Fucoxanthin /239

SUPPLEMENT MONOGRAPHS FUCOXANTHIN /239

daily can cause borborygmi and bloating. Doses greater than subjects with pseudohypolactasia than in control lactose 50 grams daily can cause cramps and diarrhea. Some are digesters. Am J Clin Nutr. 1999; 69:973-979. more sensitive to FOS and may develop gastrointestinal symptoms at lower doses. Those with lactose intolerance have been reported to experience gastrointestinal symptoms at a dose of 25 grams. Fucoxanthin

DOSAGE AND ADMINISTRATION DESCRIPTION FOS are available as nutritional supplements and in function- Fucoxanthin is a marine carotenoid and a member of the al foods. Dosing is variable and ranges from 4 to 10 grams carotenoid family of chemical substances. Fucoxanthin, like daily and sometimes higher. Those who use more than 10 other carotenoids, is a natural fat-soluble pigment (brown, in grams daily should split the dosage throughout the day. the case of fucoxanthin) and is found in algae, including LITERATURE heterokonts and seaweeds, and in diatoms (phytoplankton). Alles MS, de Roos NM, Bakx JC, et al. Consumption of Fucoxanthin is also found in the edible brown seaweeds fructo-oligosaccharides does not favorably affect blood glucose wakame (Undaria pinnatifida), hijiki (Hijikia fusiformis) and and serum lipid concentrations in patients with type 2 diabetes. kombu (Laminaria japonica), as well as in the marine algae Am J Clin Nutr. 1999; 69:64-69. Chrysophyceae, Prymneslophyceae, Bacillariophyceae, Pra- Bouhnik Y, Vahedi K, Achour L, et al. Short-chain fructo- sinophyceae and Phaeophyceae. Fucoxanthin and its metab- oligosaccharide administration dose-dependently increases fecal olites are also typically found in sea organisms that feed on bifidobacteria in healthy humans. J Nutr. 1999; 129:113-116. these carotenoids as conjugates. For example, fucoxanthin Buddington RK, Williams CH, Chen SC, Witherly SA. Dietary esters and fucoxanthinol esters are found in clams. supplement of neosugar alters the fecal flora and decreases activities of some reductive enzymes in human subjects. Am J Fucoxanthin functions in algae as a light-harvesting pigment. Clin Nutr. 1996; 63:709-716. It and chlorophyll are the two major light-harvesting Luo J, van Yperselle M, Rizkalla SW, et al. Chronic pigments in brown algae and diatoms. Fucoxanthin exists in consumption of short-chain fructo-oligasaccharides does not algae in the form of a fucoxanthin-chlorophyll alc protein affect basal hepatic glucose production or insulin resistance in complex, which is associated, in the case of brown algae and type 2 diabetics. J Nutr.2000; 130:1572-1577. diatoms, with photosystem II. The complex transfers light to Ohta A, Baba S, Takizawa T, Adachi T. Effects of fructo- chlorophyll a. The fucoxanthin protein complex shows oligasaccharides on the absorption of magnesium in the homology to the chlorophyll aIb binding polypeptides of magnesium-deficientrat model. J Nutr Sci Vitamino/ (Tokyo). higher plants. 1994; 40:171-180. Ohta A, Motohashi Y, Sakai K, et al. Dietary fructo- Fucoxanthin, as an antioxidant, protects algae against oxygen oligasaccharides increase calcium absorption and levels of toxicity. Its possible protective roles as an antioxidant, as mucosal calbindin-D9K in the large intestine of gastrectomized well as its possible anti-inflammatory and anticancer activi- rats. Scand J Gastroenterol. 1998; 33:1062-1068. ties, have become of interest to researchers in the past Ohta A, Ohtsuki M, Hosoro A, et al. Dietary fructo- decade. More recently, its possible activity as an anti-obesity oligosaccharidesprevent osteopenia after gastrectomy.J Nutr. agent has stimulated research on the carotenoid, mainly in 1998; 128:106-110. Japan. Oku T, Tokunaga T, Hosoya N. Nondigestibility of a new sweetener, "Neosugar," in the rat. J Nutr. 1984; 114:1574-1581. Fucoxanthin is chemically described as [(IS,3R)-3-hydroxy- Pierre F, Perrin P, Champ M, et al. Short-chain fructo- 4-[(3E,5E,7E,9E, lIE, 13E,15E)-18-[( IS,4S,6R)-4-hydroxy- oligosaccharides reduce the occurrence of colon tumors and 2,2,6-trimethyl-70xabicyclo[4.1.0]heptan-l-yl]-3,7, 12, 16- develop gut-associated lymphoid tissue in Min mice. Cancer tetramethyl-17-oxooctadeca-l ,3,5,7,9, 11,13, 15-octaenyli- Res. 1997; 57: 225-228. dene]-3,5, 5-trimethylcyclohexyl] acetate. It is also known Roberfroid MB, Delzenne NM. Dietary fructans. Annu Rev as3'-(Acetyloxy)-6',7' -didehydro-5,6-epoxy-5,5' ,6,6',7,8- Nutr. 1998; 18:117-143. hexahydro-3,5'-dihydroxy-8-oxo-beta,beta-carotene; Sahaafsma G, Meuling WJ, van Dokkum W, Bouley C. Effects (3'S,5'R,6' R)- 3'-acetoxy-5,6-epoxy-3,5'-dihydroxy-6', 7' -di- of a milk product, fermented by Lactobaccillus acidophilus and dehydro-5,6,7 ,8,5' ,6'-hexahydro- 13.I3-carotene-8-one; and with fructo-oligosaccharides added, on blood lipids in male (3S,3' S,5R,5' R,6S,6'R)- 3'-(aacetyloxy)-6',7' -didehydro-5,6- volunteers. Eur J Clin Nutr. 1998;52:436-440. epoxy-5,5' ,6,6',7 ,8-hexahydro-3,5'-dihydroxy-8-oxo-I3,I3- Teuri U, Vapaatalo H, Korpela R. Fructo-oligosaccharides and carotene. Its CAS registry number is 3351-86-8, its empirical lactulose cause more symptoms in-lactose maldigesters and formula is C42Hss06, and its molecular weight is 658.91.

