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PubMed2005

[Study on the preparation and bio-distribution of silybin lipid nanospheres].

OBJECTIVE: To prepare silybin lipid nanospheres (SLN) and to evaluate the properties of morphology, particle size and the silybin distribution in mice. METHOD: Silybin lipid nanospheres were prepared by thin film emulsion-high pressure homogenization technique. Concentrations of silybin in mice blood, liver, spleen, lung, kidney, brain, heart, stomach after oral administration were determined by high performance liquid chromatography. RESULT: Scanning electron micrograph showed that most of the SLN were spherical. The average diameter from photon correlation spectrometer was 148.9 nm with the polydispersity 0.17. Body distribution data indicated that SLN could increase the distribution of silybin in blood and liver, decrease the amount of silybin in stomach as compared with the preparation on market, and the drug targeting index (DTI) in liver was 1.81. CONCLUSION: SLN can increase the uptake of silybin in liver after oral administration, which must benefit the hepatitis treatment.

Administration, Oral↗

PubMed2000

Chemoenzymatic preparation of silybin beta-glucuronides and their biological evaluation.

Chemoenzymatic glucuronidation of the optically pure silybin A (1) using ovine liver glucuronyl transferase afforded three beta-glucuronides of silybin, substituted at phenolic OH groups at the positions C-20 (2), C-7 (3), and C-5 (4) formed in the yields 27, 62.5, and 2.5%, respectively. Using these standards, it was shown that the main silybin conjugate in humans is its 20-beta-D-glucuronate (2), while the C-7 regioisomer (3) was formed in lower proportion. The rate of conjugation of (natural) silybin diastereomers 10S, 11S and 10R, 11R, and therefore also their metabolism in humans is rather different. The radical scavenging activity of 2 is considerably lower than that of its aglycone (1); however, the activity of 3 is higher than in the silybin. These findings corroborate the hypothesis that, at physiological pH, the exclusive target for one-electron oxidation of the silybin molecule is the o-methoxy-phenolic structure at C-19, C-20. This is first pharmacological study using optically pure silybin.

Chromatography, High Pressure Liquid↗

PubMed1983

[Pharmacotherapy of Amanita phalloides poisoning using silybin].

A total of 18 cases of Amanita phalloides poisoning was treated by combined chemotherapy during 1980 and 1981. After attempted primary elimination of the toxin all patients received silybin as basic therapy mainly by infusion and, in two instances, silymarin orally. In order to investigate the effect of silybin therapy a retrospective study of the followed-up case records was made. The cases were arbitrarily classified into three groups of severity (light, medium and severe) according to clinical and laboratory findings. A close relationship was found between the severity of the intoxication and the time elapsed before commencement of silybin therapy. The time interval between mushroom intake and the commencement of the silybin administration averaged 71.5 hours in the "severe" group compared with 46 and 33.8 hours, respectively, in the "medium" and "light" groups. The mean silybin dosage was 33 mg/kg body weight/day; the mean duration of silybin therapy was 81.6 hours. With the exception of one fatality in a particularly high dosage suicidal intoxication, all patients survived. Administration of silybin within about 48 hours after mushroom intake seems to be an effective measure to prevent severe liver damage in Amanita phalloides poisoning.

Adult↗

PubMed2004

Oxidised derivatives of silybin and their antiradical and antioxidant activity.

Carboxylic acids derived from silybin (1) and 2,3-dehydrosilybin (2) with improved water solubility were prepared by selective oxidation of parent compounds and a new inexpensive method for preparation of 2,3-dehydrosilybin from silybin was developed and optimised. The antioxidative properties of the above-mentioned compounds and of side product 3a from oxidation of compound 1 were determined by cyclic voltammetry, free radical scavenging (DPPH, superoxide) assays, and by inhibition of in vitro generated liver microsomal lipid peroxidation. Dehydrogenation at C((2))-C((3)) in flavonolignans (silybin vs 2,3-dehydrosilybin; silybinic acid vs 2,3-dehydrosilybinic acid) strongly improved antioxidative properties (analogously as in flavonoids taxifolin vs quercetin). Thus, in antioxidative properties, dehydrosilybin was superior to silybin by one order, but its water solubility is too low for application in aqueous milieu. On the other hand, 2,3-dehydrosilybinic acid is a fairly soluble derivative with antilipoperoxidation and antiradical activities better than that of silybin.

