Squalene: Difference between revisions

| verifiedrevid = 402675279

| ImageFile = Squalene.svg

| ImageFile_Ref = {{chemboximage|correct|??}}

| ImageSize = 244

| ImageName = Skeletal formula of squalene

| ImageFile1 = Squalene-from-xtal-3D-vdW-A.png

| ImageFile1_Ref = {{chemboximage|correct|??}}

| ImageSize1 = 244

| ImageName1 = Spacefill model of squalene

| ImageFile2 = Squalene-from-xtal-3D-balls-A.png

| ImageFile2_Ref = {{chemboximage|correct|??}}

| ImageSize2 = 244

| ImageName2 = Ball and stick model of squalene

| SystematicName = 2,6,10,15,19,23-Hexamethyltetracosa-2,6,10,14,18,22-hexaene<ref>{{PubChem|1105}}</ref>

| Section1 = {{Chembox Identifiers

| CASNo = 111-02-4

| CASNo_Ref = {{cascite|correct|CAS}}

| CASNo_Comment = <small>(6''E'',10''E'',14''E'',18''E'')-6,10,14,18-tetraene</small>

| PubChem = 1105

| PubChem_Ref = {{Pubchemcite|correct|PubChem}}

| PubChem1 = 5280370

| PubChem1_Ref = {{Pubchemcite|correct|PubChem}}

| PubChem1_Comment = <small>(14''E'')-14-ene</small>

| PubChem2 = 24871318

| PubChem2_Ref = {{Pubchemcite|correct|PubChem}}

| PubChem2_Comment = <small>(6''Z'',10''Z'',14''E'',18''E'')-6,10,14,18-tetraene</small>

| PubChem3 = 11975273

| PubChem3_Ref = {{Pubchemcite|correct|PubChem}}

| PubChem3_Comment = <small>(6''Z'',10''E'',14''E'',18''E'')-6,10,14,18-tetraene</small>

| PubChem4 = 15555221

| PubChem4_Ref = {{Pubchemcite|correct|PubChem}}

| PubChem4_Comment = <small>(6''E'',10''Z'',14''E'',18''E'')-6,10,14,18-tetraene</small>

| PubChem5 = 638072

| PubChem5_Ref = {{Pubchemcite|correct|PubChem}}

| PubChem5_Comment = <small>(6''E'',10''E'',14''E'',18''E'')-6,10,14,18-tetraene</small>

| ChemSpiderID = 553635

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID1 = 4444065

| ChemSpiderID1_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID1_Comment = <small>(14''E'')-14-ene</small>

| ChemSpiderID2 = 10148626

| ChemSpiderID2_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID2_Comment = <small>(6''Z'',10''E'',14''E'',18''E'')-6,10,14,18-tetraene</small>

| ChemSpiderID3 = 10605948

| ChemSpiderID3_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID3_Comment = <small>(6''E'',10''Z'',14''E'',18''E'')-6,10,14,18-tetraene</small>

| ChemSpiderID4 = 553635

| ChemSpiderID4_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID4_Comment = <small>(6''E'',10''E'',14''E'',18''E'')-6,10,14,18-tetraene</small>

| UNII = 7QWM220FJH

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

| EINECS = 203-826-1

| KEGG = <!-- blanked - oldvalue: C00751 -->

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

| MeSHName = Squalene

| ChEBI = 15440

| ChEMBL = 458402

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| RTECS = XB6010000

| Beilstein = 1728919

| 3DMet = B00166

| SMILES = CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C

| SMILES = CC(=CCCC(=CCCC(=CCCC=C(CCC=C(CCC=C(C)C)C)C)C)C)C

| StdInChI = 1S/C30H50/c1-25(2)15-11-19-29(7)23-13-21-27(5)17-9-10-18-28(6)22-14-24-30(8)20-12-16-26(3)4/h15-18,23-24H,9-14,19-22H2,1-8H3/b27-17+,28-18+,29-23+,30-24+

