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PubMed2003

Antitumour activity of the silybin-phosphatidylcholine complex, IdB 1016, against human ovarian cancer.

This study aimed to assess, in an in vivo experimental model, the growth inhibitory effects of IdB 1016 (Silipide, a complex of silybin/phosphatidylcholine) when used as a single agent against human ovarian cancer. We also wanted to investigate the mechanism of the antiangiogenic action by assessing Vascular Endothelial Growth Factor (VEGF) levels and by using macroarray technology to evaluate the regulation of a panel of genes involved in angiogenesis. We also aimed to establish the plasma and tumour bioavailability of silybin after repeated administration of IdB 1016. Female nude mice bearing human ovarian cancer xenografts (A2780) received 450 mg/kg/day IdB 1016 daily by oral gavage until the end of the study. At sacrifice, blood and tumour specimens were collected and subsequently processed for the determination of silybin levels, VEGF levels or a gene expression profile. IdB 1016 was significantly active in inhibiting ovarian tumour growth. Treatment with 450 mg/kg/day for a total of 20 administrations produced a tumour weight inhibition (TWI%) of 78% and a Log10 Cell Kill (LCK) of 1.1. Free silybin levels were found to be 7.0+/-5.3 microg/ml and 183.5+/-85.9 ng/g tissue (mean+/-standard deviation (S.D.)) in the plasma and tumour samples, respectively. No significant differences were found in the concentration of human VEGF in xenografts from control and IdB 1016-treated mice. The array analysis suggested the downregulation of the VEGR receptor 3 and the upregulation of angiopoietin-2 as potential mechanisms for the antiangiogenic activity. In conclusion, these findings suggest IdB 1016 is a good candidate, with a relevant clinical potential, for use in the management of recurrent ovarian cancer. A phase II, non-randomised clinical study is now ongoing in our Institute aimed at evaluating the efficacy of daily administrations of IdB 1016 in the serological recurrence of ovarian cancer.

Animals↗

PubMed1987

Effects of silybin on histamine release from human basophil leucocytes.

1. Effects of a naturally occurring flavonoid, silybin, on histamine release from human basophils were examined, in order to assess the potential utility in the treatment of allergic disorders. 2. The f-met peptide and anti-IgE-induced histamine release was significantly (P less than 0.05) inhibited in a concentration-dependent fashion. Conversely, no significant (P greater than 0.05) effect on calcium ionophore A23187-induced histamine secretion was documented. The inhibitory activity was significantly (P less than 0.05) reversed by elevating extracellular calcium concentrations. 3. The anti-allergic properties of silybin can be reasonably ascribed to a membrane-stabilizing activity, possibly related to an interference in calcium influx. These results indicate that an in vivo evaluation of the anti-allergic activity of silybin would be worthwhile.

Adult↗

PubMed1991

Acetaminophen does not induce oxidative stress in isolated rat hepatocytes: its probable antioxidant effect is potentiated by the flavonoid silybin.

Acetaminophen hepatotoxicity is characterized by glutathione depletion and the formation of the reactive electrophilic metabolite N-acetyl-p-benzoquinone imine. The induction of oxidative stress, expressed as lipid peroxidation, is controversial in acute acetaminophen intoxication. Isolated rat hepatocytes develop spontaneously or when incubated with buthionine sulfoximide, a progressive lipid peroxidation which may be inhibited by the antioxidant flavonoid silybin. When cells are incubated with acetaminophen, lipid peroxidation is not observed, this antilipoperoxidative effect being potentiated by silybin. It is proposed that when hepatocytes are incubated with a high concentration of acetaminophen, the drug may accumulate in the cells due to saturation and/or inhibition of detoxification pathways (as in the case of silybin). Under these conditions the development of hepatocyte oxidative stress may be inhibited due to the antioxidant behaviour of acetaminophen.

Acetaminophen↗

PubMed1994

Inhibition of rat liver cytosolic glutathione S-transferase by silybin.

1. The naturally occurring hepatoprotective compound silybin is a potent inhibitor of glutathione S-transferase isoenzymes 1-1, 2-2, 3-3, and 4-4, displaying a high degree of isoenzyme selectivity. 2. Using CDNB at a fixed concentration of 1 mM and varying the GSH concentration, silybin exhibited competitive inhibition of isoenzyme 2-2 with a Ki of 32 microM, non-competitive and predominantly non-competitive inhibition of isoenzymes 1-1 and 4-4 with Kis of 20 and 1.2 microM, respectively, and uncompetitive inhibition of isoenzyme 3-3 with a Ki of 0.2 microM. 3. With CDNB as the variable concentration substrate silybin exhibited competitive inhibition of isoenzyme 1-1 with a Ki of 8 microM, non-competitive inhibition of isoenzyme 2-2 with a Ki of 41 microM, and non-competitive inhibition of isoenzymes 3-3 and 4-4 with Kis of 0.8 and 0.5 microM, respectively.