Animals↗

PubMed2005

Microbial transformation of silybin by Trichoderma koningii.

Microbial transformation of silybin A (1) and silybin B (2), the major hepatoprotective flavonolignan diastereomers from the fruits of Silybum marianum, with the culture broth of Trichoderma koningii gave two pairs of glucosylated derivatives. Their structures were identified as silybin A 3-O-beta-D-glucopyranoside (3), silybin A 7-O-beta-D-glucopyranoside (4), silybin B 3-O-beta-D-glucopyranoside (5) and silybin B 7-O-beta-D-glucopyranoside (6) by spectroscopic methods.

Fruit↗

PubMed2004

Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases.

Silybin, a major constituent of the milk thistle, is used to treat several liver disorders. Silybin inactivated purified, recombinant cytochromes P450 (P450) 3A4 and 2C9 in a mechanism-based manner. The inactivations were time-, concentration-, and NADPH-dependent. The inactivation of the 7-benzyloxy-4-(trifluoromethyl-)coumarin O-debenzylation activity (P450 3A4) was characterized by a K(I) of 32 microM, a k(inact) of 0.06 min(-1), and a t(1/2) of 14 min. Testosterone metabolism to 6-beta-hydroxytestosterone (P450 3A4) was also inactivated with a K(I) of 166 microM, a k(inact) of 0.08 min(-1), and a t(1/2) of 9 min. The 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity of purified human P450 2C9 was inactivated with a K(I) of 5 microM, a k(inact) of 0.14 min(-1), and a t(1/2) of 7 min. Parallel loss of heme was observed with both P450s. Activity of both P450 enzymes was not recovered after removal of silybin either by dialysis or by spin gel filtration. In addition, silybin inhibited the glucuronidation of 7-hydroxy-4-trifluoromethylcoumarin catalyzed by recombinant hepatic UDP-glucuronosyltransferases (UGTs) 1A1, 1A6, 1A9, 2B7, and 2B15, with IC(50) values of 1.4 microM, 28 microM, 20 microM, 92 microM, and 75 microM, respectively. Silybin was a potent inhibitor of UGT1A1 and was 14- and 20-fold more selective for UGT1A1 than for UGT1A9 and UGT1A6, respectively. Thus, careful administration of silybin with drugs primarily cleared by P450s 3A4 or 2C9 is advised, since drug-drug interactions cannot be excluded. The clinical significance of in vitro UGT1A1 inhibition is unknown.

Aryl Hydrocarbon Hydroxylases↗

PubMed1995

Antioxidant activity of silybin in vivo during long-term iron overload in rats.

BACKGROUND & AIMS: Hepatic iron toxicity may be mediated by free radical species and lipid peroxidation of biological membranes. The antioxidant property of silybin, a main constituent of natural flavonoids, was investigated in vivo during experimental iron overload. METHODS: Rats were fed a 2.5% carbonyl-iron diet and 100 mg.kg body wt-1.day-1 silybin for 4 months and were assayed for accumulation of hepatic lipid peroxidation by-products by immunocytochemistry, mitochondrial energy-dependent functions, and mitochondrial malondialdehyde content. RESULTS: Iron overload caused a dramatic accumulation of malondialdehyde-protein adducts into iron-filled periportal hepatocytes that was decreased appreciably by silybin treatment. The same beneficial effect of silybin was found on the iron-induced accumulation of malondialdehyde in mitochondria. As to the liver functional efficiency, mitochondrial energy wasting and tissue adenosine triphosphate depletion induced by iron overload were successfully counteracted by silybin. CONCLUSIONS: Oral administration of silybin protects against iron-induced hepatic toxicity in vivo. This effect seems to be caused by the prominent antioxidant activity of this compound.

Adenosine Triphosphate↗

PubMed1993

Protective effects of silybin and tetrandrine on the outcome of spontaneously hypertensive rats subjected to acute coronary artery occlusion.

