Arelative newcomer to the commercial

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1 The Biochemistry of Alternative Medicine The Potential of Astaxanthin A New Multipurpose, High-Power Antioxidant Joseph R. Cronin, Ph.D. Arelative newcomer to the commercial field of antioxidants is the naturally derived molecule astaxanthin (Figure 1). The compound (chemical name 3,3 -dihydr oxy-4,4 -diket o-b carotene) is a member of the carotenoid biopigment family. Its sources in nature include marine and freshwater crustaceans and algae. It also occurs in the yeast Xanthophyllomyces dendrorhous (formerly Phaffia rhodozyma). The pigment is found in the flesh of salmon and trout and in some water birds. Chemical and biochemical studies suggest that astaxanthin is an exceptional antioxidant, perhaps 80 times as potent as vitamin E. 1 A few use patents for human therapies have been awarded or are pending, but more may be in the pipeline. Some commercial production of this carotenoid involves industrial culturing of microalgae or yeast. The compound is also produced by chemical synthesis. Only a handful of companies produce astaxanthin, in either its natural or synthetic forms. While astaxanthin has not made large inroads in the human dietary-supplement market as yet, it has been used for some time in the aquaculture industry as a feed additive fo r f armed f ish, inclu ding salmon and trout. The pink flesh associated with these fish does not develop in fish raised on commercial feeds that lack the algae and crustaceans the fish eat in the wild. 44 Because of its recent appearance on the dietary supplement scene there have been few human trials of astaxanthin s efficacy and none of these have been independent studies reported in peer-reviewed journals. Chemistry of Astaxanthin There are two groups of carotenoids: (1) the hydrocarbon carotenes and (2) the oxygen-containing xanthophylls. Astaxanthin is a xanthophyll. With chiral centers at the 3 and 3 positions of the terminal rings astaxanthin can exist in three enantiomeric forms. The (3S,3 S) and (3R,3 R) enantiomers are the predominant forms found in natural sources. Synthetic astaxanthin contains a statistically dist ribut ed mixt ure o f (3S,3 S):(3S,3 R)/(3R,3 S):(3R,3 R) in the ratio of 1:2:1. One can tell when a study has used synthetic astaxanthin via the report of stereoisomers in this ratio. Natural sources of astaxanthin generally contain a mixture of geometric isomers also. The most thermodynamically stable form is the all-trans, or all-e, form of the molecule. (The E is from the German entgegen meaning opposed. ) In the all-e form, the branching methyl (CH 3 ) groups on t he line ar po rt io n of the molecule do not compete for space. Other geometrical isomers occur in natural sources. Isomers containing cis or Z (from t h e G e r m a n zusa mm en m e a n i n g together ) conformations at the 9, the 13, and the 15 carbons or at combinations of these positions are found in various plant and animal sources. There are then eight possible geometrical forms (all-e) (9Z) (13Z) (15Z) (9Z,13Z) (9Z,15Z) (13Z,15Z) and (9Z,13Z,15Z) The 3-hydroxyl groups on either ring may be free or esterified. Both mono- and diesters are found. The acid moieties come from the spectrum of fatty acids normally found in nature, e.g. lauric, palmitic, and oleic acids. The fatty-acid esters are more hydrophobic than free astaxanthin, i.e., less soluble in the aqueous environment of serum and more soluble in the lipid environment of cell membranes. The diesters are the most hydrophobic. Biochemistry Like the other carotenoids, astaxanthin is a quencher of the free radicals and reactive oxygen species responsible for much cell damage in living systems. Trapping free radicals in the cell membrane 2 and inhibiting lipid oxidation have been demonstrated in laboratory studies of astaxanthin in model systems 3 and in human ex vivo experiments. 4 One of the important commercial sources of astaxanthin is the algal species Haematococcus pluvialis. Under environmental stress, for example, in low nutrient conditions, this microalga produces large quantities of astaxanthin. The function of this production seems to be to prot e ct t h e c e l l s f r o m o x y g e n s p e c i e s generated by high-intensity light. 5 Pharmacokinetics Of the many forms astaxanthin takes in natural sources, some are more easily absorbed than others by animal species,

