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Hvigorita/sandbox
Clinical data
AHFS/Drugs.comInternational Drug Names
ATC code
Identifiers
  • (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
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC25H22O10
Molar mass482.44 g/mol g·mol−1
3D model (JSmol)
  • O=C4c5c(O)cc(O)cc5O[C@H](c2ccc1O[C@@H]([C@H](Oc1c2)c3ccc(O)c(OC)c3)CO)[C@H]4O
  • 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 checkY
  • Key:SEBFKMXJBCUCAI-HKTJVKLFSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Silibinin (INN), also known as silybin, is the major active constituent of silymarin, a 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 in vitro 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 currently being tested as a 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 Child grade ‘A’ liver cirrhosis.[8]

Pharmacology

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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] Silibinin has been reported to exert a neuroprotective effect in mice.[12]

Silymarin, as other flavonoids, has been shown to inhibit P-glycoprotein-mediated cellular efflux.[13] 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.[14]

Toxicity

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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.[15]

Similarly, its subacute and chronic toxicity are very low; the compound is also devoid of embryotoxic potential.[16] [17]

Complementary and alternative medicine

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A recent study suggested that silymarin may help patients with type II diabetes by assisting in blood sugar control.[18]

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

Biotechnology

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Silimaryn can be produced in callus and cells suspensions of Silybum marianum and substituted pyrazinecarboxamides can be used as abiotic elicitors of flavolignan production.[19]

References

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  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Mitchell, T (2009). "Intravenous Milk thistle (silibinin-legalon) for hepatic failure induced by amatoxin/Amanita mushroom poisoning". (Clinical study).
  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. Retrieved 2010-12-14.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Kidd P, Head K (2005). "A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos)" (PDF). Alternative Medicine Review : a Journal of Clinical Therapeutic. 10 (3): 193–203. PMID 16164374. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Tota, S; Kamat, PK; Shukla, R; Nath, C (2011). "Improvement of brain energy metabolism and cholinergic functions contributes to the beneficial effects of silibinin against streptozotocin induced memory impairment". Behavioural Brain Research. 221 (1): 207–15. doi:10.1016/j.bbr.2011.02.041. PMID 21382422.
  13. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ 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. Retrieved 2010-12-14.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Vogel G, Trost W, Braatz R, Odenthal KP, Brüsewitz G, Antweiler H, Seeger R (1975). "Pharmacodynamics, site and mechanism of action of silymarin, the antihepatoxic principle from Silybum mar. (L) Gaertn. 1. Acute toxicology or tolerance, general and specific (liver-) pharmacology". Arzneimittelforschung. 25 (1): 82–9. PMID 1173772. {{cite journal}}: line feed character in |title= at position 19 (help)CS1 maint: multiple names: authors list (link)
  16. ^ Fraschini F, Demartini G, Esposti D (2002). "Pharmacology of Silymarin". Clinical Drug Investigation. 22 (1): 51–65. doi:10.2165/00044011-200222010-00007.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Hahn G, Lehmann HD, Kürten M, Uebel H, Vogel G (1968). "On the pharmacology and toxicology of silymarin, an antihepatotoxic active principle from Silybum marianum (L.) gaertn". Arzneimittelforschung. 18 (6): 698–704. PMID 5755807.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Substituted Pyrazinecarboxamides as Abiotic Elicitors of Flavolignan Production in Silybum marianum (L.) Gaertn Cultures in Vitro. Lenka Tůmová, Jiří Tůma, Klara Megušar and Martin Doleža, Molecules, 2010, 15(1), pages 331-340, doi:10.3390/molecules15010331
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Category:Antidotes Category:Flavonolignans Category:Phenols

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