The effects of silybin and tetrandrine on the survival of spontaneously hypertensive rats subjected to acute coronary artery occlusion were investigated. The mortality after acute coronary occlusion in spontaneously hypertensive rats (66.7%) was higher than that of control Wistar-Kyoto rats (20%, P < 0.05). Oral administration of silybin (300 mg/kg daily) for 8-12 days reduced mortality in spontaneously hypertensive rats (0, P < 0.01 in comparison with untreated spontaneously hypertensive rats). Administration of tetrandrine 40 mg/kg daily for 8-12 days reduced the mortality to some extent (22.2%, P = 0.051, as compared with control rats). Silybin reduced blood pressure and the incidence of post-occlusion arrhythmias in spontaneously hypertensive rats to the same extent as tetrandrine. Both silybin and tetrandrine decreased the severity of ventricular hypertrophy. Although there were significant decreases in risk zone and infarct zone in silybin- and tetrandrine-treated rats, the ratio of infarct to risk zone was not changed. The results implies that silybin may be beneficial when used in hypertensive patients who develop acute myocardial infarction.

Alkaloids↗

PubMed1993

[Effects of silybin on red blood cell sorbitol and nerve conduction velocity in diabetic patients].

The effects of silybin on red blood cell (RBC) sorbitol and nerve conduction velocity in 14 non-insulin dependent diabetic patients (female 9, male 5; average age 58.2 years) were reported. Their RBC sorbitol levels averaged 72.55 +/- 21.61 nmol/g.Hb, a value almost two times of non-diabetic controls (33.31 +/- 7.82 nmol/g.Hb). After 4 weeks of silybin (231 mg/d) therapy, RBC sorbitol dropped to 39.53 +/- 14.94 nmol/g.Hb, a highly significant reduction than that before silybin therapy. Silybin treatment had no effect on fasting blood glucose. In addition, silybin treatment slightly improved nerve conduction velocity, but statistically not significant. This report suggests that silybin may be a potent aldose reductase inhibitor, and valuable in the prophylaxis and treatment of diabetic complications.

Diabetes Mellitus, Type 2↗

PubMed2006

Silybin and dehydrosilybin inhibit cytochrome P450 1A1 catalytic activity: a study in human keratinocytes and human hepatoma cells.

The flavonolignan silybin and its derivative dehydrosilybin have been proposed as candidate UV-protective agents in skin care products. This study addressed the effect of silybin and dehydrosilybin on the activity of cytochrome P450 isoform CYP1A1 in human keratinocytes (HaCaT) and human hepatoma cells (HepG2). CYP1A1 catalytic activity was assessed as O-deethylation of 7-ethoxyresorufin using fluorescence detection. Silybin and dehydrosylibin inhibited basal and dioxin-inducible CYP1A1 catalytic activity in both cell lines used. The inhibitory effect of tested compounds was more pronounced in HaCaT cells than in HepG2 cells, and dehydrosilybin was a much stronger inhibitor than silybin. Analyses on CYP1A1 human recombinant protein yielded IC(50) values of 22.9 +/- 4.7 micromol/L and 0.43 +/- 0.04 micromol/L for silybin and dehydrosilybin, respectively. Since CYP1A enzymes are some of the most prominent actors in the process of chemically induced carcinogenesis, the inhibitory activity of the flavonolignans tested against CYP1A1 favors their use as cytoprotective agents in terms of skin and hepatic metabolism. In addition, the capability of dehydrosilybin to inhibit CYP1A1 in submicromolar concentrations makes this compound a potential biological probe in CYP1A1 analyses.

Carcinoma, Hepatocellular↗

PubMed2006

A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients.

Silibinin is a polyphenolic flavonoid isolated from milk thistle with anti-neoplastic activity in several in vitro and in vivo models of cancer, including prostate cancer. Silybin-phytosome is a commercially available formulation containing silibinin. This trial was designed to assess the toxicity of high-dose silybin-phytosome and recommend a phase II dose. Silybin-phytosome was administered orally to prostate cancer patients, giving 2.5-20 g daily, in three divided doses. Each course was 4 weeks in duration. Thirteen patients received a total of 91 courses of silybin-phytosome. Baseline patient characteristics included: median age of 70 years, median baseline prostate specific antigen (PSA) of 4.3 ng/ml, and a median ECOG performance status of 0. The most prominent adverse event was hyperbilirubinemia, with grade 1-2 bilirubin elevations in 9 of the 13 patients. The only grade 3 toxicity observed was elevation of alanine aminotransferase (ALT) in one patient; no grade 4 toxicity was noted. No objective PSA responses were observed. We conclude that 13 g of oral silybin-phytosome daily, in 3 divided doses, appears to be well tolerated in patients with advanced prostate cancer and is the recommended phase II dose. Asymptomatic liver toxicity is the most commonly seen adverse event.

