injury, and this protection is likely due to anti-oxidative activity and down-regulation of inflammatory mediators through inhibition of NF-kappaB and AP-1.

Topics: Animals; Carbon Tetrachloride Poisoning; Forsythia; Furans; Lignans; Liver; Liver Diseases; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Plant Extracts; Signal Transduction

The present study was an attempt to investigate the hepatoprotective and antioxidative property of Phyllanthus amarus (P. amarus) extract and phyllanthin. Phyllanthin, one of the active lignin present in this plant species was isolated from the aerial parts, by silica gel column chromatography employing gradient elution with hexane-ethyl acetate solvent mixture. It was obtained in high yields (1.23%), compared to reported procedures and the purity was ascertained by HPTLC and reversed-phase HPLC analysis. Characterization of phyllanthin was done by mp, UV-Visible spectrophotometry, elemental analysis, FT-IR, 1H NMR, 13C NMR and mass spectral analysis. Free radical scavenging activity of P. amarus extract and phyllanthin was also examined using DPPH assay. The protective effect of P. amarus extract and phyllanthin was studied on CCl4-induced toxicity in human hepatoma HepG2 cell line. The results indicated that CCl4 treatment caused a significant decrease in cell viability. In addition, the toxin treatment initiated lipid peroxidation (LPO), caused leakage of enzymes like alanine transaminase (ALT) and lactate dehydrogenase (LDH) with a significant decrease in glutathione (GSH) levels. It was observed that phyllanthin effectively alleviated the changes induced by CCl4 in a concentration-dependent manner, with much smaller strengths as compared to P. amarus extract.

Topics: Antioxidants; Carbon Tetrachloride Poisoning; Cell Line; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Humans; Lignans; Lipid Peroxidation; Magnetic Resonance Spectroscopy; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared

Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to protect against carbon tetrachloride (CCl4) hepatotoxicity in mice. In order to elucidate the molecular mechanism underlying the hepatoprotection afforded by Sch B, the effect of Sch B treatment on the sensitivity of mitochondria to Ca2+-stimulated permeability transition (PT) was investigated in mouse livers under normal and CCl4-intoxicated conditions. CCl4 hepatotoxicity caused an increase in the sensitivity of mitochondria to Ca2+-stimulated PT in vitro. The enhanced sensitivity to mitochondrial PT was associated with increases in mitochondrial Ca2+ content as well as the extent of reactive oxidant species (ROS) production and cytochrome c release. The hepatoprotection afforded by Sch B pretreatment against CCl4 toxicity was paralleled by the decrease in the sensitivity of hepatic mitochondria to Ca2+-stimulated PT as well as the attenuations of mitochondrial Ca2+ loading, ROS production and cytochrome c release under CCl4-intoxicated condition. In conclusion, the results suggest that the hepatoprotection afforded by Sch B pretreatment against CCl4 toxicity may be related to the increase in the resistance of hepatic mitochondria to Ca2+-stimulated PT.

Topics: Animals; Calcium; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Cell Membrane Permeability; Cyclooctanes; Cytochromes c; Female; Ions; Lignans; Membrane Potentials; Mice; Mice, Inbred BALB C; Mitochondria, Liver; Molecular Structure; Polycyclic Compounds; Reactive Oxygen Species; Time Factors

The antioxidant activities of Acanthopanax senticosus stems were evaluated in CCl4-intoxicated rats. The n-butanol fraction from the water extract of the stems, when pretreated orally at 200 mg/kg/day for 7 consecutive days in rats, was demonstrated to exhibit significant increases in antioxidant enzyme activities such as hepatic cytosolic superoxide dismutase, catalase and glutathione peroxidase by 30.31, 19.82 and 155%, respectively. The n-butanol fraction whereas showed a significant inhibition of serum GPT activity (65.79% inhibition) elevated with hepatic damage induced by CCl4-intoxication. Eleutheroside B, a lignan component, isolated from the n-butanol fraction was found to cause a moderate free radical scavenging effect on DPPH, its scavenging potency as indicated in IC50 value, being 58.5 microM. These results suggested that the stems of A. senticosus possess not only antioxidant but also hepatoprotective activities.

