Silibinin

Silibinin
Systematic (IUPAC) name
(2R,3R)-3,5,7-trihydroxy-
2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)
-2,3-dihydrobenzo[b][1,4]dioxin-6-yl]chroman-4-one
Clinical data
AHFS/Drugs.com International Drug Names
Pregnancy cat.  ?
Legal status  ?
Identifiers
CAS number 22888-70-6 N
ATC code A05BA03
PubChem CID 31553
ChemSpider 29263 Y
UNII 4RKY41TBTF Y
KEGG D08515 Y
ChEMBL CHEMBL9509 N
Chemical data
Formula C25H22O10 
Mol. mass 482.44 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Silibinin (INN), also known as silybin, is the major active constituent of silymarin, standardized extract of the milk thistle seeds, containing mixture of flavonolignans consisting of among others of silibinin, isosilibinin, silicristin and silidianin. Silibinin itself is mixture of two diastereomers Silibinin A and Silybinin B in approximately equimolar ratio. Both in vitro and animal research suggest that silibinin has hepatoprotective (antihepatotoxic) properties that protect liver cells against toxins.[1][2] Silibinin has also demonstrated anti-cancer effects against human prostate adenocarcinoma cells, estrogen-dependent and -independent human breast carcinoma cells, human ectocervical carcinoma cells, human colon cancer cells, and both small and nonsmall human lung carcinoma cells.[3][4][5][6]

Chemically modified silibinin, silibinin dihydrogen disuccinate disodium (trade name Legalon SIL) a solution for injection, is used in treatment of severe intoxications with hepatotoxic substances, such as death cap (Amanita phalloides) poisoning.[7] There is also clinical evidence for the use of silibinin as a supportive element in alcoholic and grade Child ‘A’ liver cirrhosis.[8]

Contents

Pharmacology

Poor water solubility and bioavailability of silymarin led to the development of enhanced formulations. Silipide (trade name Siliphos), a complex of silymarin and phosphatidylcholine (lecithin), is about ten times more bioavailable than silymarin.[9] It has been also reported that silymarin inclusion complex with β-cyclodextrin is much more soluble than silymarin itself.[10] There have also been prepared glycosides of silybin, which show better water solubility and even stronger hepatoprotective effect.[11]

Silymarin, as other flavonoids, has been shown to inhibit P-glycoprotein-mediated cellular efflux.[12] 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.[13]

Toxicity

The acute toxicity of silymarin and silybin were investigated by oral and intravenous route in various animal species. No mortality or any signs of adverse effects were observed after silymarin at oral doses of 20 g/kg in mice and 1 g/kg in dogs. The median lethal dose (LD50) after intravenous infusion values are 400 mg/kg in mice, 385 mg/kg in rats and 140 mg/kg in rabbits and dogs. These data demonstrate that the acute toxicity of silymarin is very low.

Similarly, its subacute and chronic toxicity are very low; the compound is also devoid of embryotoxic potential.

Complementary and alternative medicine

A recent study suggested that silymarin may help patients with type II diabetes by assisting in blood sugar control.[14]

Lab experiments on mice showed that Silibinin protects the hepatic cells against a-amanitin compound found in Amanita Phalloides mushroom poisoning.

