DESCRIPTION
Silybum marianum has other common names include cardus marianus, milk thistle, blessed milk thistle, Marian Thistle, Mary Thistle, Saint Mary's Thistle, Mediterranean milk thistle, variegated thistle and Scotch thistle. This species is an annual or biennial plant of the family Asteraceae . This fairly typical thistle has red to purple flowers and shiny pale green leaves with white veins. Originally a native of Southern Europe through to Asia, it is now found throughout the world. The medicinal parts of the plant are the ripe seeds: traditional milk thistle extract is made from the seeds and it consists of about 65–80% silymarin (a flavonolignan complex) and 20–35% fatty acids, including linoleic acid . Silymarin is a complex mixture of polyphenolic molecules, including seven closely related flavonolignan and one flavonoid ( taxifolin ).
Silybum marianum, 2014
The relative abundance of each compound may vary depending on the source of botanical material, supplier, and extraction processes. Silibinin or silybin represents about 50% to 70% of the silymarin extract. Silybin can be resolved into two 1:1 diastereoisomer , silybin A and silybin B. In addition, silybin may be present as isosilybin, a 1:1 mixture of two diastereoisomeric compounds, isosilybin A and isosilybin B.
The use of silybin in the clinical setting has a long history; in its native Mediterranean region, it has been employed for liver damage since the Greco-Roman era. Herbal therapy use is consistently increasing worldwide, and some of the most common herbal supplement preparations are derived from the milk thistle plant ( Silybum marianum ).
We could argue that the history of studies on silybin reflects, in part, the epidemiological history of liver diseases. The clinical experience with silybin is mainly related to its properties as a detoxifying agent and as a hepatoprotective compound in different acute and chronic liver diseases.
THE EFFECT OF SILYBIN IN THE LIVER
In liver cells, as well as in other types of cells, the common effects of silybin may be summarized as follows: (1) Antioxidant; (2) Direct and/or indirect (through the antioxidant capability) modulator of inflammation and fibrogenesis; and (3) indirect and/or direct modulator of some intrahepatic metabolic pathways.
1-Antioxidant action
The antioxidant effects of silybin have been demonstrated in all cells studied. Silybin acts as an antioxidant because it inhibits radical formation, binds some radical species ( scavenger ), interferes with lipid peroxidation of membranes (and therefore modulates membrane permeability), and increases the intracellular content of scavengers. In fact, in the presence of oxidative and nitrosative stress, silybin inhibits the formation of superoxide anion radicals and of nitric oxide (NO), increases ATP content through the phosphorylation of ADP, decreases the content of malondialdeyde (MDA) and totally abolishes the decrease of glutathione, of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Finally, silybin acts as an antioxidant because it also serves as an iron chelator. More recently, it has been suggested that dehydrosilybin (DHS), an oxidized form of silybin, has greater antioxidant activity than silybin (about three times better), probably because of the presence of unsaturated bonds that contribute to hydrogen-donating capacity. The better scavenger activity of DHS may also be the result of its greater ability to react with cell membranes because it has higher lipophilicity than silybin.
2-Anti-inflammatory action
In general terms, silymarin and silybin interfere with the NF-κB-controlled transduction cascade.
NF-κB is an inducible and ubiquitously expressed DNA-binding protein, acting as a transcription factor for genes involved in inflammation, cell survival, differentiation, and growth. In unstimulated cells, NF-κB is sequestered in the cytoplasm by interaction with inhibitory protein IκBα . NF-κB translocates to the nucleus and, through kinase phosphorylation, drives the activation of genes supporting inflammation. Consistent with its antioxidant activity, silybin has been demonstrated to inhibit NF-κB activation and translocation through suppression of IκBα phosphorylation and degradation.
3-Antifibrotic action
In an in vitro model of human hepatic fibrogenesis, silybin demonstrated both direct and indirect antifibrotic properties. In fact, in stellate cell from human liver, silybin reduced platelet-derived growth factor (PDGF) that induced DNA synthesis and cell proliferation at a dose of 25 μmol/L. Finally, pre-treatment with 25-50 μmol/L of silybin significantly reduced the TGF-β that induced de novo synthesis of procollagen type I in cell supernatants. To investigate the role of silybin in modulating the pro-inflammatory properties of hematopoietic system cells, cells were stimulated with IL-1β (20 ng/ml), a potent pro-inflammatory cytokine; silybin inhibited, in a dose-dependent manner, IL-1-induced synthesis of human MCP-1 (monocyte chemoattractant protein 1) and human IL-8 as detected in cell supernatants. This effect was related to the effect of silybin on the inhibition of IκBα phosphorylation and to its capability to inhibit ERK, MEK, and Raf phosphorylation at any concentration used.