Topics: Administration, Oral; Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Biphenyl Compounds; Butanols; Carbon Tetrachloride Poisoning; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Eleutherococcus; Free Radical Scavengers; Glucosides; Hepatocytes; Indicators and Reagents; Lignans; Male; Phenylpropionates; Picrates; Plant Extracts; Plant Stems; Rats; Rats, Sprague-Dawley; Silymarin; Solubility; Water

In the present study, we investigated the differential role of the mitochondrial glutathione status and induction of heat shock proteins (HSPs) 25/70 in protecting against carbon tetrachloride (CCl_4) hepatotoxicity in schisandrin B (Sch B)-pretreated mice. The time-course of Sch B-induced changes in these hepatic parameters were examined. Dimethyl diphenyl bicarboxylate (DDB), a non-hepatoprotective analog of Sch B, was studied for comparison. Sch B treatment (2 mmol/kg) produced maximal enhancement in hepatic mitochondrial glutathione status as well as increases in hepatic HSP 25/70 levels at 24 h post-dosing. The stimulatory effect of Sch B then gradually subsided, but the activities of hepatic mitochondrial glutathione reductase (GR) and glutathione S-transferases (GST) as well as the level of HSP 25 remained relatively high even at 72 h post-dosing. CCl_4 challenge caused significant impairment in mitochondrial glutathione status and a decrease in HSP 70 level, but the HSP 25 level was significantly elevated. While the extent of hepatoprotection afforded by Sch B pretreatment against CCl_4 was found to inversely correlate with the time elapsed after the dosing, the protective effect was associated with the ability of Sch B to maintain the mitochondrial glutathione status and/or induce further production of HSP 25 in CCl_4-intoxicated condition. On the other hand, DDB treatment (2 mmol/kg), which did not increase mitochondrial GSH level and GST activity or induce further production of HSP 25 after CCl_4 challenge, could not protect against CCl_4 toxicity. The results suggest that the enhancement of mitochondrial glutathione status and induction of HSP 25/70 may contribute independently to the hepatoprotection afforded by Sch B pretreatment.

Topics: Analysis of Variance; Animals; Antioxidants; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Cyclooctanes; Female; Glutathione; Heat-Shock Proteins; Lignans; Liver; Mice; Mice, Inbred BALB C; Mitochondria, Liver; Polycyclic Compounds; Time Factors

The effects of schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, and dimethyl diphenyl bicarboxylate (DDB), a synthetic intermediate of schisandrin C (also a dibenzocyclooctadiene derivative), on hepatic mitochondrial glutathione redox status in control and carbon tetrachloride (CCl4)-intoxicated mice were examined. Treating mice with Sch B or DDB at a daily oral dose of 1 mmol/kg for 3 d did not produce any significant alterations in plasma alanine aminotransferase (ALT) and sorbital dehydrogenase (SDH) activities. CCl4 treatment caused drastic increases in both plasma ALT and SDH activities in mice. Pretreating mice with Sch B or DDB at the same dosage regimen significantly suppressed the CCl4-induced increase in plasma ALT activity, with the inhibitory effect of Sch B being much more potent. Sch B, but not DDB, pretreatment could also decrease the plasma SDH activity in CCl4-intoxicated mice. The lowering of plasma SDH activity, indicative of hepatoprotection against CCl4 toxicity, by Sch B pretreatment was associated with an enhancement in hepatic mitochondrial glutathione redox status as well as an increase in mitochondrial glutathione reductase (mtGRD) activity in both non-CCl4 and CCl4-treated mice. DDB pretreatment, though enhancing both hepatic mitochondrial glutathione redox status and mtGRD activity in control animals, did not produce any beneficial effect in CCl4-treated mice. The difference in hepatoprotective action against CCl4 toxicity between Sch B and DDB may therefore be related to their ability to maintain hepatic mitochondrial glutathione redox status under oxidative stress condition.

Topics: Alanine Transaminase; Animals; Antioxidants; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Female; Glutathione; Glutathione Reductase; Hydrocarbons, Chlorinated; Insecticides; L-Iditol 2-Dehydrogenase; Lignans; Mice; Mice, Inbred BALB C; Mitochondria, Liver; Oxidation-Reduction; Oxidative Stress; Polycyclic Compounds

To explore whether the methylenedioxy group and cyclooctadiene ring of the dibenzocyclooctadiene skeleton of schisandrins (Sch) play a role in the liver mitochondrial glutathione status enhancing activity.. The effects of three dibenzocyclooctadiene derivatives, Sch A, Sch B, Sch C, and a synthetic intermediate of Sch C, (dimethyl biphenyl dicarboxylate, DBD) on carbon tetrachloride (CCl4)-hepatotoxicity and liver mitochondrial glutathione status were examined in mice.. Pretreating mice with intragastric Sch B, Sch C, or DBD 1.mmol.kg-1.d-1 for 3 d protected against CCl4-hepatotoxicity. The hepatoprotection afforded by Sch B or Sch C pretreatment was associated with increases in liver mitochondrial reduced glutathione (mtGSH) level and glutathione reductase (mtGRD) activity, an indication of enhanced mitochondrial glutathione status. In contrast, the hepatoprotective action of DBD was not accompanied by any detectable changes in mtGSH level and mtGRD activity.. Both the methylenedioxy group and the cyclooctadiene ring of the dibenzocyclooctadiene molecule are important structural determinants in the enhancement of liver mitochondrial glutathione status.

