PREVENTION OF CCL<sub>4</sub>‐INDUCED LIVER CIRRHOSIS BY SILYMARIN

Mourelle, Marisabel; Muriel, Pablo; Favari, Liliana; Franco, T. T.

doi:10.1111/j.1472-8206.1989.tb00449.x

Cited by 153 publications

(76 citation statements)

References 29 publications

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“…Favari and Perez-Alvez reported that orally administered silymarin (50 mg/kg) to the rats with chronic carbon tetrachloride (CCl4) liver damage could reduce the collagen content in the liver of these animals up to 55% (increased with CCl4 approximately 4-to 6-fold as compared to controls) (Favari and Perez-Alvarez, 1997). In similar experiments, there was a reduction of collagen and pro-collagen III contents after biliary obstruction in the rat by 30% with 50 mg/kg/day although not at the level of 25 mg/kg/day of silymarin (Mourelle et al, 1989;Boigk et al, 1997). Silymarin suppressed the expression of pro-fibrogenic procollagen-α1(I) and TIMP-1 most likely via down-regulation of TGF-β1 mRNA in the rats with biliary fibrosis (Jia et al 2001).…”

Section: Antifibrotic Activitymentioning

confidence: 80%

Milk thistle in liver diseases: past, present, future

Abenavoli

Capasso²,

Milić

et al. 2010

Phytotherapy Research

502

350

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Silybum marianum or milk thistle (MT) is the most well‐researched plant in the treatment of liver disease. The active complex of MT is a lipophilic extract from the seeds of the plant and is composed of three isomer flavonolignans (silybin, silydianin, and silychristin) collectively known as silymarin. Silybin is a component with the greatest degree of biological activity and makes up 50% to 70% of silymarin. Silymarin is found in the entire plant but it is concentrated in the fruit and seeds. Silymarin acts as an antioxidant by reducing free radical production and lipid peroxidation, has antifibrotic activity and may act as a toxin blockade agent by inhibiting binding of toxins to the hepatocyte cell membrane receptors. In animals, silymarin reduces liver injury caused by acetaminophen, carbon tetrachloride, radiation, iron overload, phenylhydrazine, alcohol, cold ischaemia and Amanita phalloides. Silymarin has been used to treat alcoholic liver disease, acute and chronic viral hepatitis and toxin‐induced liver diseases. Copyright © 2010 John Wiley & Sons, Ltd.

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Section: Antifibrotic Activitymentioning

confidence: 80%

Milk thistle in liver diseases: past, present, future

Abenavoli

Capasso²,

Milić

et al. 2010

Phytotherapy Research

502

350

View full text Add to dashboard Cite

show abstract

“…In these investigations, such flavonoids reduced hepatocyte damage caused by administration of various chemicals including, among others, allyl alcohol (Miguez et al 1994), carbon tetrachloride (Mourelle et al 1989), halo-thane (Siegers et al 1983), acetaminophen (Muriel et al 1992) and phenylhydrazine (Valenzuela et al 1985). Several mechanisms of action were discussed: (1) stimulation of protein synthesis in the hepatocytes (Machicao & Sonnenbichler 1977), (2) radical scavenging and antioxidant properties (Ubeda et al 1995), (3) prevention of penetration of toxins into the cell (Münter et al 1986), and (4) inhibition of 5-lipoxygenase with reduced formation of leucotriens (Dehmlow et al 1996).…”

mentioning

confidence: 99%

Inhibitory Effects of Silibinin on Cytochrome P‐450 Enzymes in Human Liver Microsomes

Beckmann-Knopp¹,

Rietbrock²,

Weyhenmeyer³

et al. 2000

Pharmacology & Toxicology

130

101

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Silibinin, the main constituent of silymarin, a flavonoid drug from silybum marianum used in liver disease, was tested for inhibition of human cytochrome P-450 enzymes. Metabolic activities were determined in liver microsomes from two donors using selective substrates. With each substrate, incubations were carried out with and without silibinin (concentrations 3.7-300 mM) at 37ae in 0.1 M KH 2 PO 4 buffer containing up to 3% DMSO. Metabolite concentrations were determined by HPLC or direct spectroscopy. First, silibinin IC 50 values were determined for each substrate at respective K M concentrations. Silibinin had little effect (IC 50 Ͼ200 mM) on the metabolism of erythromycin (CYP3A4), chlorzoxazone (CYP2E1), S(π)-mephenytoin (CYP2C19), caffeine (CYP1A2) or coumarin (CYP2A6). A moderate effect was observed for high affinity dextromethorphan metabolism (CYP2D6) in one of the microsomes samples tested only (IC 50 Ω173 mM). Clear inhibition was found for denitronifedipine oxidation (CYP3A4; IC 50 Ω29 mM and 46 mM) and S(ª)-warfarin 7-hydroxylation (CYP2C9; IC 50 Ω43 mM and 45 mM). When additional substrate concentrations were tested to assess enzyme kinetics, silibinin was a potent competitive inhibitor of dextromethorphan metabolism at the low affinity site, which is not CYP2D6 (K i,c Ω2.3 mM and 2.4 mM). Inhibition was competitive for S(ª)-warfarin 7-hydroxylation (K i,c Ω18 mM and 19 mM) and mainly non-competitive for denitronifedipine oxidation (K i,n Ω9 mM and 12 mM). With therapeutic silibinin peak plasma concentrations of 0.6 mM and biliary concentrations up to 200 mM, metabolic interactions with xenobiotics metabolised by CYP3A4 or CYP2C9 cannot be excluded.

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“…CCl 4 causes liver necrosis, steatosis, degeneration of hepatocytes (44), and cirrhosis (7,45). CCl 4 was also found to precipitate apoptosis in the liver (46).…”

Section: Discussionmentioning

confidence: 99%