Animals↗

PubMed1975

[Phalloidine antagonists. 1. Effects of silybine derivatives on isolated perfused rat liver].

The protective effect of two silybin derivatives against phalloidin was tested in isolated rat livers, perfused with an erythrocyte free medium. Both liver swelling and potassium loss were examined for the evaluation of antagonism. Liver swelling and potassium loss were markedly decreased when silybin hemisuccinate was added to the perfusion medium before the application of phalloidin. In contrast, the protective effect of this compound was minimal after the mushroom toxin was partially absorbed by the liver. The protective efficiency of a dimer derivative (disilybin) was much greater than that of the monomer product. The binding of both derivatives in the liver cannot be very strong because the protective effect mainly could be washed out by a single change of the perfusion medium. Spectroscopical studies on isolated hepatocytes indicate that silybin inhibits the interaction of phalloidin with the cell surface.

Absorption↗

PubMed1975

[The effect of silybin-dihemisuccinate on regulation disorders in phospholipid metabolism in acute galactosamine intoxication in the rat].

1. 24 h after application of 900 mg D-galactosamine/kg body weight, an increase of total lipids, triglycerides, phosphatidyl-choline and phosphatidic acid concentrations, and also a decrease of total phospholipids and phosphatidylethanolamine can be determined in the whole rat liver. After administration of [1-14C]-palmitate, specific radioactivity of phosphatidyl-choline is diminished without alteration of specific radioactivity of other lipid fractions. Prophylactic application of silybin-dihemisuccinate abolished completely decrease of phosphatidyl-ethanolamine and diminished increase of total lipids and triglyceride concentrations. 2. Specific radioactivity of total lipids in serum of galactosamine-intoxicated rats is enhanced, specific radioactivity of triglycerides and phospholipids is diminished, simultaneously, total lipids concentration is reduced. 3. In the microsomal fraction of galactosamine-injured livers, a decrease of specific radioactivity of total phospholipids and phosphatidyl-choline can be observed. Prophylactic administration of silybin abolishes diminution of specific radioactivity of phosphatidyl-choline partially. 4. Diminution of specific radioactivity of total lipids, total phospholipids and phosphatidyl-ethanolamine, induced by galactosamine intoxication in the mitochondrial fraction, is normalized by application of silybin. 5. Diminished triglyceride infiltration in siybin-treated rats may be based onnormalization of inhibited phosphatidyl-choline turnover.

Animals↗

PubMed1991

[Alterations in insulin receptor in injured rats and the effects of dexamethasone and silybin].

The purpose of this study is to examine the alterations in hepatocyte insulin receptors in rats subjected to scald and restrained water immersion stress and the effects of dexamethasone and silybin. In scalded rats, plasma glucose and insulin levels were higher than that of normal rats, suggesting the occurrence of insulin resistance following injury. The maximal binding capacity (Ro) and highest insulin binding rate (Bo/T) of hepatocyte insulin receptors were significantly reduced in rats 72h postscalding, while there was no obvious change in affinity (Ke Kf). The Ro and Bo/T of the restrained water immersion stress rats were also reduced significantly, but the affinity was increased. Dexamethasone significantly enhanced Ro in rats 72h postscalding with significant decrease in affinity (Ke). Silybin significantly enhanced Ro and Bo/T 72h postscalding with no obvious change in affinity. It is suggested that insulin resistance following injury may be a consequence of receptor defect of the target cells, and for disturbance of glucose metabolism following injury, it is not beneficial to use dexamethasone, but silybin may be used with benefit.

Animals↗

PubMed1990

[Effects of silybin on production of oxygen free radical, lipoperoxide and leukotrienes in brain following ischemia and reperfusion].

