Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Silibinin: Difference between pages

{{short description|Chemical compound}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{primary sources|date=February 2019}}

| verifiedrevid = 464390273

| IUPAC_name = (2''R'',3''R'')-3,5,7-trihydroxy-2-[(2''R''*,3''R''*)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydrobenzo[''b''][1,4]dioxin-6-yl]chroman-4-one

| image = Silibinin A.svg

| image2 = Silibinin B.svg

| caption = Silibinin A and silibinin B structures

| routes_of_administration = [[Oral administration|Oral]] and [[Intravenous therapy|Intravenous]]

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 1265089-69-7

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 9144

| UNII_Ref = {{fdacite|correct|FDA}}

| KEGG_Ref = {{keggcite|correct|kegg}}

| ChEMBL = 9509

<!--Chemical data-->

'''Silibinin''' ([[International Nonproprietary Name|INN]]), also known as '''silybin '''(both from ''[[Silybum]]'', the [[Genus–differentia definition|generic]] name of the [[plant]] from which it is extracted), is the major active constituent of '''silymarin''', a standardized extract of the [[Silybum marianum|milk thistle]], containing a mixture of [[flavonolignan]]s consisting of silibinin, [[isosilibinin]], [[silychristin]], [[silidianin]], and others. Silibinin itself is a mixture of two [[diastereomer]]s, silybin A and silybin B, in approximately equimolar ratio.<ref>{{cite journal | vauthors = Davis-Searles P, Nakanishi Y, Nam-Cheol K, etal | year = 2005 | title = Milk Thistle and Prostate Cancer: Differential Effects of Pure Flavonolignans from Silybum marianum on Antiproliferative End Points in Human Prostate Carcinoma Cells | url = http://cancerres.aacrjournals.org/content/canres/65/10/4448.full.pdf| journal = Cancer Research | volume = 65 | issue = 10| pages = 4448–57 | doi = 10.1158/0008-5472.CAN-04-4662 | pmid=15899838| doi-access = free }}</ref> 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-[[dihydrogen]][[succinate]] [[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]].<ref>Rottapharm|Madaus. [http://www.rotta.com/en/service/media/comunicatiStampa/pdf/legalon_ENG.pdf Media Communications Legalon®]. Retrieved March 6, 2017.</ref>

Silibinin is available in many EU countries for treatment of toxic liver damage (e.g., as an intravenous formulation used in [[Amanita phalloides|death cap]] poisoning) or as [[adjunctive therapy]] in [[chronic hepatitis]] and [[cirrhosis]].{{Citation needed|date=July 2018}}<ref>{{cite journal | vauthors = Federico A, Dallio M, Loguercio C| title = Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years. | journal = Molecules | volume = 22 | issue = 2 | pages = 191 | date = Jan 2017 | pmid = 28125040 | doi = 10.3390/molecules22020191 | pmc = 6155865 | doi-access = free }}</ref><ref>{{cite book | vauthors = Yarnell E |date=2010 |title= Natural Approach to Gastroenterology | edition = 2nd |url=https://wildbrilliancepress.com/production/natural_approach_to_gastroenterology |location=Wenatchee |publisher= Wild Brilliance Press|page=1701 |isbn=978-1933350066}}</ref>

