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Milk Thistle Herb

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Title
Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin.
Author
Dehmlow C; Erhard J; de Groot H
Address
Institut für Physiologische Chemie, Universitätsklinikum, Essen, Germany.
Source
Hepatology, 23(4):749-54 1996 Apr
Abstract
The flavonoid silibinin, the main compound extracted from the milk thistle Silybum marianum, displays hepatoprotective properties in acute and chronic liver injury. To further elucidate the mechanisms by which it acts, we studied the effects of silibinin on different functions of isolated rat Kupffer cells, namely the formation of superoxide anion radical (02-), nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), prostaglandin E(2) (PGE(2)), and leukotriene B(4) (LTB(4)). Production of 02- and NO were inhibited in a dose-dependent manner, with an 50 percent inhibitory concentration (IC(50)) value around 80 micro mol/L. No effect on TNF-alpha formation was detected. Opposite effects were found on the cyclooxygenase and 5-lipoxygenase pathway of arachidonic acid metabolism. Whereas no influence on PGE(2) formation was observed with silibinin concentrations up to 100 micro mol/L, a strong inhibitory effect on LTB(4) formation became evident. The IC(50)-value for inhibiting the formation of this eicosanoid was determined to be 15 micro mol/L silibinin. The strong inhibition of LTB(4), formation by silibinin was confirmed in experiments with phagocytic cells isolated from human liver. Hence, while rather high concentrations of silibinin are necessary to diminish free radical formation by activated Kupffer cells, significant inhibition of the 5-lipoxygenase pathway already occurs at silibinin concentrations which are achieved in vivo. Selective inhibition of leukotriene formation by Kupffer cells can at least partly account for the hepatoprotective properties of silibinin.

Title
Comparative effects of colchicine and Silymarin on CCl4-chronic liver damage in rats.
Author
Favari L; Pérez-Alvarez V
Address
Departamento de Farmacología y Toxicologia, Centro de Investigación y de Estudios Avanzados del IPN, México, D.F.
Source
Arch Med Res, 28(1):11-7 1997 Spring
Abstract
The comparative effects of colchicine (10 micrograms day-1, p.o.) and Silymarin (50 mg kg-1, p.o.) each given for 5 days a week on the chronic carbon tetrachloride (CCl4) liver damage were studied. Treatment with CCl4 resulted in a marked reduction of Na+, K+, and Ca2(+)-ATPases in plasma liver membranes as compared to vehicles or either Silymarin or colchicine alone. Collagen content in livers of animals treated with CCl4 was increased about four-fold as compared to controls and histological examination of liver samples showed that collagen increase distorted the normal liver architecture. Colchicine or Silymarin treatment completely prevented all the changes observed in CCl4-cirrhotic rats (namely, lipid peroxidation, Na+, K+ and Ca(2+)-ATPases), except for liver collagen content which was reduced only 55% as compared with CCl4-treated rats and for alkaline phosphatase and glutamic pyruvic transaminase which still remained above controls. In the CCl4 + Silymarin group, the loss of glycogen content was completely prevented. However, when rats were treated with CCl4 + colchicine, liver glycogen content could not be restored. The hepatoprotective effects of colchicine or Silymarin were very similar in regard to the prevention of chronic liver damage.