.. 240 I FUCOXANTHIN PDR FOR NUTRITIONAL SUPPLEMENTS

Fucoxanthin's allenic group (=CH=C=CH-) and 5,6 monoe- and the transition of G) to the S phase. Fucoxanthin was poxide make fucoxanthin a unique chemical structure (see found to inhibit the phosphorylation of Rb. Further, the figure). Fucoxanthin is also classified as an epoxyxantho- kinase activity of cyclin D when joined with its partner phyll or epoxide-containing xanthophyll. Fucoxanthan is kinase CDK4 was suppressed by treatment with fucoxanthin. represented by the following chemical structure. Fucoxanthin also induced activity of the ubiquitin-protea- some pathway leading to degradation of cyclin D and suppressed cyclin D mRNA. Thus, it appears that fucoxanthin caused the suppression of cyclin D via promotion of proteasomal degradation and repression of cyclin D, leading to cell cycle arrest. Incidentally, apoptosis was not observed in this case Fucoxanthin Fucoxanthin reduced the viability of the human colon Fucoxanthinol is the deacetylated metabolite of fucoxanthin. adenocarcinoma WiDr cell line accompanied by the induction of cell cycle arrest at the GOGIphase of the cycle. In this ACTIONS AND PHARMACOLOGY ACTIONS case, apoptosis of the cells was also reported. In order to Fucoxanthin has antioxidant actIVIty and may have anti- understand the possible mechanism of fucoxanthin's action, cancer, anti-inflammatory and antiobesity activities. a number of factors that regulate the cell cycle were investigated, including the cyclins, the cyclin-dependent MECHANISM OF ACTION kinases (CDKs), the retinoblastoma protein Rb and p21, a Antioxidant activity: Fucoxanthin has demonstrated radical key protein in cell cycle regulation. It was p2l that appeared scavenging and singlet oxygen quenching activities. The to be affected by fucoxanthin. When p2l binds to the CDKs, quenching activity of fucoxanthin against the organic radi- it inhibits their activity. It appeared that fucoxanthin induced cals 1,I-diphenyl-2-picrylhydrazyl (DPPH, a stable free cell-cycle arrest at the GOGIphase in human cancer cells via radical), 12-doxylstearic acid (12DS), and the radical adduct upregulation of the activity of p21. of nitrobenzene with linoleic acid (NB-L) was studied using electron spin resonance (ESR). In the presence of fucoxan- Fucoxanthin was reported to reduce the viability of human thin, the ESR signals for the DPPH, 12DS and NB-L radicals prostate cancer cells via the induction of apoptosis. Apopto- were significantly reduced. Fucoxanthin also has sis induction was characterized by DNA fragmentation, an 2,2'-azinobis(3 -ethyIbenzothiazoline-6-sulfonic acid) increased percentage of hypodiploid cells and cleavages of (ATBS) radical, hydroxyl radical, superoxide anion and procaspase-3 and PARP (poly(ADP-ribose) polymerase. singlet oxygen scavenging activity. Expression of Bax and Bcl-2 proteins, but not Bcl-XL proteins, was reduced. The activation of caspase-3 by Anticancer activity: Fucoxanthin has demonstrated a number fucoxanthin was thought to be the major activity in the of anticancer activities via different mechanisms. induction of apoptosis. Fucoxanthin was found to inhibit the growth of human Fucoxanthin was found to induce apoptosis III human hepatic HepG2 carcinoma cells. In 2007, cancer of the liver promyelocytic leukemia cells. Apoptosis in these cells was was the fourth most common cause of death from cancer. associated with loss of mitochondrial membrane potential, Most of the cases of hepatocellular cancer can be found in but not with an increase in reactive oxygen species. undeveloped countries. Fucoxanthin was shown to reduce Fucoxanthin treatment caused cleavages of procapsase-3 and the viability of HepG2 cells accompanied by the induction of poly (ADP-ribose) polymerase, without any effect on the cell cycle arrest during the GaG) phase of the cell cycle. The protein level of Bcl-2, Bcl-XL or Bax. It was concluded