Silibinin

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Silibinin
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral Intravenous
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
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.041.168 Edit this at Wikidata
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 (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 seeds, containing a mixture of flavonolignans consisting of silibinin, isosilibinin, silicristin, silidianin, and others. Silibinin itself is mixture of two diastereomers, silybin A and silybin B, in approximately equimolar ratio.[1] The mixture exhibits a number of pharmacological effects, particularly in the liver, and there is some clinical evidence for the use of silibinin as a supportive element in alcoholic and child grade 'A' liver cirrhosis.[2]

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 10 times more bioavailable than silymarin.[3] An earlier study had concluded Siliphos to have 4.6 fold higher bioavailability.[4] It has been also reported that silymarin inclusion complex with β-cyclodextrin is much more soluble than silymarin itself.[5] There have also been prepared glycosides of silybin, which show better water solubility and even stronger hepatoprotective effect.[6]

Silymarin, as other flavonoids, has been shown to inhibit P-glycoprotein-mediated cellular efflux.[7] 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.[8]

Toxicity

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.[9]

Silymarin is also devoid of embryotoxic potential in animal models.[10][11]

Medical uses

Silibinin is available as drug (Legalon® SIL (Madaus) (D, CH, A) and Silimarit® (Bionorica), a Silymarin product) in some EU countries and used in the treatment of toxic liver damage (e.g. IV treatment in case of death cap poisoning); as adjunctive therapy in chronic hepatitis and cirrhosis. See also Silybum marianum#Medicinal use

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.[12]

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).[13]

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, and DNA repair for UV induced DNA damage (double strand breaks).[14]

Biotechnology

Silymarin can be produced in callus and cells suspensions of Silybum marianum and substituted pyrazinecarboxamides can be used as abiotic elicitors of flavolignan production.[15]

References

  1. ^ Davis-Searles P, Nakanishi Y, Nam-Cheol K, et al. (2005). "Milk Thistle and Prostate Cancer: Differential Effects of Pure Flavonolignans from Silybum marianum on Antiproliferative End Points in Human Prostate Carcinoma Cells". Cancer Research. 65 (10): 4448–57. doi:10.1158/0008-5472.CAN-04-4662. PMID 15899838.
  2. ^ Saller R, Brignoli R, Melzer J, Meier R (2008). "An updated systematic review with meta-analysis for the clinical evidence of silymarin". Forschende Komplementärmedizin. 15 (1): 9–20. doi:10.1159/000113648. PMID 18334810. Retrieved 2010-12-14.
  3. ^ 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. 10 (3): 193–203. PMID 16164374. Retrieved 2010-12-14.
  4. ^ Barzaghi N, Crema F, Gatti G, Pifferi G, Perucca E (1990). "Pharmacokinetic studies on IdB 1016, a silybin- phosphatidylcholine complex, in healthy human subjects". Eur J Drug Metab Pharmacokinet. 15: 333–8. doi:10.1007/bf03190223. PMID 2088770.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ Thomas W. Flaig; Daniel L. Gustafson; Lih-Jen Su; Joseph A. Zirrolli; Frances Crighton; Gail S. Harrison; A. Scott Pierson; Rajesh Agarwal; L. Michael Glodé (2007). "A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients". Investigational New Drugs. 25 (2): 139–146. doi:10.1007/s10637-006-9019-2.
  10. ^ Fraschini F, Demartini G, Esposti D (2002). "Pharmacology of Silymarin". Clinical Drug Investigation. 22 (1): 51–65. doi:10.2165/00044011-200222010-00007.
  11. ^ 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.
  12. ^ Rottapharm|Madaus. Media Communications Legalon®. Retrieved March 6 2017.
  13. ^ Bosch-Barrera J, Menendez JA (2015). "Silibinin and STAT3: A natural way of targeting transcription factors for cancer therapy". Cancer Treat. Rev. (Review). 41 (6): 540–6. doi:10.1016/j.ctrv.2015.04.008. PMID 25944486.
  14. ^ Singh, Rana P.; Agarwal, Rajesh (September 2009). "Cosmeceuticals and silibinin". Clinics in Dermatology. 27 (5): 479–484. doi:10.1016/j.clindermatol.2009.05.012. PMC 2767273. PMID 19695480.
  15. ^ Tůmová L, Tůma J, Megušar K, Doleža M (2010). "Substituted Pyrazinecarboxamides as Abiotic Elicitors of Flavolignan Production in Silybum marianum (L.) Gaertn Cultures in Vitro". Molecules. 15 (1): 331–340. doi:10.3390/molecules15010331.{{cite journal}}: CS1 maint: unflagged free DOI (link)

External links

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