Title
The effect of Silymarin, a hepatoprotective substance, on liver histones in irradiated rats
Author
KoÍzurkovÍa M; HakovÍa H; MiÍsÍurovÍa E
Address
PrÍirodovedeckÍa fakulta UPJS, KoÍsice.
Source
Vet Med (Praha), 39(2-3):85-92 1994
Abstract
Changes of concentration, total content of histones and relative portions of histone fractions were investigated in the liver of rats after administration of the hepatoprotective substance Silymarin (70 mg/kg) and after gamma-irradiation of the whole body at a dose of 3 Gy, which were examined in 30 hours and in 7 days. Administration of Silymarin alone considerably increased the concentration, particularly total content of extractable histones in the liver of rats examined in hour 30. They decreased below the level of control values after 7 days. The whole body irradiation at a dose 3 Gy of gamma-radiation caused a steep fall of the concentration and total content of histones in hour 30, which persisted also on day 7. Silymarin administered 1 hour before irradiation prevented quantitative changes of histones in hour 30, after irradiation the fall was still steeper than after irradiation without Silymarin administration. As Tab. I shows, a significant decrease in the relative portion of histone fractions H2A+H2B was found in the extracted histone of the experimental animals of all 3 groups in hour 30, as well as a decrease in the fraction H1 after irradiation without Silymarin administration. A decrease in the lysin-rich-histone portion was related to an increase in the relative portion of histone H3. In the rats which were administered Silymarin 1 hour before irradiation these changes were found to persist until day 7, and they were related to an increase in the subfraction H1 degree within the histone fraction H1 (Tab II). Hence the results document that Silymarin administration 1 hour before irradiation had a positive effect which was observed in all the investigated parameters in hour 30 after irradiation. But the radioprotective effect of Silymarin was only temporary while until day 7 after irradiation histone variations were identical or still larger than after irradiation without Silymarin administration.

Title
Therapeutical effect of Silymarin on nucleic acids in the various organs of rats after radiation injury.
Author
Haková H; Misúrová E
Address
Department of Cellular and Molecular Biology, P.J. Safarik University, Kosice, Slovakia.
Source
Radiats Biol Radioecol, 36(3):365-70 1996 May-Jun
Abstract
The therapeutical effect of the hepatoprotective drug Silymarin (Flavobion) was investigated in rats after total body gamma irradiation with a dose of 6 Gy. Silymarin (70 mg kg-1 p.o. by tube) was administered twice a day over 7 and 14 days after irradiation. At the end of therapy, the effect of Silymarin was evaluated on the basis of quantitative changes of nucleic acids in the liver (regenerating after partial hepatectomy), spleen and bone marrow. It was found that the nucleic acid changes in irradiated rats were alleviated by the post-radiation application of Silymarin in its target organ--the liver, but also in the spleen and bone marrow. We assume that the therapeutical effect of Silymarin on radiation induced changes of nucleic acids in various tissues of rats is caused mainly by the activation of cellular metabolism including the metabolism of nucleic
acids.

Title
Acetaminophen-induced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by Silymarin.
Author
Shear NH; Malkiewicz IM; Klein D; Koren G; Randor S; Neuman MG
Address
Division of Dermatology, Sunnybrook Health Science Centre, Ont., Canada.
Source
Skin Pharmacol, 8(6):279-91 1995
Abstract
The skin and liver may be targets for cytotoxicity induced by oxidative drug metabolites. We used human epidermoid A431 cells and human hepatoblastoma Hep G2 cells as the experimental model. The aim of the study was to investigate and evaluate the effect of Silymarin on acetaminophen (APAP)-induced toxicity under controlled conditions. Silymarin is known to be a potent antioxidant that diminishes toxicity induced by a variety of other hepatotoxins (e.g. Amanita phaloides, algae's toxins, carbon tetrachloride). Glutathione (GSH) depletion was enhanced by adding to the medium buthionine sulfoximine [L-buthionine-(S,R)-sulfoximine, BSO]. Cells were incubated with high-concentration 5-20 mM APAP or alpha-(minimum essential medium for 2-24 h to evaluate the drug's ability to reduce cytoviability. Viability was then quantitated by metabolism of the tetrazolium dyes (MTT) and neutral red (NR). Cytoviability was 100% for controls. For Hep G2 treated for 24 h with 20 mM, APAP viability was 56.0% by MTT and 62.5% by NR. BSO-treated cells showed an enhanced cytotoxicity, determined by both assays. Administration of 0.5 mM Silymarin reduced cytotoxicity significantly. In A431 cells, treatment with 20 mM APAP reduced viability by 57% (MTT) and 69% (NR) versus control (100%). BSO further decreased viability. Since incubation with Silymarin showed significant protection against APAP toxicity, it can be considered a cytoprotective agent in this in vitro model of drug toxicity. GSH concentrations in both cell lines decrease significantly after exposure to 20 mM APAP, or 0.5 mM versus control (p < 0.05), and increased (p < 0.001) if incubated with APAP and Silymarin. The protective effect could be through mitochondrial membrane stabilization and/or an increase in available GSH.