Antineoplastic Agents, Phytogenic↗

PubMed2005

Structure prerequisite for antioxidant activity of silybin in different biochemical systems in vitro.

Structural analogues (flavanone: 2-4 and flavone: 5 and 6, respectively) of silybin (1a) were synthesized and tested for inhibitory activity on O(2)(-) release and PKC translocation in PMA-stimulated neutrophils as well as xanthine oxidase activity in order to identify the molecular structures responsible for the antioxidant property of silybin. Concerning the prevention of hem-mediated oxidative modification of LDL by silybin, the hydroxyl radical scavenging activity of its structural analogues was also determined. We demonstrated that the basic skeleton of 1a (4) is responsible for its inhibitory activity on O(2)(-) release in PMA-stimulated neutrophils via inhibition of PKC translocation, since introduction of a double bound and hydroxyl groups at C-5 and C-7 position (5 and 6) did not result in further increase in inhibition of O(2)(-) release. It has been shown that the presence of the phenolic hydroxyl group at C-5 and C-7 of 1a is essential for the inhibition of xanthine oxidase activity. Moreover, introduction of a double bond into the C-ring of 2 and 3, resulting in flavone derivatives (5 and 6), markedly enhanced the antioxidant effect in all the tested systems. Finally, silybin (1a) and its flavon derivatives (5 and 6) directly scavenged hydroxyl radicals as well. On the basis of these results it might be concluded that different moiety of silybin is responsible for inhibition of overproduction of O(2)(-) in stimulated neutrophils, xanthine oxidase activity, and for prevention of hem-mediated oxidative modification of LDL.

Antioxidants↗

PubMed2005

Silybin and silymarin--new effects and applications.

This article aims to review critically literature published mainly within this millennium on the new and emerging applications of silymarin, the polyphenolic fraction from the seeds of Silybum marianum and its main component silybin. Silymarin and silybin used so far mostly as hepatoprotectants were shown to have other interesting activities as e.g., anticancer and canceroprotective. These activities were demonstrated in a large variety of illnesses of different organs as e.g., prostate, lungs, CNS, kidneys, pancreas and others. Besides the cytoprotective activity of silybin mediated by its antioxidative and radical-scavenging properties also new activities based on the specific receptor interaction were discovered--e.g., inhibition and modulation of drug transporters, P-glycoproteins, estrogenic receptors, nuclear receptors and some others. New derivatives of silybin open new ways to its therapeutic applications. Pharmacology dealing with optically pure silybin diastereomers may suggest new mechanisms of its action.

Humans↗

PubMed2001

Silybin, a new iron-chelating agent.

Silybin, a natural occurring flavolignan isolated from the fruits of Silibum marianum, has been reported to exert antioxidant and free radical scavenging abilities. It was suggested to act also as an iron chelator. The complexation and protonation equilibria of the ferric complex of this compound have been studied by potentiometric, spectrophotometric and electrochemical techniques. The formation of the complex silybin-Ga(III) in anhydrous DMSO-d6 has been studied by 1H NMR spectroscopy. Mass spectrometry and infrared spectroscopy on silybin-Fe(III) complex confirm all data obtained by 1H NMR spectroscopy. The experimental results show that silybin binds Fe(III) even at acidic pH. Different ternary complexes were observed at increasing methoxide ion concentration and their stability constants have been calculated. The results show the possible role of silybin in relation to the chelation therapy of chronic iron overload, as occurs in the treatment of Cooley's anemia.

Antioxidants↗

PubMed1977

[The effect of silybin dihemisuccinate on cholesterol biosynthesis in rat liver homogenates (author's transl)].