Brain ischemia was produced by occluding bilateral common carotid arteries of Mongolia gerbil with clips for 30-min and reperfusion was established by removing the clips. Superoxide dismutase (SOD) in brain tissue was measured by chemoluminescence, malondialdehyde (MDA) by fluorescence spectrometry and leukotrienes (LT) by bioassay. Decrease of SOD and increase of MDA were significant in the brain after 30-min ischemia followed by 2-min reperfusion; The level of SOD increased from 13.4 +/- 2.7 to 18.8 +/- 3.0, 19.8 +/- 2.5, 22.1 +/- 3.9 x 10(3) units/g brain tissue and MDA decreased from 218 +/- 26 to 169 +/- 41, 167 +/- 36, 167 +/- 44 nmol/g brain tissue respectively by ip silybin 100, 200 and 400 mg/kg 30-min before occlusion. LT decreased from 3.1 +/- 1.0 to 1.5 +/- 0.4 ng/g brain tissue after ip silybin 200 mg/kg. It suggested that the protective effect of silybin on ischemic brain result from the inhibition of 5-lipoxygenase and lipoperoxide and scavenging of oxygen free radical.

Animals↗

PubMed1988

Silybin inhibition of human T-lymphocyte activation.

Silybin, a 3-oxyflavone occurring in the thistle Silybum marianum, displays a dose-dependent inhibition of in-vitro lymphocyte blastogenesis induced by lectins (phytohaemagglutinin, Concanavalin A and pokeweed) and by anti-CD3 monoclonal antibody. The drug has no effect on cell viability and spontaneous 3H-thymidine incorporation, suggesting that the inhibitory activity is not due to aspecific toxicity. Since all the T-cell responses investigated require cell-membrane-associated events, the effect of silybin is probably at the level of the cell membrane, as for other flavonoids. Addition of CuSO4 prevents the inhibitory activity of silybin on PHA-induced proliferative response, indicating that the drug could exert its activity also by virtue of a chelation mechanism.

Antibodies, Monoclonal↗

PubMed1975

[General pharmacologic properties of silybine and silymarine in the rat].

Silybine is the main active substance of the polyhydroxyphenylchromanone derivatives extracted from the seeds of Silybum Marianum. In the normal albinos rat, this pure compound (from 2 mg/100 g) lowers directly the systemic blood pressure. It does not increase vascular permeability. It potentiates post-serotonine hypertension. Silybine antagonizes cutaneous oedemas and suppresses the fall of blood pressure induced by dextran polymers. It inhibits anaphylactic shock in rats sensitized by ovalbumine. Silybine seems to be a stabilizer of mastcells membranes, thus preventing histamine release.

Anaphylaxis↗

PubMed1989

Effect of silybin dihemisuccinate on the ethanol metabolizing systems of the rat liver.

Silybin dihemisuccinate produces a decrease in the ethanol metabolic rate of rats. This effect is ascribed to an inhibition of the microsomal ethanol oxidizing system (MEOS). Alcohol dehydrogenase activity, catalase activity and NADPH cytochrome c reductase activity are not affected by the flavonoid. It is proposed that the inhibition of MEOS by silybin dihemisuccinate is related to its antioxidant properties, acting as a scavenger of the free radicals involved in ethanol metabolism by this enzymatic system. This observation may have therapeutical implications because microsomal lipid peroxidation induced by hydroxyl free radicals has been related to the etiology of hepatic alcoholic disease.

Animals↗

PubMed2002

Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities.

Silybin and related flavonolignans form a major part of the Silybum marianum extract, silymarin, which has been used to treat liver diseases for hundreds of years. Although regarded as safe, many of the extract constituents remain thus far untested for their possible effects on liver biotransformation enzymes. Cytochromes P450 (CYP) are very important in this regard. We tested the effect of four flavonolignans: silybin, its hemisynthetic derivative dehydrosilybin, silydianin, and silycristin on three specific CYP activities: bufuralol 1'-hydroxylation (CYP2D6), p-nitrophenol hydroxylation (CYP2E1), and nifedipine oxidation (CYP3A4). All flavonolignans displayed dose-dependent inhibition of these activities with IC(50) values in the micromolar range. The inhibition was competitive or mixed as revealed by double reciprocal plots of kinetic experiments. However, the inhibition is not considered to be relevant for therapy because physiological concentrations of the individual flavonolignans do not exceed 0.5 microM. The data support the use of the extract as a dietary supplement.

Cytochrome P-450 CYP2D6↗

PubMed1986

Differential effect of silybin on the Fe2+-ADP and t-butyl hydroperoxide-induced microsomal lipid peroxidation.