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.<ref name=Saller2008/> 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.<ref>{{cite journal | vauthors = de Avelar CR, Nunes BV, da Silva Sassaki B, Dos Santos Vasconcelos M, de Oliveira LP, Lyra AC, Bueno AA, de Jesus RP | title = Efficacy of silymarin in patients with non-alcoholic fatty liver disease - the Siliver trial: a study protocol for a randomized controlled clinical trial | journal = Trials | volume = 24 | issue = 1 | pages = 177 | date = March 2023 | pmid = 36899430 | pmc = 10000352 | doi = 10.1186/s13063-023-07210-6 | id = Art. No. 177 | doi-access = free }}</ref> There is little evidence to support a meaningful [[antiviral]] effect of milk thistle in chronic [[hepatitis C]].<ref>{{cite web|url=https://www.webmd.com/hepatitis/milk-thistle-liver|title=Does Milk Thistle Help Your Liver?| veditors = Khatri M | vauthors = Nelson A |website=WebMD|access-date=31 December 2023|date=31 August 2022}}</ref><ref>{{cite journal | vauthors = Yang Z, Zhuang L, Lu Y, Xu Q, Chen X | title = Effects and tolerance of silymarin (milk thistle) in chronic hepatitis C virus infection patients: a meta-analysis of randomized controlled trials | journal = BioMed Research International | volume = 2014 | pages = 941085 | year = 2014 | pmid = 25247194 | pmc = 4163440 | doi = 10.1155/2014/941085 | doi-access = free | id = Art. ID 941085 }}</ref>

== 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).<ref>{{cite journal | vauthors = Bosch-Barrera J, Sais E, Cañete N, Marruecos J, Cuyàs E, Izquierdo A, Porta R, Haro M, Brunet J, Pedraza S, Menendez JA | title = Response of brain metastasis from lung cancer patients to an oral nutraceutical product containing silibinin | journal = Oncotarget | volume = 7 | issue = 22 | pages = 32006–32014 | date = May 2016 | pmid = 26959886 | pmc = 5077992 | doi = 10.18632/oncotarget.7900 | doi-access = free }}</ref>

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 [[Ultraviolet|UVB]]-induced [[epidermal hyperplasia]], and [[DNA repair]] for UV-induced [[DNA damage (naturally occurring)|DNA damage]] ([[double strand breaks]]).<ref>{{cite journal | vauthors = Singh RP, Agarwal R | title = Cosmeceuticals and silibinin | journal = Clinics in Dermatology | volume = 27 | issue = 5 | pages = 479–484 | date = September 2009 | pmid = 19695480 | pmc = 2767273 | doi = 10.1016/j.clindermatol.2009.05.012 }}</ref> Studies on mice demonstrate a significant protection on chronic unpredictable mild stress (CUMS)–induced depressive-like behavior on mice<ref>{{cite journal | vauthors = Thakare VN, Patil RR, Oswal RJ, Dhakane VD, Aswar MK, Patel BM | title = Therapeutic potential of silymarin in chronic unpredictable mild stress induced depressive-like behavior in mice | journal = Journal of Psychopharmacology | volume = 32 | issue = 2 | pages = 223–235 | date = February 2018 | pmid = 29215318 | doi = 10.1177/0269881117742666 | s2cid = 3292948 }}</ref> and increased cognition in aged rats as a result of consuming silymarin.<ref>{{cite journal | vauthors = Sarubbo F, Ramis MR, Kienzer C, Aparicio S, Esteban S, Miralles A, Moranta D | title = Chronic Silymarin, Quercetin and Naringenin Treatments Increase Monoamines Synthesis and Hippocampal Sirt1 Levels Improving Cognition in Aged Rats | journal = Journal of Neuroimmune Pharmacology | volume = 13 | issue = 1 | pages = 24–38 | date = March 2018 | pmid = 28808887 | doi = 10.1007/s11481-017-9759-0 | s2cid = 255272480 }}</ref>

Due to its [[immunomodulatory]],<ref>{{cite journal | vauthors = Balouchi S, Gharagozloo M, Esmaeil N, Mirmoghtadaei M, Moayedi B | title = Serum levels of TGFβ, IL-10, IL-17, and IL-23 cytokines in β-thalassemia major patients: the impact of silymarin therapy | journal = Immunopharmacology and Immunotoxicology | volume = 36 | issue = 4 | pages = 271–274 | date = August 2014 | pmid = 24945737 | doi = 10.3109/08923973.2014.926916 | s2cid = 21176675 }}</ref> iron-[[chelation|chelating]], and [[antioxidant]] properties, this herb has the potential to be used in [[beta-thalassemia]] patients who receive regular [[blood transfusion]]s and suffer from [[iron overload]].<ref>{{cite journal | vauthors = Moayedi Esfahani BA, Reisi N, Mirmoghtadaei M | title = Evaluating the safety and efficacy of silymarin in β-thalassemia patients: a review | journal = Hemoglobin | volume = 39 | issue = 2 | pages = 75–80 | date = 2015-03-04 | pmid = 25643967 | doi = 10.3109/03630269.2014.1003224 | s2cid = 22213963 }}</ref>

