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Silibinin

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Pharmaceutical compound
Silibinin
Silibinin A and silibinin B structures
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral and Intravenous
ATC code
Identifiers
IUPAC name
  • (2R,3R)-3,5,7-trihydroxy-2-dioxin-6-yl]chroman-4-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.041.168 Edit this at Wikidata
Chemical and physical data
FormulaC25H22O10
Molar mass482.441 g·mol
3D model (JSmol)
SMILES
  • O=C4c5c(O)cc(O)cc5O(c2ccc1O((Oc1c2)c3ccc(O)c(OC)c3)CO)4O
InChI
  • InChI=1S/C25H22O10/c1-32-17-6-11(2-4-14(17)28)24-20(10-26)33-16-5-3-12(7-18(16)34-24)25-23(31)22(30)21-15(29)8-13(27)9-19(21)35-25/h2-9,20,23-29,31H,10H2,1H3/t20-,23+,24-,25-/m1/s1
  • Key:SEBFKMXJBCUCAI-HKTJVKLFSA-N
  (what is this?)  (verify)

Silibinin (INN), also known as silybin (both from Silybum, the generic name of the plant from which it is extracted), is the major active constituent of silymarin, a standardized extract of the milk thistle, 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. Silibinin is used in pure forms as a medication, and more frequently as an active ingredient in milk thistle–derived herbal supplements.

Medical uses

For approved drug preparations and parenteral applications in the treatment of Amanita mushroom poisoning, the water-soluble silibinin-C-2',3-dihydrogensuccinate 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.

Silibinin is available in many EU countries for treatment of toxic liver damage (e.g., as an intravenous formulation used in death cap poisoning) or as adjunctive therapy in chronic hepatitis and cirrhosis.

There is limited evidence to support use of silibinin-containing products as a supplement in people with chronic liver disease. A systematic review and meta-analysis concluded that silymarin does not affect all-cause mortality in persons with cirrhosis, but it may help prevent liver-related mortality in those patients. There is mixed evidence for silibinin as an anti-inflammatory agent in alcohol-related liver disease or non-alcoholic fatty liver disease, and trials continue. There is little evidence to support a meaningful antiviral effect of milk thistle in chronic hepatitis C.

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 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, 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.

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 (a phospholipid in 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 flavonoids, has been shown to inhibit P-glycoprotein-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 enzymes and an interaction with drugs primarily cleared by P450s cannot be excluded.

Toxicity

Silibinin and all the other compounds found in silymarin, especially silychristin, blocked the MCT8 transporter according to one in vitro study. There is no published clinical information showing silymarin or silibinin cause any thyroid problems. In fact, one clinical trial found that silymarin actually helped prevent thyroid suppression that is often caused by the drug lithium.

There is limited research on milk thistle and silymarin in pregnant humans. However, the one known clinical trial found only benefits, including but not limited to effectively treating intrahepatic cholestasis of pregnancy. Silymarin is also devoid of embryotoxic potential in animal models.

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 and elevation of alanine aminotransferase) being the most commonly seen adverse event.

Biotechnology

Silymarin can be produced in callus and cell suspensions of Silybum marianum and substituted pyrazinecarboxamides can be used as abiotic elicitors 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 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. 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 and cyclization by chalcone synthase and chalcone isomerase to yield naringenin. Through flavanone 3-hydroxylase 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 to enable the single electron reaction to couple two fragments generating silybin (silibinin A + silibinin B).

Biosynthesis of silybin (silibinin A and silibinin B)

References

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Further reading

External links

Bile and liver therapy (A05)
Bile therapy
Liver therapy
Types of lignans
Lignans
Lignan glycosides
Mammalian lignans (enterolignans)
Neolignans
Flavonolignans
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