References

  1. ^ Al-Anati L, Essid E, Reinehr R, Petzinger E (2009). "Silibinin protects OTA-mediated TNF-alpha release from perfused rat livers and isolated rat Kupffer cells". Molecular Nutrition & Food Research 53 (4): 460–6. doi:10.1002/mnfr.200800110. PMID 19156713. 
  2. ^ Jayaraj R, Deb U, Bhaskar AS, Prasad GB, Rao PV (2007). "Hepatoprotective efficacy of certain flavonoids against microcystin induced toxicity in mice". Environmental Toxicology 22 (5): 472–9. doi:10.1002/tox.20283. PMID 17696131. 
  3. ^ Mokhtari MJ, Motamed N, Shokrgozar MA (2008). "Evaluation of silibinin on the viability, migration and adhesion of the human prostate adenocarcinoma (PC-3) cell line". Cell Biology International 32 (8): 888–92. doi:10.1016/j.cellbi.2008.03.019. PMID 18538589. http://linkinghub.elsevier.com/retrieve/pii/S1065-6995(08)00384-3. 
  4. ^ Bhatia N, Zhao J, Wolf DM, Agarwal R (1999). "Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin". Cancer Letters 147 (1–2): 77–84. doi:10.1016/S0304-3835(99)00276-1. PMID 10660092. 
  5. ^ Hogan FS, Krishnegowda NK, Mikhailova M, Kahlenberg MS (2007). "Flavonoid, silibinin, inhibits proliferation and promotes cell-cycle arrest of human colon cancer". Journal of Surgical Research 143 (1): 58–65. doi:10.1016/j.jss.2007.03.080. PMID 17950073. http://linkinghub.elsevier.com/retrieve/pii/S0022-4804(07)00241-7. 
  6. ^ Sharma G, Singh RP, Chan DC, Agarwal R (2003). "Silibinin induces growth inhibition and apoptotic cell death in human lung carcinoma cells". Anticancer Research 23 (3B): 2649–55. PMID 12894553. 
  7. ^ Mitchell, T (2009). "Intravenous Milk thistle (silibinin-legalon) for hepatic failure induced by amatoxin/Amanita mushroom poisoning". (Clinical study). http://clinicaltrials.gov/ct2/show/NCT00915681. 
  8. ^ Saller R, Brignoli R, Melzer J, Meier R (2008). "An updated systematic review with meta-analysis for the clinical evidence of silymarin". Forschende Komplementärmedizin (2006) 15 (1): 9–20. doi:10.1159/000113648. PMID 18334810. http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=000113648. Retrieved 2010-12-14. 
  9. ^ Kidd P, Head K (2005). "A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos)". Alternative Medicine Review : a Journal of Clinical Therapeutic 10 (3): 193–203. PMID 16164374. http://www.thorne.com/altmedrev/.fulltext/10/3/193.pdf. Retrieved 2010-12-14. 
  10. ^ Voinovich D, Perissutti B, Grassi M, Passerini N, Bigotto A (2009). "Solid state mechanochemical activation of Silybum marianum dry extract with betacyclodextrins: Characterization and bioavailability of the coground systems". Journal of Pharmaceutical Sciences 98 (11): 4119–29. doi:10.1002/jps.21704. PMID 19226635. 
  11. ^ Kosina P, Kren V, Gebhardt R, Grambal F, Ulrichová J, Walterová D (2002). "Antioxidant properties of silybin glycosides". Phytotherapy Research : PTR 16 Suppl 1: S33–9. doi:10.1002/ptr.796. PMID 11933137. 
  12. ^ Zhou S, Lim LY, Chowbay B (2004). "Herbal modulation of P-glycoprotein". Drug Metabolism Reviews 36 (1): 57–104. doi:10.1081/DMR-120028427. PMID 15072439. http://www.informapharmascience.com/doi/abs/10.1081/DMR-120028427. 
  13. ^ Wu JW, Lin LC, Tsai TH (2009). "Drug-drug interactions of silymarin on the perspective of pharmacokinetics". Journal of Ethnopharmacology 121 (2): 185–93. doi:10.1016/j.jep.2008.10.036. PMID 19041708. http://linkinghub.elsevier.com/retrieve/pii/S0378-8741(08)00621-1. Retrieved 2010-12-14. 
  14. ^ Huseini HF, Larijani B, Heshmat R, Fakhrzadeh H, Radjabipour B, Toliat T, Raza M (2006). "The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial". Phytotherapy Research 20 (12): 1036–9. doi:10.1002/ptr.1988. PMID 17072885. 

External links

Bile and liver therapy (A05)
Bile therapy
Liver therapy

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anat(t, g, p)/phys/devp/enzy

noco/cong/tumr, sysi/epon

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Flavonolignans
Cinchonain-Ib | Dehydrosilybin | Deoxysilycistin | Deoxysilydianin | Hydnocarpin | Hydnowightin | Neosilyhermin | Palstatin | Rhodiolin | Salcolin A | Salcolin B | Scutellaprostin A, B, C, D, E and F | Silandrin | Silyamandin | Silibinin | Silybinome | Silicristin | Silydianin | Silyhermin | Tricin 4'-O-(erythro-beta-guaiacylglyceryl) ether | Tricin 4'-O-(threo-beta-guaiacylglyceryl) ether