==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.<ref name=Kidd2005/> An earlier study had concluded Siliphos to have 4.6 fold higher bioavailability.<ref>{{cite journal | vauthors = Barzaghi N, Crema F, Gatti G, Pifferi G, Perucca E | year = 1990 | title = Pharmacokinetic studies on IdB 1016, a silybin- phosphatidylcholine complex, in healthy human subjects| pmid = 2088770| journal = Eur J Drug Metab Pharmacokinet | volume = 15 | issue = 4| pages = 333–8 | doi=10.1007/bf03190223| s2cid = 26047183 }}</ref>{{primary source inline|date=February 2019}} It has been also reported that silymarin inclusion complex with β-[[cyclodextrin]] is much more soluble than silymarin itself.<ref name=Voinovich2009/> There have also been prepared [[glycoside]]s of silybin, which show better water solubility and even stronger hepatoprotective effect.<ref name=Kosina2002/>

Silymarin, like other [[flavonoid]]s, has been shown to inhibit [[P-glycoprotein]]-mediated cellular efflux.<ref name=Zhou2004/> 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.<ref name=Wu2009/>

== Toxicity ==

Silibinin and all the other compounds found in silymarin, especially [[silychristin]], blocked the [[Monocarboxylate transporter 8|MCT8]] transporter according to one in vitro study.<ref name=":0">{{Cite journal|vauthors=Johannes J, Jayarama-Naidu R, Meyer F, Wirth EK, Schweizer U, Schomburg L, Köhrle J, Renko K |date=2016|title=Silychristin, a Flavonolignan Derived From the Milk Thistle, Is a Potent Inhibitor of the Thyroid Hormone Transporter MCT8 |journal=Endocrinology|volume=157|issue=4|pages=1694–2301|doi=10.1210/en.2015-1933|pmid=26910310|doi-access=free}}</ref> 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.<ref>{{cite journal | vauthors = Ataei S, Mahdian MR, Ghaleiha A, Matinnia N, Nili-Ahmadabadi A | title = Silymarin Improves Thyroid Function in Lithium-treated Bipolar Patients: A Randomized, Double-blind, Placebo-controlled Pilot Study | journal = Current Drug Therapy | volume = 18 | date = July 2023 | issue = 3 | pages = 346–353 | doi = 10.2174/1574885518666230710122712 | s2cid = 259869834 }}</ref>

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.<ref>{{cite journal | vauthors = Soleimani V, Delghandi PS, Moallem SA, Karimi G | title = Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review | journal = Phytotherapy Research | volume = 33 | issue = 6 | pages = 1627–1638 | date = June 2019 | pmid = 31069872 | doi = 10.1002/ptr.6361 | s2cid = 148569634 }}</ref><ref>{{cite journal | vauthors = Hernández R, Nazar E | title = Effect of silymarin in intrahepatic cholestasis of pregnancy (preliminary communication) | journal = Revista chilena de obstetricia y ginecología. | volume = 47 | issue = 1 | pages = 22–29 | date = 1982 | pmid = 6927150}}</ref> Silymarin is also devoid of embryotoxic potential in animal models.<ref name=Fraschini2002/><ref name=Hahn1968/>

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.<ref>{{cite journal | vauthors = Flaig TW, Gustafson DL, Su LJ, Zirrolli JA, Crighton F, Harrison GS, Pierson AS, Agarwal R, Glodé LM | title = A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients | journal = Investigational New Drugs | volume = 25 | issue = 2 | pages = 139–146 | date = April 2007 | pmid = 17077998 | doi = 10.1007/s10637-006-9019-2 | s2cid = 20240838 }}</ref>