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| InChI = 1/C30H50/c1-25(2)15-11-19-29(7)23-13-21-27(5)17-9-10-18-28(6)22-14-24-30(8)20-12-16-26(3)4/h15-18,23-24H,9-14,19-22H2,1-8H3

| StdInChIKey = YYGNTYWPHWGJRM-AAJYLUCBSA-N

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| Section2 = {{Chembox Properties

| C = 30

| H = 50

| ExactMass = 410.391251600 g mol^-1

| Appearance = Pale yellow, translucent liquid

| Density = 0.858 g cm^-3

| MeltingPtC = -75

| BoilingPtC = 285

| Boiling_notes = at 3.3 kPa

| LogP = 12.188

| Viscosity = 12 cP (at 20 °C)

| Section3 = {{Chembox Hazards

| FlashPt = 110 °C

'''Squalene''' is a natural [[organic compound]] originally obtained for commercial purposes primarily from [[shark liver oil]], though plant sources (primarily vegetable oils) are used as well, including [[amaranth]] seed, rice bran, wheat germ, and olives. All plants and animals produce squalene, including [[human]]s. Squalene has been proposed to be an important part of the [[Mediterranean diet]] as it may be a [[Chemoprophylaxis|chemopreventative]] substance that protects people from cancer.<ref>{{cite journal |pages=1841–8 |doi=10.1517/13543784.9.8.1841 |title=Squalene: potential chemopreventive agent |year=2000 |last1=Smith |first1=Theresa J |journal=Expert Opinion on Investigational Drugs |volume=9 |issue=8 |pmid=11060781}}</ref><ref>{{cite journal |pages=319–26 |doi=10.1097/01.cej.0000130221.19480.7e |title=Olives and olive oil in cancer prevention |year=2004 |last1=Owen |first1=R W |last2=Haubner |first2=R |last3=Würtele |first3=G |last4=Hull |first4=W E |last5=Spiegelhalder |first5=B |last6=Bartsch |first6=H |journal=European Journal of Cancer Prevention |volume=13 |issue=4 |pmid=15554560}}</ref>

Squalene is a [[hydrocarbon]] and a [[triterpene]], and is a natural and vital part of the synthesis of cholesterol, steroid hormones, and vitamin D in the human body.<ref>http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm#prenyl</ref> Squalene is used in cosmetics, and more recently as an [[immunologic adjuvant]] in vaccines.

== Role in steroid synthesis ==

Squalene is the biochemical precursor to the whole family of [[steroids]].<ref>{{cite journal |pages=47–92 |doi=10.3109/10409238309102790 |title=Sterol, Structure and Membrane Functio |year=1983 |last1=Bloch |first1=Konrad E. |journal=Critical Reviews in Biochemistry and Molecular Biology |volume=14}}</ref> Oxidation (via [[squalene monooxygenase]]) of one of the terminal double bonds of squalene yields [[squalene oxide|2,3-squalene oxide]], which undergoes enzyme-catalyzed cyclization to afford [[lanosterol]], which is then elaborated into [[cholesterol]] and other steroids.

[[Image:Sterol synthesis.svg|thumb|left|350px|Simplified version of the steroid synthesis pathway with the intermediates [[isopentenyl pyrophosphate]] (IPP), [[dimethylallyl pyrophosphate]] (DMAPP), [[geranyl pyrophosphate]] (GPP) and squalene shown. Some intermediates are omitted.]]

<br style="clear: left; " />

== Biosynthesis ==

* Two molecules of [[farnesyl pyrophosphate]] condense with reduction by [[NADPH]] to form squalene - by ''[[squalene synthase]]''.