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Drugs, Chinese Herbal; Female; Glutathione; Glutathione Reductase; Lignans; Mice; Mice, Inbred BALB C; Mitochondria, Liver; Polycyclic Compounds; Structure-Activity Relationship

Pretreating female Balb/c mice with schisandrin B (Sch B) at increasing daily doses (1-4 mmol/kg) for 3 days caused dose-dependent increases in hepatic glutathione S-transferase (GST) and glutathione reductase (GRD) activities. However, the activities of glucose-6-phosphate dehydrogenase (G6PDH), Se-glutathione peroxidase (GPX), and gamma-glutamylcysteine synthetase (GCS) were down-regulated to varying degrees in a dose-dependent manner. While there were biphasic changes in hepatic reduced glutathione (GSH) level as well as susceptibility of hepatic tissue homogenates to in vitro peroxide-induced GSH depletion, a gradual decrease in hepatic malondialdehyde content was observed. The beneficial effect of Sch B on the hepatic GSH anti-oxidant system became more evident after CCl4 challenge. The same Sch B pretreatment regimen caused a dose-dependent protection against carbon tetrachloride (CCl4)-induced hepatotoxicity. The hepatoprotection was associated with significant enhancement in hepatic GSH status, as indicated by the substantial increase in tissue GSH levels and the corresponding decrease in susceptibility of tissue homogenates to GSH depletion. Where the activities of GST and GRD were increased linearly over non-CCl4 control values, there was also a gradual elevation in G6PDH activity upon administration of increasing doses of Sch B. In contrast, GPX activity was moderately down-regulated. The ensemble of results suggests that the hepatoprotection afforded by Sch B pretreatment may mainly be attributed to the enhancement in the functioning of the hepatic GSH anti-oxidant system, possibly through stimulating the activities of GSH related enzymes.

Topics: Animals; Antioxidants; Carbon Tetrachloride Poisoning; Cyclooctanes; Female; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Lignans; Liver; Medicine, Chinese Traditional; Mice; Mice, Inbred BALB C; Plants, Medicinal; Polycyclic Compounds

The effect of a lignan-enriched extract of the fruits of Schisandra chinensis (FS) on hepatic glutathione (GSH) status was examined in both control and carbon tetrachloride (CCl4)-treated rats. FS treatment caused a dose-dependent enhancement in hepatic GSH status, as evidenced by significant increases in hepatic GSH level and activities of hepatic glucose-6-phosphate and glutathione reductase (GRD), as well as a decreased susceptibility of hepatic tissue homogenates to in vitro peroxide-induced GSH depletion. The beneficial effect of FS treatment on hepatic GSH status became more evident after CCl4 challenge. Pretreating rats with FS extract at increasing daily doses ranged from 0.2 to 3.2 g/kg for 3 days caused a dose-dependent protection against the CCl4-induced impairment in hepatic GSH status. The enhancement in hepatic GSH status was associated with corresponding decreases in tissue malondialdehyde levels and plasma alanine aminotransferases activities, indicating a significant reduction in the extent of oxidative hepatocellular damage. Our results indicate that the molecular mechanism of hepatoprotection afforded by FS pretreatment may involve the facilitation of GSH regeneration via the GRD-catalyzed and NADPH-mediated reaction.