that cell cycle is the series of events that takes place in a cell the fucoxanthin induction of apoptosis was likely due to leading to its replication. The cell cycle consists of four mitochondrial membrane permeabilization and caspase-3 distinct phases Gj, S, G2 and the M phase, where the cell activation. divides forming two new cells. Go is the postmitotic phase prior to G I. Two key classes of regulatory molecules- Anti-inflammatory activity: Endotoxin-induced uveitis (EIU) cyclins and cyclin-dependent kinases (CDKs)-acting in (induced by lipopolysaccharide [LPS]) is an acute, anterior partnership, determine a cell's progress through the cell segment intraocular inflammation (uveitis). Fucoxanthin was cycle. The retinoblastoma protein Rb, a tumor suppressor studied to see how it affected LPS-induced inflammation in protein, prevents excessive growth by inhibiting the cell vitro in a mouse macrophage cell line and in vivo in male cycle when Rb is hypophosphorylated. The phosphorylation Lewis rats. EIU was induced in the rats via footpad injection. of Rb plays a crucial role in the progression of the G1 phase Immediately following the LPS injection, varying doses of SUPPLEMENT MONOGRAPHS FUCOXANTHIN /241 fucoxanthin were injected intravenously. Fucoxanthin sup- expression of UCP I in WAT, which may contribute to pressed the development of EIU in a dose-dependent fashion, reducing WAT weight-in rats. In another Japanese study, and treatment with fucoxanthin decreased PGEz (prostaglan- the investigators found that fucoxanthin and its deacetylated din Ez), NO (nitric oxide) and TNF (tumor necrosis factor)- metabolite, fucoxanthinol, suppressed adipocyte differentia- alpha concentrations in the aqueous humor. On the in vitro tion in mouse 3T3-Ll cells. They concluded that this effect side, mouse macrophage cells were pretreated with various was probably mediated via the upregulation of peroxisome doses of fucoxanthin for 24 hours, after which they were proliferator-activated receptor gamma (PPAR-gamma), incubated with LPS for an additional 24 hours. The which regulates adipogenic gene expression. It turned out expression of COX (cyclooxygenase) and iNOS (inducible also that the fucoxanthin metabolite, fucoxanthinol, had even nitric oxide synthase) was significantly reduced compared greater suppressive effects than fucoxanthin on adipocyte with the untreated group. It was concluded that fucoxanthin differentiation. In still another study, the researchers reported suppressed the inflammatory response by blocking iNOS and that a dietary combination of fucoxanthin and fish oil COX protein expression. Significantly, the anti-inflammato- attenuated the weight gain of white adipose tissue and ry effect of fucoxanthin on the eyes was comparable with the decreased blood glucose in obese/diabetic KK-AY mice. effect of prednisolone in comparable doses. They reported that fucoxanthin decreased the blood glucose Antiobesity activity: Obesity is a growing health problem and plasma insulin concentration in KK-AYmice, along with worldwide, predisposing people to a wide variety of dis- downregulating tumor necrosis factor (TNF)-alpha mRNA. eases, including type 2 diabetes, cardiovascular disease, Further, the combination of fucoxanthin and fish oil was musculoskeletal problems, certain cancers and a shortened more effective for attenuating the weight gain of WAT than lifespan. There is great interest in research circles in fucoxanthin alone. understanding the biochemistry of adipogenesis and the molecular events that underlie the differentiation of white Further studies to elucidate the mechanism of this possible versus brown adipocytes. Brown adipocytes, found in brown antiobesity effect of fucoxanthin and its metabolites are adipose tissue (BAT), express uncoupling protein' I (UCPI) needed and warranted, as are clinical studies. and have high energy expenditure potential. The attainment