==Interactive pathway map==

== Shark squalene ==

Squalene is a low density compound often stored in the bodies of [[Chondrichthyes|cartilaginous fish]] such as [[shark]]s, which lack a [[swim bladder]] and must therefore reduce their body density with fats and oils. Squalene, which is stored mainly in the shark's [[liver]], is lighter than water with a specific gravity of 0.855. Recently it has become a trend for sharks to be hunted to process their livers for the purpose of making squalene health capsules. Environmental and other concerns over shark hunting have motivated its extraction from vegetable sources,<ref>[[EWG]]: [http://www.enviroblog.org/2008/02/unilever-takes-a-bite-out-of-your-face-cream.html Unilever takes a bite out of your face cream]</ref> or biosynthetic processes instead.<ref>

[[Amyris]]: [http://www.amyris.com/en/newsroom/118-amyris-soliance Amyris and Soliance Partner to Commercialize Renewable Bio-Sourced Cosmetics]

</ref>

== Derivative used as a skin moisturizer in cosmetics ==

Squalene oil is the most common fat and antioxidant produced in and on human skin. It is a natural [[moisturizer]].

[[Squalane]] is a [[saturation (chemistry)|saturated]] form of squalene in which the double bonds have been eliminated by [[hydrogenation]]. Squalane is less susceptible to [[organic redox reaction|oxidation]] than squalene. Squalane is thus more commonly used than squalene in personal care products, such as [[moisturizer]]s.

Toxicology studies have determined that in the concentrations used in cosmetics, both squalene and squalane have low acute toxicity, and are not significant human skin irritants or sensitizers.<ref>{{cite journal |pages=37–56 |doi=10.3109/10915818209013146 |title=Final Report on the Safety Assessment of Squalane and Squalene |year=1982 |journal=International Journal of Toxicology |volume=1 |issue=2}}</ref>

== Use as an adjuvant in vaccines ==

[[Immunologic adjuvant]]s are substances, administered in conjunction with a [[vaccine]], that stimulate the [[immune system]] and increase the response to the vaccine. Squalene is not itself an adjuvant, but it has been used in conjunction with [[surfactant]]s in certain adjuvant formulations.<ref name="who.int" />

An adjuvant using squalene is [[Novartis]]' proprietary adjuvant [[MF59]], which is added to influenza vaccines to help stimulate the human body's immune response through production of [[CD4]] memory cells. It is the first oil-in-water [[influenza vaccine]] adjuvant to be commercialized in combination with a seasonal influenza virus vaccine. It was developed in the 1990s by researchers at [[Ciba-Geigy]] and [[Chiron Corporation|Chiron]]; both companies were subsequently acquired by Novartis.<ref>[http://www.novartis.com/downloads/newsroom/MF59-Adj-fact-sheet.pdf MF59 Adjuvant Fact Sheet], Novartis, June 2009.</ref> It is present in the form of an [[emulsion]] and is added to make the vaccine more immunogenic.<ref name="who.int">[http://www.who.int/vaccine_safety/topics/adjuvants/squalene/questions_and_answers/en/ Squalene-based adjuvants in vaccines], Global Advisory Committee on Vaccine Safety, [[World Health Organization]]</ref> However, the mechanism of action remains unknown. MF59 is capable of switching on a number of genes that partially overlap with those activated by other adjuvants.<ref>{{cite journal |pages=10501–6 |doi=10.1073/pnas.0804699105 |title=Molecular and cellular signatures of human vaccine adjuvants |year=2008 |last1=Mosca |first1=F. |last2=Tritto |first2=E. |last3=Muzzi |first3=A. |last4=Monaci |first4=E. |last5=Bagnoli |first5=F. |last6=Iavarone |first6=C. |last7=O'Hagan |first7=D. |last8=Rappuoli |first8=R. |last9=De Gregorio |first9=E. |journal=Proceedings of the National Academy of Sciences |volume=105 |issue=30}}</ref> How these changes are triggered is unclear; to date, no receptors responding to MF59 have been identified. One possibility is that MF59 affects the cell behavior by changing the lipid metabolism, namely by inducing accumulation of neutral lipids within the target cells.<ref>{{cite journal |pages=350–5 |doi=10.1016/j.bbrc.2009.12.062 |title=Squalene-based oil-in-water emulsion adjuvants perturb metabolism of neutral lipids and enhance lipid droplet formation |year=2010 |last1=Kalvodova |first1=Lucie |journal=Biochemical and Biophysical Research Communications |volume=393 |issue=3 |pmid=20018176}}</ref> An MF59-adjuvanted influenza vaccine (Fluad, developed by Chiron, which contains about 10&nbsp;mg of squalene per dose) has been approved by health agencies and used in several European countries for seasonal flu shots since 1997.<ref name="NYT-20090921">Andrew Pollack. [http://www.nytimes.com/2009/09/22/health/22vacc.html Benefit and Doubt in Vaccine Additive], ''[[The New York Times]]'', September 21, 2009.</ref> However, the [[Food and Drug Administration]] has not authorized the use of such adjuvants in the United States.<ref>Rob Stein. [http://www.washingtonpost.com/wp-dyn/content/article/2009/08/22/AR2009082202337_2.html?sid=ST2009082300274 Swine Flu Campaign Waits on Vaccine]. ''[[The Washington Post]]'', August 23, 2009.</ref> [[Glaxo Smith Kline]] used the squalene-based [[AS03]] adjuvant in their 2009 influenza pandemic vaccine [[Pandemrix]] and [http://www.gsk.ca/english/docs-pdf/Arepanrix_PIL_CAPA01v01.pdf Arepanrix].