Title
The pathology of liver injury induced by the chronic administration of alcohol and 'low-dose' carbon tetrachloride in Porton rats.
Author
Hall PM; Plummer JL; Ilsley AH; Ahern MJ; Cmielewski PL; Williams RA
Address
Department of Histopathology, Flinders Medical Centre, Bedford Park, Australia.
Source
J Gastroenterol Hepatol, 9(3):250-6 1994 May-Jun
Abstract
We have previously established a model for micronodular cirrhosis by feeding Wistar rats alcohol, in the Lieber-DeCarli liquid diet, and exposing them to 'low-dose' carbon tetrachloride (CCl4) vapour for 10 weeks. This study reports the spectrum of liver pathology seen in male Porton rats exposed to 'low-dose' CCl4 vapour 5 nights/week, 6 h/night while being fed alcohol (300 kcal/L) in the Lieber-DeCarli diet. Micronodular cirrhosis developed in all animals after 5-7 weeks of treatment. The simultaneous administration of Silymarin, a putative hepatoprotective agent, in the liquid diet, did not alleviate or prevent the chronic liver injury. The histopathological features of the liver injury are described, with particular emphasis on the presence of small epithelial cells ('progenitor or stem cell'), which appear to be playing a role in liver regeneration.

Title
Putative effect of Silymarin on sawfly (Arge pullata)-induced hepatotoxicosis in sheep.
Author
Thamsborg SM; Jorgensen; Brummerstedt E; Bjerregard J
Address
Department of Clinical Studies, Royal Veterinary and Agricultural University, Frederiksberg, Denmark.Source
Vet Hum Toxicol, 38(2):89-91 1996 Apr
Abstract
The prevention of hepatotoxicity from sawfly larvae (Arge pullata) was studied in 8 lambs by using Silymarin, a botanical compound isolated from Silybum marianum. Of 2 lambs dosed orally with larvae only, 1 had a marked toxic response whereas the other responded poorly as judged from clinical parameters, blood biochemistry and pathology. Two lambs treated with penicillin, glucose and Silymarin 7 and 24 h after larvae dosing were not affected by toxicosis, whereas 2 lambs treated similarly but without Silymarin responded intermediate to the other 2 groups. Our study suggests a favorable effect using Silymarin in treatment of sawfly larvae-induced ruminant hepatotoxicosis.

Title
The effect of Silymarin on concentration and total content of nucleic acids in tissues of continuously irradiated rats.
Author
Haková H; Misúrová E; Kropácová K
Address
P. J. Safárik University, Faculty of Sciences, Kosice, Slovak Republic.
Source
Vet Med (Praha), 41(4):113-9 1996 Apr
Abstract
The effect of the hepatoprotective drug Silymarin (Flavobion) on the radiation injury of rats continuously irradiated with gamma rays (60Co) was studied. The rats were irradiated during 14 days by the dose rates of 0.2 and 0.6 Gy/day. In the course of irradiation the animals were treated with Silymarin twice daily (70 mg/kg p. o. by tube). Silymarin effect was evaluated on the basis of quantitative changes of nucleic acids in the regenerating liver (after 70% hepatectomy), spleen, bone marrow and blood. Silymarin administration in the course of continuous gamma irradiation influenced beneficially the radiation-induced changes of DNA and RNA especially in the bone marrow.