== Biotechnology ==

Silymarin can be produced in [[callus (cell biology)|callus]] and cell suspensions of ''[[Silybum marianum]]'' and substituted [[pyrazinecarboxamide]]s can be used as abiotic [[elicitor]]s of flavolignan production.<ref>{{cite journal | vauthors = Tůmová L, Tůma J, Megušar K, Doleža M | year = 2010 | title = Substituted Pyrazinecarboxamides as Abiotic Elicitors of Flavolignan Production in Silybum marianum (L.) Gaertn Cultures in Vitro | journal = Molecules | volume = 15 | issue = 1| pages = 331–340 | doi = 10.3390/molecules15010331 | pmid = 20110894 | pmc = 6256978 | doi-access = free }}</ref>

== Biosynthesis ==

The biosynthesis of silibinin A and silibinin B is composed of two major parts, [[taxifolin]] and [[coniferyl alcohol]].<ref>{{cite journal | vauthors = Lv Y, Gao S, Xu S, Du G, Zhou J, Chen J | title = Spatial organization of silybin biosynthesis in milk thistle [Silybum marianum (L.) Gaertn] | journal = The Plant Journal | volume = 92 | issue = 6 | pages = 995–1004 | date = December 2017 | pmid = 28990236 | doi = 10.1111/tpj.13736 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Prasad RR, Paudel S, Raina K, Agarwal R | title = Silibinin and non-melanoma skin cancers | journal = Journal of Traditional and Complementary Medicine | volume = 10 | issue = 3 | pages = 236–244 | date = May 2020 | pmid = 32670818 | pmc = 7340873 | doi = 10.1016/j.jtcme.2020.02.003 }}</ref> Coniferyl alcohol is synthesized in milk thistle seed coat. Starting with the transformation of phenylalanine into cinnamic acid mediated by [[phenylalanine ammonia-lyase]].<ref>{{cite journal | vauthors = Barros J, Escamilla-Trevino L, Song L, Rao X, Serrani-Yarce JC, Palacios MD, Engle N, Choudhury FK, Tschaplinski TJ, Venables BJ, Mittler R, Dixon RA | title = 4-Coumarate 3-hydroxylase in the lignin biosynthesis pathway is a cytosolic ascorbate peroxidase | journal = Nature Communications | volume = 10 | issue = 1 | pages = 1994 | date = April 2019 | pmid = 31040279 | pmc = 6491607 | doi = 10.1038/s41467-019-10082-7 | bibcode = 2019NatCo..10.1994B }}</ref> 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).

[[File:Silybin biosynthesis .jpg|thumb|440px|Biosynthesis of silybin (silibinin A and silibinin B)|none]]

== References ==

{{Reflist|30em|refs=

<ref name=Kidd2005>{{cite journal |vauthors=Kidd P, Head K |title=A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos) |journal=Alternative Medicine Review |volume=10 |issue=3 |pages=193–203 |year=2005 |pmid=16164374 |url=http://www.thorne.com/altmedrev/.fulltext/10/3/193.pdf |access-date=2010-12-14 |url-status=dead |archive-url=https://web.archive.org/web/20110728045923/http://www.thorne.com/altmedrev/.fulltext/10/3/193.pdf |archive-date=2011-07-28 }}</ref>

<ref name=Kosina2002>{{cite journal |vauthors=Kosina P, Kren V, Gebhardt R, Grambal F, Ulrichová J, Walterová D |title=Antioxidant properties of silybin glycosides |journal=Phytotherapy Research |volume=16 | issue = Suppl 1 |pages=S33–S39 |year=2002 |pmid=11933137 |doi= 10.1002/ptr.796|doi-access=free }}</ref>