A 2009 [[meta-analysis]] by researchers at Novartis Vaccines and Diagnostics that was published in the journal ''Vaccine'' brought together data from 64 clinical trials of influenza vaccines with the squalene-containing adjuvant MF59 and compared them to the effects of vaccines with no adjuvant. The analysis reported that the adjuvanted vaccines were associated with slightly lower risks of chronic diseases, but that neither type of vaccines altered the rate of autoimmune diseases; the authors concluded that their data "supports the good safety profile associated with MF59-adjuvanted influenza vaccines and suggests there may be a clinical benefit over non-MF59-containing vaccines".<ref name=pmid19751689>{{cite journal |pages=6959–65 |doi=10.1016/j.vaccine.2009.08.101 |title=MF59-adjuvanted versus non-adjuvanted influenza vaccines: Integrated analysis from a large safety database |year=2009 |last1=Pellegrini |first1=Michele |last2=Nicolay |first2=Uwe |last3=Lindert |first3=Kelly |last4=Groth |first4=Nicola |last5=Della Cioppa |first5=Giovanni |journal=Vaccine |volume=27 |issue=49 |pmid=19751689}}</ref>

== Health controversy ==

There have been attempts to link squalene to [[Gulf War Syndrome]] mainly due to the idea that squalene might have been present in an anthrax vaccine given to some military personnel during the 1991 Persian Gulf War. Studies led by Dr. Pam Asa of Tulane University found that deployed Persian Gulf War Syndrome patients are significantly more likely to have antibodies to squalene (95 percent) than asymptomatic Gulf War veterans (0 percent; p&lt;.001);.<ref>{{cite journal |pages=19–27 |doi=110.1006/exmp.2002.2429 |title=Antibodies to Squalene in Recipients of Anthrax Vaccine |year=2002 |last1=Asa |first1=P |journal=Experimental and Molecular Pathology |volume=73 |pmid=12127050 |last2=Wilson |first2=R |last3=Garry |first3=RF |issue=1}}</ref><ref>{{cite journal |pages=55–64 |doi=10.1006/exmp.1999.2295 |title=Antibodies to Squalene in Gulf War Syndrome |year=2000 |last1=Asa |first1=P |journal=Experimental and Molecular Pathology |volume=68 |pmid=10640454 |last2=Cao |first2=Y |last3=Garry |first3=RF |issue=1}}</ref> The first of these published results concludes with the following statement: "It is important to note that our laboratory-based investigations do not establish that squalene was added as adjuvant to any vaccine used in military or other personnel who served in the Persian Gulf War era." The second publication, however, links the incidence of anti-squalene antibodies and Gulf War Syndrome to five specific lots of vaccine. Furthermore, they cite results of 1999 testing by the U.S. Food and Drug Administration which found these specific lots of vaccine to contain squalene.<ref>Committee on Government Reform Hearings for the United States House of Representatives, October 3rd and 11th, 2000. "Accountability of DoD, FDA and BioPort Officials for the Anthrax Vaccine Immunization Program (AVIP)."