Title
Long-term (12 months) treatment with an anti-oxidant drug (Silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients.
Author
Velussi M; Cernigoi AM; De Monte A; Dapas F; Caffau C; Zilli M
Address
Anti-Diabetes Centre, Monfalcone Hospital, Gorizia, Italy.
Source
J Hepatol, 26(4):871-9 1997 Apr
Abstract
BACKGROUND/AIMS: Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance. As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes, anti-oxidizing agents may be useful in treating or preventing damage due to free radicals. The aim of this study was to ascertain whether long-term treatment with Silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis. METHODS: A 12-month open, controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis. One group (n=30) received 600 mg Silymarin per day plus standard therapy, while the control group (n=30) received standard therapy alone. The efficacy parameters, measured regularly during the study, included fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria levels, glycosylated hemoglobin (HbA1c) and malondialdehyde levels. RESULTS: There was a significant decrease (p<0.01) in fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria and HbA1c levels already after 4 months of treatment in the Silymarin group. In addition, there was a significant decrease (p<0.01) in fasting insulin levels and mean exogenous insulin requirements in the treated group, while the untreated group showed a significant increase (p<0.05) in fasting insulin levels and a stabilized insulin need. These findings are consistent with the significant decrease (p<0.01) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group. Another interesting finding was the significant decrease (p<0.01) in malondialdehyde/levels observed in the treated group. CONCLUSIONS: These results show that treatment with Silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance, significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration.

Title
Effect of portal vein ligation and Silymarin treatment on aspirin metabolism and disposition in rats.
Author
Favari L; Soto C; Mourelle M
Address
Departamento de Farmacologia y Toxicologia, Cinvestav-I.P.N., Mexico.
Source
Biopharm Drug Dispos, 18(1):53-64 1997 Jan
Abstract
The influence of portal hypertension on the metabolism and pharmacokinetics of aspirin was evaluated after the administration of a single oral dose of acetylsalicylic acid (20 mgkg(-1)) in portal-vein-ligated (PVL) rats. Experiments were also performed in control (sham-operated rats) and in rats that received an oral daily dose (150 mgkg(-1)) of Silymarin from the tenth day after surgery for 7 d. Plasma concentration profiles of all groups exhibited monoexponential decay but with important changes in pharmacokinetic parameters. The aspirin elimination constant (k) for PVL rats was lower than for control rats, whereas the plasma half-life and area under the curve were greater than those in the control group. However, Cmax was comparable with that of the control rats. Urinary excretion of the metabolites (salicylic acid and glucuronides) was significantly altered in PVL rats: the urinary glucuronides were reduced and urinary salicylic acid was increased. The activities of plasma and liver esterases were increased significantly in PVL rats, while the activity of p-nitroanisole-O-demethylase was not affected. Depletion of cytochrome P 450 was also noted in the same group of rats. Silymarin markedly reversed the alterations found in the PVL group.

Title
Silymarin and its components are inhibitors of beta-glucuronidase.
Author
Kim DH; Jin YH; Park JB; Kobashi K
Address
College of Pharmacy, Kyunghee University, Seoul, Korea.
Source
Biol Pharm Bull, 17(3):443-5 1994 Mar
Abstract
Silymarin, a commercial crude drug used as a hepatoprotective, was found to inhibit 53% of beta-glucuronidase activity at a final concentration of 0.8 mg/ml. Of three compounds A, silybin and C, which were isolated from Silymarin, A and silybin potently inhibited the enzyme activity, followed by C. beta-Glucuronidases of intestinal bacteria, HGU-1 and HGU-2, and E. coli HB101 were noncompetitively inhibited by silybin. beta-Glucuronidase of the feces of a healthy human and of a human with colon cancer were also inhibited by silybin, Silymarin and saccharic acid 1,4-lactone at 0.03-0.15 mg/ml. Silymarin and silybin protected the increase in enzyme activity in the serum of the rats treated with CCl4.