<ref name=Saller2008>{{cite journal|vauthors=Saller R, Brignoli R, Melzer J, Meier R|title=An updated systematic review with meta-analysis for the clinical evidence of silymarin|year=2008|journal=Forschende Komplementärmedizin|volume=15|issue=1|pages=9–20|pmid=18334810|doi=10.1159/000113648|s2cid=23468345 |url=https://www.zora.uzh.ch/id/eprint/12530/ }}</ref>

<ref name=Voinovich2009>{{cite journal |vauthors=Voinovich D, Perissutti B, Grassi M, Passerini N, Bigotto A |title=Solid state mechanochemical activation of ''Silybum marianum'' dry extract with betacyclodextrins: Characterization and bioavailability of the coground systems |journal=Journal of Pharmaceutical Sciences |volume=98 |issue=11 |pages=4119–29 |year=2009 |pmid=19226635 |doi=10.1002/jps.21704}}</ref>

<ref name=Wu2009>{{cite journal |vauthors=Wu JW, Lin LC, Tsai TH |title=Drug-drug interactions of silymarin on the perspective of pharmacokinetics |journal=Journal of Ethnopharmacology |volume=121 |issue=2 |pages=185–93 |year=2009 |pmid=19041708 |doi=10.1016/j.jep.2008.10.036 }}</ref>

<ref name=Zhou2004>{{cite journal |vauthors=Zhou S, Lim LY, Chowbay B |title=Herbal modulation of P-glycoprotein |journal=Drug Metabolism Reviews |volume=36 |issue=1 |pages=57–104 |year=2004 |pmid=15072439 |doi=10.1081/DMR-120028427 |s2cid=25946443 }}</ref>

<ref name=Fraschini2002>{{cite journal |vauthors=Fraschini F, Demartini G, Esposti D |title=Pharmacology of Silymarin |journal=Clinical Drug Investigation |volume=22 |issue=1 |pages=51–65 |year=2002 |doi=10.2165/00044011-200222010-00007 |s2cid=20133887 |url=http://adisonline.com/druginvestigation/Abstract/2002/22010/Pharmacology_of_Silymarin.7.aspx |url-status=dead |archive-url=https://web.archive.org/web/20121027121930/http://adisonline.com/druginvestigation/Abstract/2002/22010/Pharmacology_of_Silymarin.7.aspx |archive-date=2012-10-27 }}</ref>

<ref name=Hahn1968>{{cite journal |vauthors=Hahn G, Lehmann HD, Kürten M, Uebel H, Vogel G |title=On the pharmacology and toxicology of silymarin, an antihepatotoxic active principle from Silybum marianum (L.) gaertn |journal=Arzneimittelforschung |volume=18 |issue=6 |pages=698–704 |year=1968 |pmid=5755807 }}</ref>

}}

== Further reading ==

{{refbegin}}

* {{cite web | url = http://www.mayoclinic.com/health/silymarin/NS_patient-milkthistle | archive-url = https://web.archive.org/web/20120105052450/http://www.mayoclinic.com/health/silymarin/NS_patient-milkthistle | archive-date = 5 January 2012 | title = Milk thistle (Silybum marianum) | work = Mayo Clinic }}

*{{cite journal |vauthors=Morazzoni P, Bombardelli E |title=''Silybum marianum'' (cardus marianus) |journal=Fitoterapia |volume=66 |pages=3–42 |year=1994}}

*{{cite journal |vauthors=Saller R, Meier R, Brignoli R |title=The use of silymarin in the treatment of liver diseases |journal=Drugs |volume=61 |issue=14 |pages=2035–63 |year=2001 |pmid=11735632 |doi=10.2165/00003495-200161140-00003 |s2cid=27948885 }}

{{refend}}

== External links ==

* {{MeshName|Silymarin}}

{{Bile and liver therapy}}

{{lignan}}

[[Category:Antidotes]]

[[Category:Flavonolignans]]

[[Category:Resorcinols]]

[[Category:3-Hydroxypropenals]]

[[Category:Benzodioxans]]