of brown adipocyte features in white adipocytes, found in PHARMACOKINETICS white adipose tissue (WAT), is receiving a lot of recent There is little information on the pharmacokinetics of attention. Some believe that the solution to this issue might fucoxanthin in humans. In one recent human study, fucoxan- be the holy grail of obesity research. The problem is that thin was found to be very poorly absorbed after oral intake, humans have very little BAT, and most of the fat in the body and the main form found in the plasma was the deacetylated is stored in WAT. metabolite of fucoxanthin, fucoxanthinol. This was consis- Uncoupling proteins 1-3 (UCPI-3) belong to the mitochon- tent with an earlier study using Caco-2 human intestinal cells drial anion carrier family. The first uncoupling protein and mice. In that study, it was found that fucoxanthin was discovered, UCP I or thermogenin, is a thermogenic protein taken up by Caco-2 cells incubated with micellar fucoxan- specifically expressed in brown adipocytes where it converts thin, and fucoxanthinol was found in the medium and cells, mitochondrial proton-motive force into heat. UCPI catalyzes with its level increasing significantly in a time-dependent a proton leak in the inner mitochondrial membrane that can manner. No conjugated forms of fucoxanthin or fucoxanthi- be activated by free fatty acids. Upon sympathetic stimula- nol were found in either the medium or the cells. In the tion of lipolysis in brown adipocytes, increased free fatty animal study, fucoxanthinol was detected in the plasma of acid levels activate the proton leak catalyzed by UCPI. This the mice one hour after intubation of fucoxanthin. These UCPI-mediated proton leak serves for nonshivering thermo- results strongly suggest that dietary fucoxanthin is incorpo- genesis in brown adipose tissue, either to defend normot- rated as the deacetylated form, fucoxanthinol, from the hermic body temperature in animals exposed to the cold or to digestive tract into the circulatory system of mammals. combat excess food energy in response to diets of high Further study of the pharmacokinetics of fucoxanthin, caloric density. including absorption, distribution, metabolism and excretion Some Japanese researchers have been studying how fucoxan- is needed and warranted. thin might fit into this puzzle. These researchers have been using rats and mice as test systems and, among other things, INDICATIONS AND USAGE have found that fucoxanthin showed an antiobesity effect in Preliminary in vitro and animal data suggest that the rats via UCP I expression in white adipose tissue (WAT). carotenoid fucoxanthin may have antiobesity, anticancer, The researchers concluded that fucoxanthin upregulates the antiangiogenic and anti-inflammatory properties. 242/ FUCOXANTHIN PDR FOR NUTRITIONAL SUPPLEMENTS