</ref> In response to these results, a committee of the US [[Institute of Medicine]] stated that "The committee does not regard this study as providing evidence that the investigators have successfully measured antibodies to squalene", since the authors did not perform the normal [[scientific control]]s needed show that their test was specific to anti-squalene antibodies.<ref>{{cite book |author=Sox, Harold C.; Fulco, Carolyn; Liverman, Catharyn T. |title=Gulf War and health |publisher=National Academy Press |location=Washington, D.C |year=2000 |page=311 |isbn=0-309-07178-X}}</ref> It has also been determined that the anthrax vaccines given to those US military personnel did not use squalene as an adjuvant.<ref name=DelGiudice>{{cite journal |pages=1010–3 |doi=10.1128/CVI.00191-06 |title=Vaccines with the MF59 Adjuvant Do Not Stimulate Antibody Responses against Squalene |year=2006 |last1=Del Giudice |first1=G. |last2=Fragapane |first2=E. |last3=Bugarini |first3=R. |last4=Hora |first4=M. |last5=Henriksson |first5=T. |last6=Palla |first6=E. |last7=O'Hagan |first7=D. |last8=Donnelly |first8=J. |last9=Rappuoli |first9=R. |journal=Clinical and Vaccine Immunology |volume=13 |issue=9 |pmid=16960112 |pmc=1563566}}</ref><ref>[http://www.gao.gov/archive/1999/ns99005.pdf Gulf War illnesses: questions about the presence of squalene antibodies in veterans can be resolved,] ''United States General Accounting Office'' 1999</ref><ref name=Henig>Jess Henig [http://www.newsweek.com/id/218513 Innoculation Misinformation: Claims that the swine flu vaccine is dangerous range from overblown to false] ''Newsweek'' Oct 19, 2009</ref> The vaccines were also tested for squalene, and none was detected with standard methods.<ref>{{cite journal |pages=183–93 |doi=10.1016/S0731-7085(02)00009-2 |title=Development and application of an analytical method for the determination of squalene in formulations of anthrax vaccine adsorbed |year=2002 |last1=Spanggord |first1=R |journal=Journal of Pharmaceutical and Biomedical Analysis |volume=29 |pmid=12062677 |last2=Wu |first2=B |last3=Sun |first3=M |last4=Lim |first4=P |last5=Ellis |first5=WY |issue=1–2}}</ref> A much more sensitive method was then developed, which again found no squalene in 37 of the 38 lots tested. One lot contained traces of squalene, at less than ten parts per billion, which is about 30-fold less than the level found in human blood.<ref>{{cite journal |pages=494–9 |doi=10.1016/j.jpba.2006.04.009 |title=Enhancement of an analytical method for the determination of squalene in anthrax vaccine adsorbed formulations |year=2006 |last1=Spanggord |first1=Ronald J. |last2=Sun |first2=Meg |last3=Lim |first3=Peter |last4=Ellis |first4=William Y. |journal=Journal of Pharmaceutical and Biomedical Analysis |volume=42 |issue=4 |pmid=16762524}}</ref> The FDA stated that this trace of squalene probably came from a fingerprint, since the oils on human skin contain enough squalene to send these extremely sensitive tests "off the chart".<ref>[http://www.fda.gov/ohrms/DOCKETS/dockets/80n0208/80n-0208-c000037-15-01-vol151.pdf The Facts on Squalene] ''FDA'' 2005</ref>