Title
Hepatoprotective mechanism of Silymarin: no evidence for involvement of cytochrome P450 2E1.
Author
Miguez MP; Anundi I; Sainz-Pardo LA; Lindros KO
Address
Biomedical Research Center, ALKO Ltd, Helsinki, Finland.
Source
Chem Biol Interact, 91(1):51-63 1994 Apr
Abstract
The involvement of the alcohol-inducible cytochrome P450 2E1 in the hepatoprotective mechanism of the plant flavonoid extract Silymarin, and its main active component silybin, was investigated in isolated hepatocytes. Allyl alcohol toxicity, associated lipid peroxidation and GSH depletion was efficiently counteracted by Silymarin (0.01-0.5 mM), and at higher concentrations by silybin. Cell damage by t-butyl hydroperoxide was also prevented by Silymarin and silybin, but less efficiently. However, the covalent binding of the acetaminophen intermediate, formed via P450 2E1, was unaffected by addition of the flavonoids. silybin did not influence microsomal 2E1-catalyzed demethylation of N-nitrosodimethylamine. Neither did demethylation of N-nitrosodimethylamine or aminopyrine by isolated microsomes affect the in vivo administration of silybin. Addition of Silymarin or silybin to primary cultures of isolated hepatocytes did not prevent cell damage induced by exposure to the P450 2E1 substrate CCl4. In contrast, the mere presence of low concentrations (25-50 microM) of these compounds was found to inhibit cell attachment to the matrix and eventually resulted in cell damage. We conclude that contrary to earlier reports we found no evidence for an interaction of Silymarin or silybin with cytochrome P450 2E1. This suggests that the antioxidant and free radical scavenging properties may account for most of the therapeutic effect of these compounds. The untoward effect of Silymarin on cultured cells may have consequences when considering long-term prescription of this therapeutic agent.

Title
Hepatoprotective effect of the fractions of Ban-zhi-lian on experimental liver injuries in rats.
Author
Lin CC; Shieh DE; Yen MH
Address
Graduate Institute of Natural Products of Kaohsiung Medical College, Taiwan.
Source
J Ethnopharmacol, 56(3):193-200 1997 May
Abstract
The hepatoprotective effect of various fractions (n-hexane, CHCl3, EtOAc, n-BuOH, and H2O) of Ban-zhi-lian derived from Scutellaria rivularis Benth was studied against carbon tetrachloride (CCl4), D-galactosamine (D-GalN) and acetaminophen (APAP)-induced acute hepatotoxicity in rats. Liver damage was assessed by quantifying serum activities of glutamate oxaloacetate transaminase (sGOT) and glutamate pyruvate transaminase (sGPT), as well as by histopathological examination. The results indicated that the CHCl3 fraction and EtOAc fractions exhibited the greatest hepatoprotective effects on CCl4-induced liver injuries, the CHCl3 fraction and n-hexane fraction are most potent against D-GalN-induced intoxication, and the CHCl3 fraction represented the most liver-protective effect on APAP-induced hepatotoxicity. The pathological changes of hepatic lesions caused by these three hepatotoxicants were improved by treatment with the fractions mentioned above, which were compared to Glycyrrhizin (GLZ) and Silymarin as standard reference medicines.

Title
Gastroprotection induced by Silymarin, the hepatoprotective principle of Silybum marianum in ischemia-reperfusion mucosal injury: role of
neutrophils.
Author
AlarcÍon de la Lastra AC; MartÍin MJ; Motilva V; JimÍenez M; La Casa C; LÍopez A
Address
Departamento de Farmacia y TecnologÍia FarmacÍeutica, Facultad de
Farmacia, Sevilla, Spain.
Source
Planta Med, 61(2):116-9 1995 Apr
Abstract
Investigations were carried out to determine the antiulcer effects of Silymarin, the hepatoprotective principle of Silybum marianum L. Gaertn., in gastric injury induced by ischemia-reperfusion and its effects on mucosal myeloperoxidase activity, an index of polymorphonuclear leukocyte infiltration, after injury in rats. These results were compared with those from rats that received allopurinol, an inhibitor of xanthine oxidase and with those from rats made neutropenic by prior administration of dexamethasone and methotrexate. Pretreatment with Silymarin prevented post-ischemic mucosal injury. The mean ulcer indexes (U.I.) of rats treated with 25, 50 mg, and 100 mg Silymarin/kg body weight (4.79 +/- 0.75, 4.50 +/- 0.81, and 3.63 +/- 0.74, respectively) were significantly lower (p < 0.05, 0.05, and p < 0.005) than that of control rats. Allopurinol was considerably more potent in reducing the U.I. than Silymarin, with a calculated U.I. of 2.33 +/- 0.45, p < 0.001. These protective effects were specifically related to a reduction in the number of neutrophils in the gastric mucosa. Reduction in the numbers of circulating neutrophils by treating rats with methotrexate (MPO level of 7.2 x 10(-2) +/- 0.56 x 10(-2)U/mg wt) and dexamethasone (MPO level of 6.97 x 10(-2) +/- 0.68 x 10(-2)U/mg wt) also resulted in a significant reduction in the susceptibility to gastric damage induced by ischemia-reperfusion. These results suggest that neutrophils play an important role in the gastric mucosal dysfunction associated with ischemia-reperfusion. These findings also indicate that the inhibitory effects of Silymarin on neutrophil function may contribute significantly to its gastroprotective actions.

