Squalene
IUPAC name	(6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene
Identifiers
CAS number	111-02-4 Y
SMILES	C\C(C)=C\CCC(\C)=C\CCC(\C)=C\CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)C
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/b27-17+,28-18+,29-23+,30-24+
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
Y (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 botanic sources (primarily vegetable oils) are used as well, including amaranth seed, rice bran, wheat germ, and olives. All higher organisms produce squalene, including humans. It is a hydrocarbon and a triterpene. Squalene is a natural and vital part of the synthesis of cholesterol, steroid hormones, and vitamin D in the human body.^[1] Squalene is used in cosmetics, and more recently as an immunologic adjuvant in vaccines.

[edit] Role in steroid synthesis

Squalene is the biochemical precursor to the whole family of steroids.^[2] 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.

[edit] Biosynthesis

• Two molecules of farnesyl pyrophosphate condense with reduction by NADPH to form squalene - by squalene synthase.

[edit] 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.^[3]

[edit] 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, it is more commonly used in personal care products than squalene. 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.^[4]

[edit] 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.^[5] It is added to improve the efficacy of several vaccines, including pandemic flu and malaria vaccines.

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.^[6] It is present in the form of an emulsion and is added to make the vaccine more immunogenic.^[7] 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.^[5] However, the Food and Drug Administration has not authorized the use of such adjuvants in the United States.^[8] Glaxo Smith Kline used the squalene-based AS03 adjuvant in their 2009 influenza pandemic vaccine Pandemrix and Arepanrix.

[edit] Health controversy

There have been attempts to link squalene to Gulf War Syndrome mainly due to squalene supposedly being present in an Anthrax vaccine given to some military personal 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),^[9]; 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." A later study reported that many humans have squalene antibodies in their blood, regardless of whether or not they received squalene from a vaccination.^[10]

However, subsequent investigation revealed that the study in question, which attempted to link squalene to Gulf War Syndrome, had several technical deficiencies in the way in which it analyzed its data. On top of this, it has been determined that the anthrax vaccines given to those US military personnel, did not use squalene as an adjuvant.^[7]

Oil-water suspensions, including MF59, were associated with the ability to induce lupus autoantibodies in non-autoimmune mice ^[11]. In one study, endogenous squalene was linked to autoimmune arthritis in rats.^[12]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.^[13]

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.^[14][7]

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.^[7]

The US DoD concluded that there are still many doubts to whether or not squalene containing vaccines are safe at all^{[citation needed]}. Some animal research to study arthritis used injections of tuberculosis-like bacteria (mycobacteria) dissolved in squalene (e.g., arthritis-prone rats, mice)^{[citation needed]}. Based on other research, it is clear that whether squalene causes harm or not is related to selected conditions of concentration, dose, route of application, and other factors^[15][16].

[edit] References

1. ^ http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm#prenyl
2. ^ K. Bloch:"Sterol structure and membrane function",CRC Crit. Rev.,14:47-92.
3. ^ EWG: Unilever takes a bite out of your face cream
4. ^ "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. 
5. ^ ^{a b} Andrew Pollack. Benefit and Doubt in Vaccine Additive, The New York Times, September 21, 2009.
6. ^ MF59® Adjuvant Fact Sheet, Novartis, June 2009.
7. ^ ^{a b c d} Squalene-based adjuvants in vaccines, Global Advisory Committee on Vaccine Safety, World Health Organization
8. ^ Rob Stein. Swine Flu Campaign Waits on Vaccine. The Washington Post, August 23, 2009.
9. ^ Asa, P. B., Cao, Y. & Garry, R. F. (2000): Antibodies to squalene in Gulf War Syndrome. In: Experimental and Molecular Pathology. 68, 55-64.
10. ^ http://www.anthrax.osd.mil/resource/qna/qaAll.asp?cID=319
11. ^ M. Satoh et.al.: Induction of lupus autoantibodies by adjuvants. J Autoimmun. 2003 Aug;21(1):1-9. [1]
12. ^ 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.
13. ^ Pellegrini et al, 2009 http://preview.ncbi.nlm.nih.gov/pubmed/19751689
14. ^ Asano KG, Bayne CK, Horsman KM, Buchanan MV (2002). "Chemical composition of fingerprints for gender determination". Journal of Forensic Science 47: 805–807. 
15. ^ Benisek et al, 2004
16. ^ http://www.anthrax.osd.mil/resource/qna/qaAll.asp?cID=319#1107