RESEARCH SUMMARY PRECAUTIONS Fucoxanthin, a carotenoid found in some edible seaweeds, Pregnant women and nursing mothers should avoid fucoxan- such as Hijikia fusiformis and Undaria pinnatifida. has thin-containing supplements. recently excited some attention by exhibiting effects some hope presage a role for it in weight control. At present the Those who wish to try fucoxanthin-containing supplements data are very preliminary and are limited to in vitro and a for the support of any health condition should first discuss its few animal studies. Feeding rats and mice lipids derived use with his or her physician. from Undaria pinnatifida resulted in reduction of abdominal white adipose tissue weights. It was determined that a major Those who desire to obtain fucoxanthin from edible seaweed active constituent of these lipids is fucoxanthin. The same sources should be aware that seaweed contains iodine and research group subsequently showed that the carotenoid is that high intake of iodine could cause adverse events in some able to suppress differentiation of precursor fat cells to fat people. Moderate intake of edible seaweed, however, should cells in an in vitro cell line study. The researchers concluded not be a problem. that fucoxanthin might thus be able to inhibit weight gain ADVERSE REACTIONS through this process. In related recent research by some of No reports. the same researchers, a combination of fucoxan'thin with fish oil was said to attenuate weight gain of white adipose tissue INTERACTIONS and concomitantly decrease blood glucose in obese/diabetic DRUGS mice. In another study, also utilizing an obese/diabetic Cholestyramine: Concomitant intake of cholestyramine and mouse model, fucoxanthin was reported to increase levels of fucoxanthin may decrease the' absorption of fucoxanthin. docosahexaenoic acid (DHA, see DHA) in the livers of these animals. The researchers stated that enhanced DHA levels Colestipol: Concomitant intake of colestipol and fucoxanthin have been associated with reduced obesity and diabetes. may decrease the absorption of fucoxanthin. More research is needed and warranted. Mineral oil: Concomitant intake of mineral oil and fucoxan- Several recent in vitro studies point to a possible role for thin may reduce the absorption of fucoxanthin. fucoxanthin in cancer therapy. Fucoxanthin has demonstrated some test tube efficacy in a number of cancer cell Or/istat (Alii, Xenical): OrJistat may decrease the absorption lines, including prostate, colon, leukemia, hepatic and others. of fucoxanthin. It has also shown some efficacy in animal models of cancer, NUTRITIONAL SUPPLEMENTS inhibiting chemically induced mouse duodenal carcinogene- Beta-carotene: Concomitant intake of beta-carotene and sis, two-stage mouse skin cancer and spontaneous liver fucoxanthin may increase the absorption of fucoxanthin. cancer in mice. Cell cycle arrest and induction of apoptosis have been observed in several of these studies. An antian- Medium-chain triglycerides: Concomitant intake of medium- giogenic effect has been reported in another in vitro study, chain triglycerides and fucoxanthin may enhance the absorp- suggesting yet another possible anticancer mode of action. tion of fucoxanthin. Again, much more study will be needed before any conclusions can be reached about a possible clinical anti- Pectin: Concomitant intake of pectin and fucoxanthin may cancer role for this carotenoid. decrease the absorption of fucoxanthin.

Anti-inflammatory effects have also been reported by FOODS researchers working with fucoxanthin. In one study, an anti- Oils: Dietary oils, such as fish oils and olive oil, may inflammatory effect was observed in endotoxin-induced enhance the absorption of fucoxanthin. uveitis in rats. The eye inflammation was said to be reduced in a dose-dependent fashion, and the overall anti-inflamma- Olestra: OIestra may reduce the absorption offucoxanthin. tory effect of the carotenoid was said to be equal to that of HERBS prednisolone when used in this context in similar doses. A No known interactions. number of inflammatory markers were significantly reduced by fucoxanthin. More research is needed and warranted. OVERDOSAGE There have been no reports of overdosage. CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS

CONTRAINDICA TIONS DOSAGE AND ADMINISTRATION Fucoxanthin is contraindicated in those hypersensitive to any The optimal dose of fucoxanthin for the support of any component of a fucoxanthin-containing product. health condition is not known. SUPPLEMENT MONOGRAPHS GAMMA-BUTYROLACTONE (GBL) /243