Topics: Animals; Carbon Tetrachloride Poisoning; Drugs, Chinese Herbal; Glutathione; Lignans; Liver; Oxidative Stress; Plant Extracts; Rats

The absorption and excretion of gomisin A (TJN-101) in rats whose livers were injured by carbon tetrachloride (CCl4) were investigated. After intravenous administration of TJN-101 at a dose of 5 mg/kg, the terminal elimination half-life was 1.5 h in the CCl4-treated rats, which was two times that in normal rats. The mean area under the blood concentration-time curve (AUC) value of TJN-101 in the CCl4-treated rats was twice that in normal rats, and this difference was significant (p less than 0.05). Therefore, the total body clearance of TJN-101 in the CCl4-treated rats decreased less than half of that in normal rats. Similar results were observed when it was administered orally. In the CCl4-treated rats, the serum concentration of Met. B, which was identified as a demethylenated substance and one of major metabolites, tended to decrease more than that in normal rats. On the other hand, the cumulative biliary excretion ratio of TJN-101 in 24 h after dosing in the CCl4-treated rats was 2.5 times that in normal rats. The excretion rate of Met. B in the bile in the CCl4-treated rats tended to be delayed. However, the quantitative variance of biliary excretion of Met. B was not found in both groups. The urinary excretion of TJN-101 or Met. B in 72 h after dosing in the CCl4-treated rats was lower than that in normal rats. Similar results were also observed in excretion in the feces.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Blood Proteins; Carbon Tetrachloride Poisoning; Cyclooctanes; Dioxoles; Injections, Intravenous; Lignans; Male; Polycyclic Compounds; Protein Binding; Rats; Rats, Inbred Strains

TJN-101 ((+)-(6S,7S,R-biar)-5,6,7,8-tetrahydro-1,2,3,12-tetramethoxy -6,7-dimethyl-10,11-methylenedioxy-6-dibenzo[a,c]cyclooctenol) is one of the lignan compounds isolated from Schisandra fruits. 1) Effect of TJN-101 on liver fibrosis was investigated in rats which were injected with CCl4 (1 ml/kg) subcutaneously twice a week for 12 weeks. TJN-101 was given orally at the dose of 10 or 30 mg/kg/day for 6 or 3 weeks beginning on the 6th or 9th week after the start of CCl4-intoxication, respectively. The elevations of serum transaminase activities and the increase of liver 4-hydroxyproline content were observed depending on the period of CCl4-intoxication. These changes were marked on the 9th and 12th weeks after. In the histopathological study, the degenerative fatty change on the 6th week after and the formation of pseudolobule caused by fibrosis proliferation on the 9th or 12th week after were mainly observed. When rats were treated with TJN-101, the abnormalities in biochemical parameters and the fibrosis proliferation caused by CCl4-intoxication were improved. 2) Chronic liver injury was induced by the treatment with CCl4 (1 ml/kg) subcutaneously twice a week for 10 weeks to investigate the effect of TJN-101 on liver regeneration after partial hepatectomy. TJN-101, which was given orally at the dose of 10, 30 or 100 mg/kg/day for 6 days from the 1st day after partial hepatectomy, dose-dependently increased the liver regeneration rate and improved the serum BSP retention rate. These results suggest that TJN-101 suppresses the fibrosis proliferation and accelerates both the liver regeneration and the recovery of liver function after partial hepatectomy in chronic liver injury.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Carbon Tetrachloride Poisoning; Cyclooctanes; Dioxoles; Hepatectomy; Lignans; Liver Cirrhosis, Experimental; Liver Regeneration; Male; Plant Extracts; Polycyclic Compounds; Rats; Rats, Inbred Strains

Effects of oral administration of gomisin A, one of the components isolated from Schizandra fruits, on liver injuries induced by CCl4, d-galactosamine and dl-ethionine and on liver microsomal drug-metabolizing enzyme activities were investigated. Gomisin A suppressed the increase of serum transaminase activities and the appearances of histological changes such as degeneration and necrosis of hepatocyte, inflammatory cell infiltration and fatty deposition in each type of liver injury. The repeated administration of gomisin A (30 or 100 mg/kg, p.o., daily for 4 days) induced an apparent increase of liver weight in liver-injured and normal rats. Gomisin A decreased serum triglyceride and lipid contents of the liver in biochemical studies. Increases of microsomal cytochrome b5 and P-450, elevations of NADPH cytochrome C reductase, aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase activities and decrease of 3,4-benzo(a)pyrene hydroxylase activity per cytochrome P-450 were observed after the administration of gomisin A. In addition, gomisin A was found to enhance the incorporation of 14C-phenylalanine into liver protein and to shorten the hexobarbital-induced sleeping time. These changes caused by gomisin A were similar to those by phenobarbital. However, gomisin A is distinctly different from phenobarbital in the finding that phenobarbital lessened the survival ratio of CCl4-intoxicated mice, but gomisin A did not. Our observation suggest that gomisin A shows an antihepatotoxic action by oral application and also has hypolipidemic (mainly triglyceridemic) and liver protein synthesis-facilitating actions and that the enlargement of the liver seen with gomisin A is the adaptive hypertrophy which is due to the induction of drug-metabolizing enzymes.