2 ALTERNATIVE & COMPLEMENTARY THERAPIES FEBRUARY although there is no consistency among species. Some fish species absorb the all- E form in preference to other isomers. 6 Other species show preference for the 13Z or 9Z isomers. 7 Addition of the synthetic, optically inactive astaxanthin to fish diets leads to selective distribution of the optically active isomers in some organs. 7 In vitro metabolism experiments show that astaxanthin has a halfl i f e o f a p p r o x i m a t e l y 2 4 h o u r s i n rat-liver cultures. 8 A study of astaxanthin absorption after a single ingest ion of the compound by hu man su bjects has been reported. 9 Three middle-age males took a single 100-mg dose of free (unesterified) astaxanthin. The astaxanthin was a mixture of geometric isomers (74 percent all-e-, 9 percent 9Z-, and 17 percent 13Z). The o p t i c a l i s o m e r s w e r e i n t h e r a t i o (3R,3 R:3R,3 S:3S,3 S)of 1:2:1. Maximum levels of astaxanthin in the subjects plasma and lipoprotein fractions (1.3 mg/l) were reached after 7 hours. Half of the astaxanthin was eliminated between 10 and 32 hours after ingestion. The Z-astaxanthin isomers were accumulated selectively, whereas the distribution of the optical isomers did not differ from the experimental meal. About half of the astaxanthin was present in the very lowdensity lipoprotein ( VLDL) fraction. Low-density lipoprotein (LDL) and highdensity lipoprotein (HDL) contained approximately 30 percent and 20 percent of total astaxanthin, respectively. The astaxanthin isomer distribution in plasma, VLDL, LDL, and HDL was not affected by time. Dietary supplementation with astaxanthin 1 or 3 weeks before inoculation with fibrosarcoma cells inhibited tumor growth in mice. Astaxanthin (3, 3 -dihydroxy-4,4 -diketo-b Safety Animal safety studies have been conducted on the H. pluvialis meal by commercial providers of astaxanthin, 10,11 and the U.S. Food and Drug Administration (FDA) has approved astaxanthin s use as a food colorant and in fish feed. The LD 50 for rats has been established to be greater than 12 g/kg. 12 Studies of the astaxanthin in rats feed showed no harmful effects on body/organ weight, enzyme activities, pregnancy, or litter size. 13,14 Sources Natural food sources of astaxanthin are found mainly in aquatic animals. Table 1 shows total levels of the compound found in various wild and cultured fish species and in some wild crustaceans. carotene). Animal Studies Some recent laboratory studies in animal models suggest that astaxanthin may have some inhibitory effect on the growth of tumors. Dietary supplementation with astaxanthin 1 or 3 weeks before inoculation with fibrosarcoma cells inhibited tumor growth in mice. This inhibition was accompanied by increased cytotoxic T-lymphocyte activity and interferon-g production in lymph node and spleen cells. 17 Stimulation of splenocyte function, lymphocyte cytotoxicity, and inhibition of mammary tumor growth have been reported in studies on laboratory mice over the past 2 years. 18,19 Groups of mice were inoculated in the mammary fat pads with breast-cancer cells 3 weeks after dietary supplementation with various carotenoids. Controls received no supplementation. After 45 days, the mice

3 46 ALTERNATIVE & COMPLEMENTARY THERAPIES FEBRUARY 2002 Many utility patents have been granted for astaxanthin preparations in the past year. Table 1. Astaxanthin in Some Aquaculture and Wild Species and in Other Sources Species Content (mg/kg) Reference Sockeye salmon (aqua) ,16 Sockeye salmon (wild) Coho salmon (aqua) ,16 Coho salmon (wild) Other sources Copepods Krill Crayfish meal Arctic shrimp who were fed 0-, 0.1-, or 0.4-percent astaxanthin diets showed a dose-dependent inhibition o f m am mary t umo r growth that was higher than the other carotenoids (beta-carotene and canthaxanthin). Patents Around the World Many utility patents have been granted for astaxanthin preparations in the past year. It should be noted that, for granting these use patents, the U.S. Patent Office relies less on inclusion of controlled clinical studies than the FDA does for its approval of drugs. The patents cited here involved in the vitro and ex vivo studies to justify their claims of efficacy. There were some human safety studies cited as well. The efficacy claims are all based o n the assumption that the results of in vitro and ex vivo laboratory experiments translate into the possibility of positive therapeutic results. Potential for Protection Against Eye Damage A 1996 utility patent, now held by La Haye Laboratories, Inc., Redwood, Washington, described astaxanthin use for treating, retarding, and preventing eye diseases and injuries such as age-related macular degen eration, central nervous system degenerative diseases, photic injury, ischemic diseases, and inflammatory diseases. 