Some fucoxanthin-containing dietary supplements are avail- picrylhydrazyl (DPPH). Biochem Mol Bioi Int. 1997;42(2):361- able. They typically contain five mg of fucoxanthin dis- 370. solved in oil. Okuzumi J, Takahashi T, Yamane T, et al. Inhibitory effects of fucoxanthin, a natural carotenoid, on N-ethyl-N'-nitro-N- LITERATURE nitrosoguanidine-induced mouse duodenal carcinogenesis. Cancer Asai A, Sugawara T, Ono H, et al. Biotransformation of Leu. 1993;68(2-3):159-168. fucoxanthinol into amarouciaxanthin A in mice and HepG2 cells: formation and cytotoxicity of fucoxanthin metabolites. Sachindra NM, Sato E, Maeda H, et al. Radical scavenging and Drug Metab Dispos. 2004;32(2):205-211. singlet oxygen quenching activity of marine carotenoid fucoxanthin and its metabolites. J Agric Food Chem. Asai A, Yonekura L, Nagao A. Low bioavailability of dietary 2007;55(21 ):8516-8522. epoxyxanthophylls in humans. Br J Nutr. 2008; 100(2):273-277. Shiratori K, Ohgami K, lIieva I, et al. Effects of fucoxanthin Das SK, Hashimoto T, Kanazawa K. Growth inhibition of on lipopolysaccharide-induced inflammation in vitro and in human hepatic carcinoma HepG2 cells by fucoxanthin is vivo. Exp Eye Res. 2005;81(4):422-428. associated with down-regulation of cyclin D. Biochim Biophys Acta. 2008; 1780(4):743-749. Sugawara T, Baskaran V, Tsuzuki W, et al. Brown algae fucoxanthin is hydrolyzed to fucoxanthinol during absorption by Das SK, Hashimoto T, Shimizu K, et al. Fucoxanthin induces Caco-2 human intestinal cells and mice. J Nutr. cell cycle arrest at GO/GI phase in human colon carcinoma 2002; 132(5):946-951. cells through up-regulation of p21WAFl/Cipi. Biochim Biophys Acta. 2005; 1726(3):328-335. Sugawara T, Matsubara K, Akagi R, et al. Antiangiogenic activity of brown algae fucoxanthin and its deacetylated Hosokawa M, Kudo M, Maeda H, et al. Fucoxanthin induces product, fucoxanthinol.J Agric Food Chem. 2006;54(26):9805- apoptosis and enhances the antiproliferative effect of the 9810. PPARgamma ligand, troglitazone, on colon cancer cells. Biochim Biophys Acta. 2004;1675(1-3):113-119. Terasaki M, Asai A, Zhang H, et al. A highly polar xanthophyll of 9'-cis-neoxanthin induces apoptosis in HCTll6 Konishi I,. Hosokawa M, Sashima T, et al. Halocynthiaxanthin human colon cancer cells through mitochondrial dysfunction. and fucoxanthinol isolated from Halocynthia roretzi induce apoptosis in human leukemia, breast and colon cancer cells. Mol Cell Biochem. 2007;300(1-2):227-237. Comp Biochem Physiol C Toxicol Pharmacol. 2006; 142(1-2):53- Tsukui T, Konno K, Hosokawa M, et al. Fucoxanthin and 59. fucoxanthinol enhance the amount of docosahexaenoic acid in Kotake-Nara E, Asai A, Nagao A. Neoxanthin and fucoxanthin the liver of KKAy obese/diabetic mice. J Agric Food Chem. induce apoptosis in PC-3 human prostate cancer cells. Cancer 2007;55( 13):5025-5029. Lett. 2005;220(1 ):75-84. Yan X, Chuda Y, Suzuki M, et al. Fucoxanthin as the major Kotake-Nara E, Terasaki M, Nagao A. Characterization of antioxidant in Hijikia fusiformis, a common edible seaweed. apoptosis induced by fucoxanthin in human promyelocytic Biosci Biotechnol Biochem. 1999;63(3):605-607. leukemia cells. Biosci Biotechnol Biochem. 2005;69( I):224-227. Yoshiko S, Hoyoku N. Fucoxanthin, a natural carotenoid, Maeda H, Hosokawa M, Sashima T, et al. Effect of medium- induces G I arrest and GADD45 gene expression in human chain triacylglycerols on anti-obesity effect of fucoxanthin. J cancer cells. In Vivo. 2007;21(2):305-309. Oleo Sci. 2007;56(12):615-621. Maeda H, Hosokawa M, Sashima T, et al. Fucoxanthin from edible seaweed, Undaria pinnatifida, shows antiobesity effect through UCPI expression in white adipose tissues. Biochem Gamma- Butyrolactone Biophys Res Commun. 2005;332(2):392-397. (GBL) Maeda H, Hosokawa M, Sashima T, et al. Dietary combination of fucoxanthin and fish oil attenuates the weight gain of white adipose tissue and decreases blood glucose in obese/diabetic Products containing gamma-butyrolactone (GBL) or KK-Ay mice. J Agric Food Chem. 2007;55(19):7701-7706. I, 4 butanediol (BD) should not be used by anyone for supplementation. Maeda H, Hosokawa M, Sashima T, et al. Fucoxanthin and its metabolite, fucoxanthinol, suppress adipocyte differentiation in

3T3-L1 cells. Int J Mol Med. 2006;18(1):147-152. DESCRIPTION Nishino H, Tsushima M, Matsuno T, et al. Anti-neoplastic Gamma-butyrolactone or GBL is an organic oily liquid that effect of halocynthiaxanthin, a metabolite of fucoxanthin. is used as an intermediate in the synthesis of such substances Anticancer Drugs. 1992;3(5):493-497. as polyvinypyrrolidone and is also used as a solvent for Nomura T, Kikuchi M, Kubodera A, et al. Proton-donative polyacrylonitrile and cellulose acetate, among others. GBL is antioxidant activity of fucoxanthin with I, l-diphenyl-2- a constituent of paint removers, textile oils and drilling oils.