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Ethionine; Galactosamine; Lignans; Liver Diseases; Male; Microsomes, Liver; Mixed Function Oxygenases; Protein Biosynthesis; Rats; Rats, Inbred Strains; Sleep

The effects of wuweizisu C, a lignan component of schizandra fruits, on liver injuries induced by carbon tetrachloride (CCl4), d-galactosamine and dl-ethionine were investigated by means of serum-biochemical and histopathological examinations in rats. Pretreatment or combined administration of wuweizisu C dose-dependently reduced the elevation of serum transaminase activity and histological changes such as fatty degeneration, cell necrosis, inflammatory cell infiltration, etc., which were caused by the single administration of 1 ml/kg, p.o., or the repeated administration of 0.2 ml/kg, s.c., daily for 4 days of CCl4, respectively. The effects of wuweizisu C on the liver injuries induced by a low dose (200 mg/kg, i.p.) and a high dose (400 mg/kg, i.p.) of d-galactosamine were compared with those of uridine. Wuweizisu C significantly lowered the rise of serum transaminase activity after the administration of a low dose of d-galactosamine in the serum-biochemical analysis. A tendency was also shown to inhibit cell necrosis and inflammatory cell infiltration caused by both doses of d-galactosamine in the histopathological examination. On the other hand, uridine markedly repaired the serum-biochemical and histopathological changes after the administrations of both doses of d-galactosamine. Also wuweizisu C cured the liver injury by the repeated administration of 150 mg/kg, i.p., daily for 4 days of d-galactosamine. After the repeated administration of 250 mg/kg, s.c., daily for 4 days of ethionine, liver cell atrophy, diffuse fatty degeneration and decrease of serum triglyceride were observed, but not cell necrosis. Wuweizisu C dose-dependently inhibited fatty degeneration and decrease of serum triglyceride. These findings suggest that wuweizisu C can be protective and/or therapeutic on hepatocellular phenomena such as cell necrosis, fatty degeneration, inflammatory cell infiltration, etc., in human hepatitis.

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Ethionine; Fatty Liver; Galactosamine; Hepatitis; Lignans; Liver Diseases; Male; Plant Extracts; Plants, Medicinal; Polycyclic Compounds; Rats; Rats, Inbred Strains

The effects of gomisin A, which is a lignan component of schizandra fruits, on liver functions in various experimental liver injuries and on bile secretion in CCl4-induced liver injury were studied. Gomisin A weakly accelerated the disappearance of plasma ICG by itself at a high dose (100 mg/kg, i.p.). All of the hepatotoxic chemicals used in this study inhibited the excretion of ICG from plasma. Gomisin A showed a tendency to prevent the delays of the disappearance of plasma ICG induced by CCl4, d-galactosamine and orotic acid, but not that by ANIT. Bile flow and biliary outputs of total bile acids and electrolytes (Na+, K+, Cl- and HCO3-) were decreased in CCl4-treated rats. Gomisin A maintained bile flow and biliary output of each electrolyte nearly to the level of the vehicle-treated group, but did not affect biliary output of total bile acids. These findings suggest that gomisin A possesses a liver function-facilitating property in normal and liver injured rats and that its preventive action on CCl4-induced cholestasis is due to maintaining the function of the bile acids-independent fraction.

Topics: 1-Naphthylisothiocyanate; Animals; Bile; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Galactosamine; Indocyanine Green; Lignans; Liver; Liver Function Tests; Male; Orotic Acid; Polycyclic Compounds; Rats; Rats, Inbred Strains

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Dioxoles; Lignans; Male; Microsomes, Liver; Polycyclic Compounds; Rats; Rats, Inbred Strains

Among phyllanthin, hypophyllanthin, triacontanal and tricontanol isolated from a hexane extract of Phyllanthus niruri, phyllanthin and hypophyllanthin protected against carbon tetrachloride- and galactosamine-induced cytotoxicity in primary cultured rat hepatocytes, while triacontanal was protective only against galactosamine-induced toxicity.

Topics: Animals; Carbon Tetrachloride Poisoning; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Galactosamine; Lignans; Plant Extracts; Plants, Medicinal; Rats

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cyclooctanes; Cycloparaffins; Drug Evaluation, Preclinical; Lignans; Liver Diseases; Male; Plant Extracts; Plants, Medicinal; Polycyclic Compounds; Rats; Rats, Inbred Strains