20 The patent holder s claims are based on the demonstrated free-radical and reactive oxygen quenching ability of astaxanthin 21,22 and on experiments conducted on animal models in the patent petitioner s laboratory. The company s studies demonstrated an th axan th in s abi li ty t o cr o ss t he blood retina barrier in laboratory rats. The researchers administered twelve interperitoneal injections of an astaxanthin solution into the rats over a period of 3 days. The total dose was 37.5 mg/kg of body weight. Six hours after the final injection, the retinal astaxanthin content was 0.17 µg/mg of wet retinal tissue. In another experim ent the rats eyes were subjected to mechanical and photic injuries. The damage to various elements of ocular structure in astaxanthin treated and control animals was then compared. The mechanical injury was inflicted by means of elevated pressure delivered to the anterior wall of the eye through a cannula. Subsequently the thickness of the retinal layers of control-group rats and rats treated with two peritoneal injections of astaxanthin solutions were compared. The treated rats showed only approximately 85 percent of the ischemic damage experienced by the control-group rats. For the photic-injury experiments, treated rats and untreated controls were exposed to high-intensity light. The thickn e s s o f t h e r e t i n a l w a l l s a n d t h e rhodopsin contents of their retinas were then compared. In this case, the treatment was not by injection but by oral administration of 80 mg/day of astaxanthin for 9 days before exposure to the high-intensity light. The treated rats experienced both a smaller initial reduction of rhodopsin and a more rapid increase in rhodopsin after 6 and 13 days. Anti-Infective, Muscle-Building Properties Astacarotene AB, Gustavsberg, Sweden, received two U.S. patents in One was for using astaxanthin to treat

4 ALTERNATIVE & COMPLEMENTARY THERAPIES FEBRUARY Astaxanthin s ability to inhibit prostate cancer cell growth was measured and found to be slightly higher than that of saw palmetto extract. Helicobacter pylori infection. 23 The other was for improving muscle function and treating mammalian muscle disorders. 24 The preparation used in the H. pylori experiments was the algal meal produced from Haematococcus spp., which was commercially cultured by the company. The company tested the astaxanthin preparation for its effect on H. pylori infection in mice. Fifty mice were infected with the bacterium by gastric insertion of H. pylori culture. Fourteen days after infection, ten animals were euthanized and stomach sections were tested for H. pylori infection. Twenty- one days after infection, treatment of half of the remaining mice began. Treatment consisted of oral doses of algal meal as a feed supplement. Dose level corresponded to 0.3 mg astaxanthin per day. The remaining animals were controls and received no astaxanthin supplement. After 30 days, half of the mice from the treated and untreated groups were euthanized and tested for gastric infection. After 40 days, the rest of the animals were similarly tested. Eighty percent of the untreated group showed infection after fourteen and thirty days. After 40 days, 70 percent of the untreated animals were infected. None of the mice who had received the astaxanthin supplement had infections after 30 or 40 days. These results were also reported in a peer-reviewed journal. 25 In the experiments for the muscle function patent, the researchers measured human strength/endurance in test and control groups of 20 healthy individuals. After 6 months of daily ingestion of either 4 mg of astaxanthin or placebo in capsule Table 2. Inhibition of 5-a -Reductase by Some Haematococcus pluvialis and Saw Palmetto (Serenoa repens) Preparations Product/extract Composition Reductase concentration H. pl./lesp inhibition Placebo Vegetable oil 1% Control 1 LESP alone 49% Sample 1 10% H. pl. meal 43% Sample 2 5% H. pl. meal 43% Sample 3 2.5% H pl. meal 42% Sample 4 1% H. pl. meal 34% Sample 5 0.5% H. pl. meal 34% Sample 6 100% H. pl. meal 98% H. pl. = H. pluvialis; LESP = lipid extract of saw palmetto. form, the groups of subjects underwent a test for the number of knee bends they c o u l d p e r f o r m w i t h a k g l o a d. Although both the test and control groups improved the number of bends achieved, the subjects in the astaxanthin-treated group improved by 62 percent and the subjects in the placebo group improved by 24 percent. Other strength and condition tests on humans revealed no effect of astaxanthin supplementation. Prevention and Treatment of Benign Prostatic Hyperplasia Triarco Industries, Inc., Wayne, New Jersey, holds a patent using astaxanthin to prevent and treat benign prostate hyperplasia. 