We have observed a differential effect of silybin dihemisuccinate on rat liver microsomal oxygen consumption and on lipid peroxidation induced by NADPH-Fe2+-ADP and t-butyl hydroperoxide. These results are ascribed to the antioxidant properties of the flavonoid. The differences observed in the effect of the catalysts may be a consequence of the different capacity of silybin to act as a scavenger of free radicals formed by NADPH-Fe2+-ADP or t-butyl hydroperoxide.

Adenosine Diphosphate↗

PubMed1985

Protective effect of the flavonoid silybin dihemisuccinate on the toxicity of phenylhydrazine on rat liver.

Phenylhydrazine is a hemolytic agent whose mechanism of action is related with the formation of free radicals and the induction of lipid peroxidation. The flavonoid silybin dihemisuccinate is an antihepatotoxic principle used in the treatment of many liver diseases; its mechanism of action has been ascribed to its antioxidant properties. This work demonstrates, using a hemoglobin-free perfusion system, the protective effect of the in vivo treatment of the rat with silybin dihemisuccinate on the hepatic glutathione depletion and lipid peroxidation induced by the infusion of phenylhydrazine into the perfusion buffer.

Animals↗

PubMed2006

New derivatives of silybin and 2,3-dehydrosilybin and their cytotoxic and P-glycoprotein modulatory activity.

Large series of O-alkyl derivatives (methyl and benzyl) of silybin and 2,3-dehydrosilybin was prepared. Selective alkylation of the silybin molecule was systematically investigated. For the first time we present here, for example, preparation of 19-nor-2,3-dehydrosilybin. All prepared silybin/2,3-dehydrosilybin derivatives were tested for cytotoxicity on a panel of drugs sensitive against multidrug resistant cell lines and the ability to inhibit P-glycoprotein mediated efflux activity. We have identified effective and relatively non-cytotoxic inhibitors of P-gp derived from 2,3-dehydrosilybin. Some of them were more effective inhibitors at concentrations lower than a standard P-gp efflux inhibitor cyclosporin A. Another group of 2,3-dehydrosilybin derivatives also had better inhibitory effects on P-gp efflux but a cytotoxicity comparable with that of parent 2,3-dehydrosilybin. Structural requirements for improving inhibitory activity and reducing toxicity of 2,3-dehydrosilybin were established. Effect of E-ring substitution as well as an influence of the substituent size at the C-7-OH position of A-ring on P-gp-inhibitory activity was evaluated for the first time in this study.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Separation and characterization of silybin, isosilybin, silydianin and silychristin in milk thistle extract by liquid chromatography-electrospray tandem mass spectrometry.

A selective and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed for the characterization of silymarin in commercially available milk thistle extract. In this study, six main active constituents, including silydianin, silychristin, diastereomers of silybin (silybin A and B) and diastereomers of isosilybin (isosilybin A and B) in silymarin, were completely separated on a YMC ODS-AQ HPLC column using a gradient mobile phase system comprised of ammonium acetate and methanol/water/formic acid. Identification and characterization of the major constituents were based not only on the product ion scan, which provided unique fragmentation information of a selected molecular ion, but also on the specific fragmentation of multiple reaction monitoring (MRM) data, which confirmed the retention times of LC chromatographic peaks. The method was applied in the analysis of human plasma samples in the presence of silymarin and appeared to be suitable for the pharmacokinetic studies in which the discrimination of silymarin constituents is essential.

Chromatography, High Pressure Liquid↗

PubMed1989

Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver.

Acetaminophen hepatotoxicity is characterized by glutathione depletion, cellular necrosis, and, in some instances, by the induction of lipid peroxidation. Silybin dihemisuccinate, a soluble form of the flavonoid silymarin, protects rats against liver glutathione depletion and lipid peroxidation induced by acute acetaminophen intoxication. Other biochemical parameters such as serum transaminases did not show the drastic increase observed under acetaminophen intoxication when animals were treated with the flavonoid. Preliminary results suggest that silybin dihemisuccinate may be another antidote against acetaminophen hepatotoxicity.

Acetaminophen↗

PubMed2006

Silybin reduces lipid peroxidation of rat hepatocyte membrane caused by cyclosporin A.

An effect of cyclosporin A on lipid peroxidation in isolated rat hepatocytes was tested. A significant increase in lipid peroxidation marker (the concentration of lipofuscin-like pigments) was observed in samples incubated with cyclosporin A in comparison with the control. When hepatoprotective flavonoid silybin was added, the production of lipofuscin-like pigments decreased significantly. This result indicates a potential positive role of silybin in lowering of cyclosporin A side effects associated with the production of reactive oxygen species and plasma membrane damage.

Animals↗