Squalene: Wikis

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Squalene
Skeletal formula of squalene
Ball-and-stick model of squalene
Space-filling model of squalene
IUPAC name
Identifiers
CAS number 111-02-4 Yes check.svgY
SMILES
InChI
Properties
Molecular formula C30H50
Molar mass 410.72 g mol−1
Density 0.855 g/cm3
Melting point

-100 °C

Boiling point

285 °C at 25 mmHg

 Yes check.svgY (what is this?)  (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

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 higher organisms produce squalene, including humans. Squalene has been proposed to be an important part of the Mediterranean diet as it may be a chemopreventative substance that protects people from cancer.[1][2]

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.[3] Squalene is used in cosmetics, and more recently as an immunologic adjuvant in vaccines.

Contents

Role in steroid synthesis

Squalene is the biochemical precursor to the whole family of steroids.[4] Oxidation (via squalene monooxygenase) of one of the terminal double bonds of squalene yields 2,3-squalene oxide, which undergoes enzyme-catalyzed cyclization to afford lanosterol, which is then elaborated into cholesterol and other steroids.

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.


Biosynthesis

Cholesterol-Synthesis-Reaction10.png

Shark squalene

Squalene is a low density compound often stored in the bodies of cartilaginous fish such as sharks, 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 instead.[5]

Use as a skin moisturizer in cosmetics

Squalene is used in cosmetics as a natural moisturizer. It penetrates the skin quickly, does not leave a greasy feeling on the skin and blends well with other oils and vitamins. Squalane is a saturated form of squalene in which the double bonds have been eliminated by hydrogenation. Because squalane is less susceptible to oxidation than squalene, it is more commonly used in personal care products. 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.[6]

Use as an adjuvant in vaccines

Immunologic adjuvants are substances, administered in conjunction with a vaccine, that stimulate the immune system and increase the response to the vaccine. Squalene is one of those adjuvants.[7] It is added to improve the efficacy of several vaccines, including pandemic flu and malaria vaccines. This includes several European countries, which use these formulations in their 2009 flu pandemic vaccines.[8]

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; both companies were subsequently acquired by Novartis.[9] It is present in the form of an emulsion and is added to make the vaccine more immunogenic.[10] An MF59-adjuvanted influenza vaccine (Fluad, developed by Chiron, which contains about 10 mg of squalene per dose) has been approved by health agencies and used in several European countries for seasonal flu shots since 1997.[7] However, the Food and Drug Administration has not authorized the use of such adjuvants in the United States.[11] Glaxo Smith Kline used the squalene-based AS03 adjuvant in their 2009 influenza pandemic vaccine Pandemrix and 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".[12]

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. One study 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<.001);[13] however, the study 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." However, 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 controls needed show that their test was specific to anti-squalene antibodies.[14] It has also been determined that the anthrax vaccines given to those US military personnel did not use squalene as an adjuvant.[15][16][17] The vaccines were also tested for squalene, and none was detected with standard methods.[18] 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.[19] 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".[20]

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.[21] 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.[15] A third study showed that these naturally-occurring antibodies were no more common in Gulf war veterans than in the general population.[22]

Oil-water suspensions, including MF59, were associated with the ability to induce lupus autoantibodies in non-autoimmune mice.[23] In one study, endogenous squalene was linked to autoimmune arthritis in rats.[24] 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.[25]

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.[26][10] 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.[10]

