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Silibinin ( INN), also known as silybin (both from '' Silybum'', the
generic Generic or generics may refer to: In business * Generic term, a common name used for a range or class of similar things not protected by trademark * Generic brand, a brand for a product that does not have an associated brand or trademark, other ...
name of the plant from which it is extracted), is the major active constituent of silymarin, a standardized extract of the milk thistle seeds, containing a mixture of flavonolignans consisting of silibinin, isosilibinin, silychristin, silidianin, and others. Silibinin itself is a mixture of two diastereomers, silybin A and silybin B, in approximately equimolar ratio. The mixture exhibits a number of pharmacological effects, particularly in the fatty liver, non-alcoholic fatty liver, non-alcoholic steatohepatitis, and there is great clinical evidence for the use of silibinin as a supportive element in alcoholic and Child–Pugh grade 'A' liver cirrhosis. However, despite its several beneficial effects on the liver, silibinin and all the other compounds found in silymarin, especially silychristin seem to act as potent disruptors of the thyroid system by blocking the
MCT8 Monocarboxylate transporter 8 (MCT8) is an active transporter protein that in humans is encoded by the ''SLC16A2'' gene. Function MCT8 actively transports a variety of iodo- thyronines including the thyroid hormones T3 and T4. Clinical sig ...
transporter. The long term intake of silymarin can lead to some form of thyroid disease and if taken during pregnancy, silymarin can cause the development of the Allan–Herndon–Dudley syndrome. Although this information is not being taken into consideration by all regulatory bodies, several studies now consider silymarin and especially silychristin to be important inhibitors of the MCT8 transporter and a potential disruptor of the thyroid hormone functions.


Pharmacology

Poor water solubility and bioavailability of silymarin led to the development of enhanced formulations. Silipide (trade name Siliphos, not to be confused with the water treatment compound of the same name, a glass-like polyphosphate containing sodium, calcium magnesium and silicate, formulated for the treatment of water problems), a complex of silymarin and phosphatidylcholine (lecithin), is about 10 times more bioavailable than silymarin. An earlier study had concluded Siliphos to have 4.6 fold higher bioavailability. It has been also reported that silymarin inclusion complex with β- cyclodextrin is much more soluble than silymarin itself. There have also been prepared glycosides of silybin, which show better water solubility and even stronger hepatoprotective effect. Silymarin, like other
flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...
s, has been shown to inhibit
P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...
-mediated cellular efflux. The modulation of P-glycoprotein activity may result in altered absorption and bioavailability of drugs that are P-glycoprotein substrates. It has been reported that silymarin inhibits
cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
enzymes and an interaction with drugs primarily cleared by P450s cannot be excluded.


Toxicity

Several studies have documented the potentially dangerous effects of the silymarin mixture on the
thyroid system The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
. All of the flavonolignan compounds found in the silymarin mixture seem to block the uptake of thyroid hormones into the cells by selectively blocking the
MCT8 Monocarboxylate transporter 8 (MCT8) is an active transporter protein that in humans is encoded by the ''SLC16A2'' gene. Function MCT8 actively transports a variety of iodo- thyronines including the thyroid hormones T3 and T4. Clinical sig ...
transmembrane transporter. The authors of this study noted that especially silychristin, one of the compounds of the silymarin mixture seems to be perhaps the most powerful and selective inhibitor for the
MCT8 Monocarboxylate transporter 8 (MCT8) is an active transporter protein that in humans is encoded by the ''SLC16A2'' gene. Function MCT8 actively transports a variety of iodo- thyronines including the thyroid hormones T3 and T4. Clinical sig ...
transporter. Due to the essential role played by the thyroid hormone in human metabolism in general it is believed that the intake of silymarin can lead to disruptions of the thyroid system. Because the thyroid hormones and the
MCT8 Monocarboxylate transporter 8 (MCT8) is an active transporter protein that in humans is encoded by the ''SLC16A2'' gene. Function MCT8 actively transports a variety of iodo- thyronines including the thyroid hormones T3 and T4. Clinical sig ...
as well are known to play a critical role during early and fetal development, the administration of silymarin during pregnancy is especially thought to be dangerous, potentially leading to the Allan–Herndon–Dudley syndrome, a brain development disorder that causes both moderate to severe intellectual disability and problems with speech and movement. A phase I clinical trial in humans with prostate cancer designed to study the effects of high dose silibinin found 13 grams daily to be well tolerated in patients with advanced prostate cancer with asymptomatic liver toxicity (
hyperbilirubinemia Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
and elevation of alanine aminotransferase) being the most commonly seen adverse event. Silymarin is also devoid of embryotoxic potential in animal models.