The effect of silybin dihemisuccinate on the hepatic biosynthesis of cholesterol was studied by measuring the incorporation of [1-14C]-acetate and [2-14C]-mevalonate in the postmitochondrial supernatant of liver homogenates. 2. Under absolute in vitro conditions, silybin dihemisuccinate inhibits the biosynthesis of cholesterol in dependence on its concentration. With [1-14C]-acetate or [2-14C]-mevalonate the concentrations of silybin for 50% inhibition are 0.37 mM or 0.40 mM, resp. 3. 30 min after i.v. injection of 150.6 mg silybin dihemisuccinate/kg with both precursors the biosynthesis of cholesterol studied in vitro is diminished in comparison to controls. 60 min or 24 h after i.v. injection of silybin no effects on in vitro biosynthesis of cholesterol can be observed.

Animals↗

PubMed2006

Solubility of silybin in aqueous poly(ethylene glycol) solution.

Silybin is a main component in silymarin, which is an antihepatotoxic polyphenolic substance isolated from the milk thistle plant, Silybum marianum. A major problem in the development of an oral solid dosage form of this drug is the extremely poor aqueous solubility. In present work, the solubility of silybin in aqueous poly(ethylene glycol) 6,000 (PEG 6,000) solution at the temperature range from 293.15 to 313.15K was measured by a solid liquid equilibrium method. The aim of this study is to investigate the possible effect of poly(ethylene glycol) concentration and temperature on the solubility of the drug, and to reveal the solubilization capacity of the polymer for the drug. Experimental results reveal that the solubility of silybin increases with the increase both in PEG's concentration and temperature. With the increase in PEG's concentration, the transfer enthalpy and entropy for silybin from water to aqueous PEG solution increases first in a positive region, and then decreases to a negative region. The transfer enthalpy is lower than the entropy term. A modified Universal Quasi Chemical (UNIQUAC) model was used to correlate solubility data.

Silybum marianum↗

PubMed2005

Effects of silymarin flavonolignans and synthetic silybin derivatives on estrogen and aryl hydrocarbon receptor activation.

Silymarin, a standardized mixture of flavonolignans, or its major constituents could be effective for prevention and treatment of hepatic damage or skin cancer. However, their potential side effects, such as modulation of endocrine functions via the disruption of estrogen receptor (ER) and/or aryl hydrocarbon receptor (AhR) activation, are largely unknown. In the present study, we investigated impact of silymarin, its constituents and a series of their synthetic derivatives on ER- and AhR-mediated activities using in vitro reporter gene assays. We found that none of the compounds under study affected the AhR-mediated activity in rat hepatoma cells. Contrary to that, several compounds behaved as either partial or full ER agonists. Silymarin elicited partial ER activation, with silybin B being probably responsible for a majority of the weak ER-mediated activity of silymarin; silybin A and other flavonolignans were found to be inactive and potent ER agonist taxifolin is only a minor constituent of silymarin. To our knowledge, this is probably the first time, when receptor-specific in vitro effects of separated diastereomers have been demonstrated. In contrast to silymarin constituents, the synthetic silybin derivatives, potentially useful as chemoprotective agents, did not modulate the ER-mediated activity, with exception of 23-O-pivaloylsilybin. Interestingly, 7-O-benzylsilybin potentiated ER-mediated activity of 17beta-estradiol despite possessing no estrogenic activity. In conclusion, our data suggest that estrogenicity of some silymarin constituents should be taken in account as their potential side effect when considered as chemopreventive compounds. These results also stress the need to study biological activities of purified or synthesized diastereomers of silybin derivatives.

Animals↗

PubMed2003

[Determination of concentration and encapsulation efficiency of silybin liposomes].

OBJECTIVE: To determine the encapsulation efficiency of silybin liposomes. METHOD: After Silybin liposomes solution was separated through sphadex G-100 column, eluent collected was determined by the first derivative UV spectrometry. RESULT: The calibration curve of Silybin was linear in the range of 0.5-30.0 mg x L(-1) (r = 0.9998). The average recovery was 101.7%. The relative standard deviation was 1.8%. The results showed that the encapsulation efficiency ranged from 65.1%-83.0% when the drug/phospholipid ratio varied from 0.02-0.06. The concentration of SLB in liposomes prepared by optimum technique was 760.4 mg x L(-1) (n = 4). CONCLUSION: The method is accurate, simple and suitable for the quality control of Silybin liposomes.

Drug Delivery Systems↗