Title
Biochemical bases of the pharmacological action of the flavonoid Silymarin and of its structural isomer silibinin.
Author
Valenzuela A; Garrido A
Address
Unidad de Bioquímica Farmacológica y Lípidos, Universidad de Chile, Santiago.
Source
Biol Res, 27(2):105-12 1994
Abstract
The flavonoid Silymarin and one its structural components, silibinin, have been well characterized as hepato-protective substances. However, little is known about the biochemical mechanisms of action of these substances. This review deals with recent investigations to elucidate the molecular action of the flavonoid. Three levels of action have been proposed for Silymarin in experimental animals: a) as an antioxidant, by scavenging prooxidant free radicals and by increasing the intracellular concentration of the tripeptide glutathione; b) regulatory action of the cellular membrane permeability and increase of its stability against xenobiotic injury; c) at the nuclear expression, by increasing the synthesis of ribosomal RNA by stimulating DNA polymerase I and by exerting a steroid-like regulatory action on DNA transcription. The specific hepatoprotective action of silibinin against the toxicity of ethanol, phenylhydrazine and acetaminophen is also discussed. It is suggested that the biochemical effects observed for the flavonoid in experimental models may settle the basis for understanding the pharmacological action of Silymarin and silibinin.

Title
Alcohol and liver fibrosis--pathobiochemistry and treatment.
Author
Schuppan D; Atkinson J; Ruehl M; Riecken EO
Address
Klinikum Benjamin Franklin, Abteilung für Gastroenterologie und Hepatologie, Freie Universität, Berlin, Germany.
Source
Z Gastroenterol, 33(9):546-50 1995 Sep
Abstract
In Western societies roughly 50% of all cases of liver cirrhosis are related to alcohol abuse. The oxidative metabolite of ethanol, acetaldehyde, often in conjunction with viral or metabolic liver disease, is implicated as the major cause for liver fibrogenesis. Acetaldehyde damages cell membranes, initiates lipid peroxidation and forms noxious protein adducts, resulting in the activation of Kupffer cells and perisinusoidal lipocytes/portal fibroblasts. The activation of lipocytes and fibroblasts to a proliferative and collagen-producing myofibroblast-like phenotype is triggered by the release of fibrogenic factors such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) from the activated Kupffer cells. Due to the socioeconomic burden inflicted by cirrhosis, antifibrotic treatment is urgently needed. Strategies to prevent or reverse cirrhosis must interrupt the continuous process of pathological wound healing in the liver. An antifibrotic effect has been demonstrated for the interferons, prostaglandins E and relaxin. Polyunsaturated lecithin, Silymarin and ursodeoxycholic acid, agents with a high hepatotropism and a good safety-profile, appear to have antifibrotic properties. Targeted approaches include the specific removal of matrix-bound fibrogenic growth factors and the induction of stress-relaxation of the activated mesenchymal cells by biologically active matrix-peptides and their stable analogues. Since serum tests for the non-invasive assessment of collagen synthesis and degradation in the liver are now available, rapid progress in the development and clinical application of antifibrotic drugs can be anticipated.

 

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