26 The claim is based on astaxanthin s abilit y to inhibit t he e nzym e 5-a -reductase in human subjects. The enzyme converts testosterone to dihydrotestosterone, which is considered to be the primary androgen that encourages prostate growth. 27 Inhibition of the 5-a -reductase was measured in vitro, using various amounts of H. pluvialis meal (which was obtained from Cyaonotech Corporation, Kailua- Kona, Hawaii ) either alone or in combination with saw palmetto (Serenoa repens) extract. The preparations tested were first subjected to a simulated, human digestion protocol involving both gastric and intestinal stages. The resulting material was then used in the inhibition experiments. The astaxanthin from H. pluvialis in combination with saw palmetto extract showed a fairly constant percent inhibition of the enzyme activity regardless of astaxanthin content in the mixture. The inhibition ranged from 34 to 43

5 48 ALTERNATIVE & COMPLEMENTARY THERAPIES FEBRUARY 2002 Astaxanthin is a relatively new product on the dietary-supplement market. Commercial Sources for Astaxanthin Cyanotech Corporation Queen Kaahamanu Highway Suite #102 Kailua-Kona, HI Phone: (800) Fax: (808) info@cyanotech.com Web site: Aquasearch, Inc Queen Kaahumanu Highway, Suite 110 Kailua-Kona, HI, Phone: (808) Fax: (808) aqse@aquasearch.com Web site: percent. When the ast ax anthin w as used alone the inhibition of 5-a -reductase activity was 98 percent (see Table 2). Astaxanthin s ability to inhibit prostate cancer cell growth was also measured and found to be slightly higher than that of saw palmetto extract. Stress Reduction Suntory Ltd., Osaka, Japan, is the assignee for an astaxanthin use patent for treating stress. 28 Inducing stress in groups of mice by means of physical restraint, the company tested the effect of astaxanthin on various stress-related parameters. The physical restraint on the mice decreased thymus-gland weight, reduced immune-system cell activity, increased liver peroxide levels, and increased transplanted liver-cancer cell La Haye Laboratories, Inc nd Avenue NE Redwood, WA Phone: (800) Fax: (425) info@lahaye.com Web site: home.html Astacarotene AB Idrottsvägen Gustavsberg, Sweden Phone: Fax: info@astacarotene.se Web site: /index.html metastasis. All of these effects were ameliorated in mice who were treated with orally administered astaxanthin. Relief of Carpal Tunnel Syndrome Symptoms Finally, Cyanotech Corporation is the assignee for a use patent awarded last year for treating carpal tunnel syndrome. 29 In the patent document Cyanotech describes two cases of individuals with diagnosed carpal tunnel syndrome. One individual had taken anti-inflammatory drugs that were not effective. After 1 week of twicedaily, 3-mg doses of astaxanthin, the patient experienced a diminution of tingling and numbness and complete mitigation of symptoms after an additional 3 weeks. A second subject experienced similar relief after the same dose regimen. After 3 weeks of supplementation, the subject reported that pain was alleviated and there was no longer a need to use a wrist brace at work. Sunburn Protection Cyaonotech has reported in p ress releases and on the its Web site that the company s astaxanthin product, BioAstin, has undergone clinical trials on its ability to provide sunburn protection. 30 The tests were conducted by the Photobiology Department of the Consumer Product Testing Company, Fairfield, New Jersey, under contract to Cyanotech Corporation. For this trial, 21 subjects were initially tested for their threshold sensitivity to burning when exposed to a xenon arc light source that simulated sunlight. The subjects then took 4-mg daily supplements of BioAstin for 2 weeks and were retested. The results varied from no effect to 50 percent more exposure required to produce skin reddening. The average over the entire group was 20 percent increased exposure required to produce skin reddening. No placebo controls were used in the testing. Suggestions and Caveats It would be wise to remember some things about astaxanthin. It is a relatively new product on the dietary-supplement market. Thus, long-term studies on its effects on human subjects are not available. There are no extensive, independent, clinical studies of astaxanthin s efficacy for treating or preventing disease. Yet, toxic effects do not seem to be a concern, any more than for any of the other carotenoid supplements.