References

  1. ^ Smith TJ (August 2000). "Squalene: potential chemopreventive agent". Expert Opin Investig Drugs 9 (8): 1841–8. doi:10.1517/13543784.9.8.1841. PMID 11060781.  
  2. ^ Owen RW, Haubner R, Würtele G, Hull E, Spiegelhalder B, Bartsch H (August 2004). "Olives and olive oil in cancer prevention". Eur. J. Cancer Prev. 13 (4): 319–26. PMID 15554560.  
  3. ^ http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm#prenyl
  4. ^ K. Bloch:"Sterol structure and membrane function",CRC Crit. Rev.,14:47-92.
  5. ^ EWG: Unilever takes a bite out of your face cream
  6. ^ "Final report on the safety assessment of squalane and squalene". Journal of the American College of Toxicology 1 (2): 37–56. 1982. doi:10.3109/10915818209013146. http://ijt.sagepub.com/cgi/content/abstract/1/2/37.  
  7. ^ a b Andrew Pollack. Benefit and Doubt in Vaccine Additive, The New York Times, September 21, 2009.
  8. ^ Squalene-based adjuvants in vaccines World Health Organization
  9. ^ MF59® Adjuvant Fact Sheet, Novartis, June 2009.
  10. ^ a b c Squalene-based adjuvants in vaccines, Global Advisory Committee on Vaccine Safety, World Health Organization
  11. ^ Rob Stein. Swine Flu Campaign Waits on Vaccine. The Washington Post, August 23, 2009.
  12. ^ Pellegrini M, Nicolay U, Lindert K, Groth N, Della Cioppa G (November 2009). "MF59-adjuvanted versus non-adjuvanted influenza vaccines: integrated analysis from a large safety database". Vaccine 27 (49): 6959–65. doi:10.1016/j.vaccine.2009.08.101. PMID 19751689.  
  13. ^ Asa, P. B., Cao, Y. & Garry, R. F. (2000). "Antibodies to squalene in Gulf War Syndrome". Experimental and Molecular Pathology 68 (1): 55–64. doi:10.1006/exmp.1999.2295. PMID 10640454. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WFB-45F4JKG-1X&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=af819311d3e5c842e347f25e64da6882.  
  14. ^ Sox, Harold C.; Fulco, Carolyn; Liverman, Catharyn T. (2000). Gulf War and health. Washington, D.C: National Academy Press. pp. 311. ISBN 0-309-07178-X.  
  15. ^ a b Del Giudice G, Fragapane E, Bugarini R, et al. (September 2006). "Vaccines with the MF59 adjuvant do not stimulate antibody responses against squalene". Clin. Vaccine Immunol. 13 (9): 1010–3. doi:10.1128/CVI.00191-06. PMID 16960112.  
  16. ^ Gulf War illnesses: questions about the presence of squalene antibodies in veterans can be resolved, United States General Accounting Office 1999
  17. ^ Jess Henig Innoculation Misinformation: Claims that the swine flu vaccine is dangerous range from overblown to false Newsweek Oct 19, 2009
  18. ^ Spanggord RJ, Wu B, Sun M, Lim P, Ellis WY (June 2002). "Development and application of an analytical method for the determination of squalene in formulations of anthrax vaccine adsorbed". J Pharm Biomed Anal 29 (1-2): 183–93. PMID 12062677.  
  19. ^ Spanggord RJ, Sun M, Lim P, Ellis WY (October 2006). "Enhancement of an analytical method for the determination of squalene in anthrax vaccine adsorbed formulations". J Pharm Biomed Anal 42 (4): 494–9. doi:10.1016/j.jpba.2006.04.009. PMID 16762524. http://www.vaccines.army.mil/documents/library/JPB42%282006%29494%E2%80%93499.pdf.  
  20. ^ The Facts on Squalene FDA 2005
  21. ^ Matyas GR, Rao M, Pittman PR, et al. (March 2004). "Detection of antibodies to squalene: III. Naturally occurring antibodies to squalene in humans and mice". J. Immunol. Methods 286 (1-2): 47–67. doi:10.1016/j.jim.2003.11.002. PMID 15087221.  
  22. ^ Phillips CJ, Matyas GR, Hansen CJ, Alving CR, Smith TC, Ryan MA (June 2009). "Antibodies to squalene in US Navy Persian Gulf War veterans with chronic multisymptom illness". Vaccine 27 (29): 3921–6. doi:10.1016/j.vaccine.2009.03.091. PMID 19379786.  
  23. ^ M. Satoh et.al.: Induction of lupus autoantibodies by adjuvants. J Autoimmun. 2003 Aug;21(1):1-9. [1]
  24. ^ Barbro C. Carlson, Åsa M. Jansson, Anders Larsson, Anders Bucht and Johnny C. Lorentzen: The Endogenous Adjuvant Squalene Can Induce a Chronic T-Cell-Mediated Arthritis in Rats. In: American Journal of Pathology. 2000;156:2057-2065.
  25. ^ Pellegrini et al, 2009 http://preview.ncbi.nlm.nih.gov/pubmed/19751689
  26. ^ Asano KG, Bayne CK, Horsman KM, Buchanan MV (2002). "Chemical composition of fingerprints for gender determination". Journal of Forensic Science 47: 805–807.  
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