Medical uses

Silibinin is available as drug (Legalon SIL (Madaus) (D, CH, A) and Silimarit (Bionorica), a Silymarin product) in many EU countries and used in the treatment of toxic liver damage (e.g. IV treatment in case of
death cap ''Amanita phalloides'' (), commonly known as the death cap, is a deadly poisonous basidiomycete fungus, one of many in the genus ''Amanita''. Widely distributed across Europe, but now sprouting in other parts of the world, ''A. phalloides ...
poisoning); as adjunctive therapy in chronic hepatitis and cirrhosis. For approved drug preparations and parenteral applications in the treatment of ''Amanita'' mushroom poisoning, the water-soluble silibinin-C-2',3-dihyrogensuccinate disodium salt is used. In 2011, the same compound also received Orphan Medicinal Product Designation for the prevention of recurrent hepatitis C in liver transplant recipients by the European Commission.


Potential medical uses

Silibinin is under investigation to see whether it may have a role in cancer treatment (e.g. due to its inhibition of STAT3 signalling). Silibinin also has a number of potential mechanisms that could benefit the skin. These include chemoprotective effects from environmental toxins, anti-inflammatory effects, protection from UV induced photocarcinogenesis, protection from sunburn, protection from UVB-induced
epidermal hyperplasia The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water relea ...
, and DNA repair for UV induced DNA damage (double strand breaks). Studies on mice demonstrate a significant protection on chronic unpredictable mild stress (CUMS) induced depressive-like behavior on mice and increased cognition in aged rats as a result of consuming silymarin. Due to its immunomodulatory, iron chelating and antioxidant properties, this herb has the potential to be used in beta-thalassemia patients who receive regular blood transfusions and suffer from iron overload.


Biotechnology

Silymarin can be produced in callus and cells suspensions of '' Silybum marianum'' and substituted
pyrazinecarboxamide Pyrazinamide is a medication used to treat tuberculosis. For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol. It is not generally recommended for the treatment of latent tuberculosis. It i ...
s can be used as abiotic
elicitor Elicitors in plant biology are extrinsic or foreign molecules often associated with plant pests, diseases or synergistic organisms. Elicitor molecules can attach to special receptor proteins located on plant cell membranes. These receptors are able ...
s of flavolignan production.


Biosynthesis

The biosynthesis of silibinin A and silibinin B is composed of two major parts, taxifolin and coniferyl alcohol. Coniferyl alcohol is synthesized in milk thistle seed coat. Starting with the transformation of phenylalanine into cinnamic acid mediated by phenylalanine ammonia-lyase. Cinnamic acid will then go through two rounds of oxidation by
trans-cinnamate 4-monooxygenase In enzymology, a trans-cinnamate 4-monooxygenase () is an enzyme that catalyzes the chemical reaction :trans-cinnamate + NADPH + H+ + O2 \rightleftharpoons 4-hydroxycinnamate + NADP+ + H2O The 4 substrates of this enzyme are trans-cinnamate, N ...
and 4-coumarate 3-hydroxylase to give caffeic acid. The meta position alcohol is methylated by caffeic acid 3-''O''-methyltransferase to produce ferulic acid. From ferulic acid, the production of coniferyl alcohol is carried out by 4-hydroxycinnamate CoA ligase, cinnamoyl CoA reductase, and
cinnamyl alcohol dehydrogenase In enzymology, a cinnamyl-alcohol dehydrogenase () is an enzyme that catalyzes the chemical reaction :cinnamyl alcohol + NADP+ \rightleftharpoons cinnamaldehyde + NADPH + H+ Thus, the two substrates of this enzyme are cinnamyl alcohol and NA ...
. For taxifolin, its genes for the biosynthesis can be overexpressed in flowers as the transcription is light dependent. The production of taxifolin utilizes a similar pathway as for synthesizing ''p''-coumaric acid followed by three times of carbon chain elongation with
malonyl-CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...
and cyclization by chalcone synthase and chalcone isomerase to yield naringenin. Through
flavanone 3-hydroxylase The flavanones, a type of flavonoids, are various aromatic, colorless ketones derived from flavone that often occur in plants as glycosides. List of flavanones * Blumeatin * Butin * Eriodictyol * Hesperetin * Hesperidin * Homoeriodictyol * I ...
and flavonoid 3'-monooxygenase, taxifolin is furnished. To merge taxifolin and coniferyl alcohol, taxifolin can be translocated from the flower to the seed coat through symplast pathway. Both taxifolin and coniferyl alcohol will be oxidized by
ascorbate peroxidase 1 Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) an ...
to enable the single electron reaction to couple two fragments generating silybin (silibinin A + silibinin B).


References


External links


Review of the Quality of Evidence for Milk Thistle Use from MayoClinic.com
* * * {{lignan Antidotes Flavonolignans Resorcinols 3-Hydroxypropenals Benzodioxans