6 ALTERNATIVE & COMPLEMENTARY THERAPIES FEBRUARY Some of the commercially backed studies noted above do assert that evidence of effects can be seen relatively quickly. However, these studies have not been well-controlled and many of the claims of the manufacturers are based on analogy with the effects of other carotenoid supplements. There are more patent applications in the pipeline and the studies backing these may provide more evidence in the usefulness of this product. In short, there is no final word on astaxanthin yet, but there seems to be no reason to fear its use either. References 1. Di Mascio, P., et al. Antioxidant defense systems: The role of carotenoids, tocopherols, and thiols. Am J Clin Nutr 53: , Goto, S., et al. Efficient radical trapping at the surface and inside the phospholipid membrane is responsible for highly potent antiperoxidative activity of the carotenoid astaxanthin. Biochim Biophys Acta 1512: , Naguib, Y.M. Antioxidant activities of astaxanthin and related carotenoids. J Agric Food Chem 48: , Iwamoto, T., et al. Inhibition of low-density l ip oprotei n oxi da ti on b y a sta xan th in. J Atheroscler Thromb 7: , Fan, L., et al. Does astaxanthin protect Haematococcus against light damage? Z Naturforsch 53:93 100, Bjerkeng, B., Berge, G.M. Apparent digestibility coefficients and accumulation of astaxanthin E/Z isomers in Atlantic salmon (Salmo salar) and Atlantic halibut (Hippoglossus hippoglossus). Comp Biochem Physiol 127: , Osterlie, M., et al. Accumulation of astaxanthin all-e, 9Z and 13Z geometrical isomers and 3 and 3 RS optical isomers in rainbow trout (Oncorhynchus myki ss) is selective. J Nutr 129: , There is no final word on astaxanthin yet, but there seems to be no reason to fear its use either. 8. Wolz, E., et al. Characterization of metabolites of astaxanthin in primary cultures of rat hepatocytes. Drug Metab Dispos 27: , Osterlie, M., et al. Plasma appearance and distribution of astaxanthin E/Z and R/S isomers in plasma lipoproteins of men after single dose administration of astaxanthin. J Nutr Biochem 11: , Online document at: com/pdfs/axbul78.pdf 11. Online document at: astax.htm 12. Online document at: pdfs/axbul78.pdf 13. Nishikawa, Y., et al. Physiological and biochemical effects of carotenoid (beta-carotene and astaxanthin) on rats. Kashien Daigkyu Kiyo 25:19 25, Ono, A., et al. A 13-week subchronic oral toxicity study of haematococcus color in F344 rats. Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku (Japan) 117:91 98, Torissen, O.J., e t al. Pigmentation of sa lm oni ds ca rotenoi d deposition a nd metabolism. Crit Rev Aquatic Sci 1: , Turujman, S.A., et al. Rapid liquid chromatographic method to distinguish wild salmon from aquacultured salmon fed synthetic astaxanthin. J AOAC Int 80: , Jyonouchi, H., et al. Antitumor activity of astaxanthin and its mode of action. Nutr Cancer 36:59 65, Chew, B.P., et al. Dietary beta-carotene and astaxanthin but not canthaxanthin stimulate splenocyte function in mice. Anticancer Res 19: , Chew, B.P., et al. A comparison of the anticancer activities of dietary beta-carotene, canthaxanthin and astaxanthin in mice in vivo. Anticancer Res 19: , Tso, M.O.M., et al. Method of retarding and ameliorating central nervous system and eye damage. USP 5,527,533. Assignee: Board of Trustees of the University of Illinois, Urbana, IL, June 18, Krinsky, N.I., et al., Interaction of oxygen and oxy-radicals with carotenoids. J Nat Cancer Inst 69: , Kurashige, M., et al. Inhibition of oxidative injury of biological membranes by astaxanthin. Physiol Chem Phys Med NMR 22:27 38, Wadstrom, T., et al. Oral preparation for the prophylactic and therapeutic treatment of Helicobacter spp. infection. USP 6,262,316. Assignee: Astacarotene AB, Gustavsberg, Sweden, July 17, Wadstrom, T., et al. Me di cament for improvement of duration of muscle function or treatment of muscle disorders or diseases. USP 6,245,818. Assignee: Astacarotene AB, Gustavsberg, Sweden, June 12, Wang, X., et al. Astaxanthin-rich algal meal and vitamin C inhibit Helicobacter pylori infection in BALB/cA mice. Antimicrob Agents Chemother 44: , Anderson, M., Method of inhibiting 5-a - reductase with astaxanthin to prevent and treat benign prostate hyperplasia (BPH) and prostate c a nc e r i n hum an m al e s. U SP 6,2 77, Assignee: Triarco Industries, Inc., Wayne, NJ, August 21, Stoner, E. The clinical development of a 5-a - reductase inhibitor, finasteride. J Steroid Biochem Mol Biol 37: , Asami, S., et al. Anti-stress composition. USP 6,265,450. Assignee: Suntory, Ltd., Osaka, Japan, July 24, Lorenz, R., et al. Method of retarding and ameliorating carpal tunnel syndrome. USP 6,258,855. Assignee: Cyanotech Corporation, Kailua-Kona, HI, July 10, Online document at: news/01/ html To order reprints of this article, write to or call: Karen Ballen, ALTERNATIVE & COMPLE- MENTARY THERAPIES, Mary Ann Liebert, Inc., 2 Madison Avenue, Larchmont, NY , (914)

Color Your Customers Healthy With Carotenoids

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