A later study reported that about one in ten people have squalene antibodies in their blood, regardless of whether or not they received squalene from a vaccination.<ref>{{cite journal |pages=47–67 |doi=10.1016/j.jim.2003.11.002 |title=Detection of antibodies to squalene III. Naturally occurring antibodies to squalene in humans and mice |year=2004 |last1=Matyas |first1=G |journal=Journal of Immunological Methods |volume=286 |pmid=15087221 |last2=Rao |first2=M |last3=Pittman |first3=PR |last4=Burge |first4=R |last5=Robbins |first5=IE |last6=Wassef |first6=NM |last7=Thivierge |first7=B |last8=Alving |first8=CR |issue=1–2}}</ref> A later study confirmed this result, and also showed that vaccination with squalene-containing vaccines do not alter the levels of these naturally-occurring antibodies.<ref name=DelGiudice/> A third study showed that these naturally-occurring antibodies were no more common in Gulf war veterans than in the general population.<ref>{{cite journal |pages=3921–6 |doi=10.1016/j.vaccine.2009.03.091 |title=Antibodies to squalene in US Navy Persian Gulf War veterans with chronic multisymptom illness |year=2009 |last1=Phillips |first1=Christopher J. |last2=Matyas |first2=Gary R. |last3=Hansen |first3=Christian J. |last4=Alving |first4=Carl R. |last5=Smith |first5=Tyler C. |last6=Ryan |first6=Margaret A.K. |journal=Vaccine |volume=27 |issue=29 |pmid=19379786}}</ref>

Oil-water suspensions, including [[MF59]], were associated with the ability to induce lupus autoantibodies in non-autoimmune mice.<ref>{{cite journal |pages=1–9 |doi=10.1016/S0896-8411(03)00083-0 |title=Induction of lupus autoantibodies by adjuvants |year=2003 |last1=Satoh |first1=M |journal=Journal of Autoimmunity |volume=21 |pmid=12892730 |last2=Kuroda |first2=Y |last3=Yoshida |first3=H |last4=Behney |first4=KM |last5=Mizutani |first5=A |last6=Akaogi |first6=J |last7=Nacionales |first7=DC |last8=Lorenson |first8=TD |last9=Rosenbauer |first9=RJ |issue=1}}</ref> In one study, endogenous squalene was linked to autoimmune arthritis in rats.<ref>{{cite journal |pages=2057–65 |doi=10.1016/S0002-9440(10)65077-8 |title=The Endogenous Adjuvant Squalene Can Induce a Chronic T-Cell-Mediated Arthritis in Rats |year=2000 |last1=Carlson |first1=Barbro C. |last2=Jansson |first2=Åsa M. |last3=Larsson |first3=Anders |last4=Bucht |first4=Anders |last5=Lorentzen |first5=Johnny C. |journal=The American Journal of Pathology |volume=156 |issue=6 |pmid=10854227 |pmc=1850095}}</ref> An epidemiologic analysis of safety data on MF59 seasonal and pandemic influenza vaccines showed no evidence of increased risk of vaccine adverse events of potential autoimmune origin.<ref name=pmid19751689/>

The [[World Health Organization]] and the [[US Department of Defense]] have both published extensive reports that emphasize that squalene is a chemical naturally occurring in the human body, present even in oils of human fingerprints.<ref name="who.int"/><ref>{{cite journal |pmid=12136987 |year=2002 |last1=Asano |first1=KG |last2=Bayne |first2=CK |last3=Horsman |first3=KM |last4=Buchanan |first4=MV |title=Chemical composition of fingerprints for gender determination |volume=47 |issue=4 |pages=805–7 |journal=Journal of forensic sciences |doi=10.1520/JFS15460J}}</ref> WHO goes further to explain that squalene has been present in over 22 million flu vaccines given to patients in Europe since 1997 and there have never been significant vaccine-related adverse events.<ref name="who.int"/>

== References ==

{{reflist}}

[[Category:Alkenes]]

[[Category:Ichthyology]]

[[ar:سكوالين]]

[[ca:Escualè]]

[[cs:Skvalen]]

[[de:Squalen]]

[[es:Escualeno]]

[[fr:Squalène]]

[[ko:스쿠알렌]]

[[it:Squalene]]

[[lv:Skvalēns]]

[[lt:Skvalenas]]

[[nl:Squaleen]]

[[ja:スクアレン]]

[[pl:Skwalen]]

[[pt:Esqualeno]]

[[ru:Сквален]]

[[fi:Skvaleeni]]

[[zh:鲨烯]]