Silybin interferes with some mechanisms of action of insulin. In fact, it modulates the uptake of glucose in adipocytes by blocking the insulin-dependent glucose transporter 4. In rat hepatocytes, silybin, in concentrations ranging from 25 to 100 μmol/L, lowers glucose formation from different gluconeogenic substrates through an inhibitory effect on pyruvate kinase activity. As previously reported in cultured hepatocytes, low doses of silybin reduce reactive oxygen species formation from mitochondria; this reduction leads to a decrease in oxidation of carbons arising from glycolysis. Moreover, silybin inhibits, in a dose-dependent manner, gluconeogenesis and glycogenolysis , both in basal conditions and after a glucagon-dependent stimulation, by blocking glucose-6-phosphate hydrolysis.
Silybin and the liver: From basic research to clinical practice ,2011
SILYBIN AS A DETOXIFING AND HEPATOPROTECTIVE SUBSTANCE
Several chemotherapeutic agents are metabolized by the liver and can exert hepatotoxicity, with the net result of drug reductions or withdrawal. Cancer patients taking these therapies often self-medicate with milk thistle because of its reputation as a liver protectant. The rationale of milk thistle use is to provide support to the liver while it performs multiple functions, including responding to the increased metabolic demands caused by tumor growth, assisting in metabolizing products generated when a tumor is killed or reduced by chemotherapy and radiation, and aiding in the processing of drugs prescribed to cancer patients. Oxidative stress and inflammation are also involved in cellular damage of many other tissues and their role in the development and toxic reactions in patients receiving cancer therapies is established. The protective effects of silymarin and silibinin, demonstrated in various tissues, suggest a clinical application in cancer patients as an adjunct to established therapies, to prevent or reduce their toxicity.
Toward the definition of the mechanism of action of silymarin: activities related to cellular protection from toxic damage induced by chemotherapy, 2007
H3. SILYBIN IN ACUTE LIVER DAMAGE
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. 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.
Pharmacotherapy of Amanita phalloides poisoning using silybin 1983
H3. SILYBIN IN CHRONIC LIVER DISEASE
Silymarin and silibinin both inhibit HCV infection in cell culture by variably blocking viral entry, viral fusion, viral RNA and protein synthesis, RNA polymerase activity and virus transmission. An intravenous formulation of silibinin, SIL, retains many of the same antiviral properties of the parent silibinin including inhibiting HCV fusion, replication, and production of infectious progeny virus. In addition, patients treated intravenously with SIL displayed log-fold reductions in viral load when given to HCV mono-infected patients because SIL inhibits both HCV infection and T cell proliferation, we hypothesized that SIL inhibits HIV infection. Several experiments demonstrate that SIL attenuates cellular functions required for activation, proliferation, and HIV infection.. Silymarin-derived compounds provide cytoprotection by suppressing virus infection, immune activation, and inflammation, and as such may be relevant for both HIV mono-infected and HIV/HCV co-infected subjects.
Silymarin inhibits in vitro T cell proliferation and cytokine production in hepatitis C virus, 2010
Silibinin inhibits HIV-1 infection by reducing cellular activation and proliferation, 2012
CONCLUSIONS
There is an increasing interest in silybin and its compounds and a continuous improvement in knowledge about the molecular actions of this substance. However, in the clinical setting, there is currently a lack of definitive data about its efficacy in patients with chronic liver disease. The only well-defined finding is the absence of adverse events at high doses.The absence of significant adverse effects of silybin even at high doses, the good compliance by the patient, the availability of a purified form of the compound, represent characteristics that allow to obtain commercially available products containing almost 600 mg of pure silybin to ensure a good concentration in tissues. In clinical practice, there is the need for drugs that can be used in the long term without serious adverse events. Researchers should definitively demonstrate if silybin has potential in this regard
