What Are the Sources of Astaxanthin?

Astaxanthin is a non-vitamin A, fat-soluble, keto-type carotenoid that is widely distributed in marine animals and plants, microalgae and yeast [1]. Its unique chemical structure gives it the ability to effectively quench active oxygen, making it by far the strongest antioxidant found in nature. Astaxanthin cannot be synthesized in the human body and can only be obtained through dietary intake. The US Food and Drug Administration (FDA) prohibits the chemical synthesis of astaxanthin for use in food production as a dietary supplement, but approves its use as a coloring agent in animal and aquatic feeds and the daily chemical industry. The European Commission approves the use of natural astaxanthin as a food coloring agent in the food industry[2].

In nature, the main dietary sources of natural astaxanthin are marine food and Haematococcus pluvialis [3]. At present, the efficacy of astaxanthin on human health has been confirmed by a large number of studies, and astaxanthin is the only carotenoid found to be able to penetrate the blood-brain and blood-retina barriers, which can have a positive effect on the central nervous system and brain function [4]. Therefore, the use of natural astaxanthin as a dietary supplement in foods, health products or pharmaceuticals is of practical significance for improving human health. This paper provides an overview of the sources, distribution, physiological activity and absorption and metabolism of astaxanthin, and integrates and analyzes relevant data, with a view to providing an effective reference for the development and application of astaxanthin resources.

1 Structural characteristics, sources and forms of astaxanthin

1.1 Structural characteristics of astaxanthin

Astaxanthin, also known as shrimp yellow pigment or lobster shell pigment, has the chemical name 3,3′-dihydroxy-4,4′ -dione-β , β′-carotene, with the molecular formula C40H52O4. Its chemical structure is composed of four isoprene units connected by conjugated double bonds, with two isoprene units at each end forming a six-membered ring structure [2]. On the one hand, there are two chiral carbon atoms, 3C and 3′C, and each chiral carbon atom can have two conformations (i.e., R or S), so there are three optical isomers: a pair of racemic astaxanthin (3S, 3′ S and dextrorotatory 3R, 3′R) and one meso-astaxanthin (3S, 3′R). On the other hand, the conjugated long-chain structure formed by multiple carbon-carbon double bonds in the astaxanthin molecule makes it prone to cis-trans isomerization, forming a variety of geometric isomers [5].

In the cis configuration, there is usually a large steric hindrance between the hydrogen atoms near the cis double bond or between the hydrogen atoms and the methyl group. Therefore, in nature, most astaxanthin in the free state exists as all-trans astaxanthin, which does not compete for the spatial position of the branched group (methyl group) of this isomer, giving it relatively good structural stability [6]. However, all-trans astaxanthin is susceptible to geometric isomerization reactions due to the influence of factors such as solvent properties, light, heat, oxygen, and metal ions, which convert it into a variety of cis-configured isomers [7-8]. The literature currently reports [7] that the main forms of astaxanthin cis-isomers are: 9-cis-astaxanthin, 13-cis-astaxanthin, 15-cis astaxanthin (15-cis-astaxanthin), 13,15-di-cis-astaxanthin (13,15-di-cis-astaxanthin), the structure of each astaxanthin isomer is shown in Figure 1.

1.2 Astaxanthin sources and forms

1.2.1 Astaxanthin sources

Currently commercialized astaxanthin products are mainly derived from Haematococcus pluvialis, red yeast, synthetic astaxanthin, and some shrimp oil products rich in astaxanthin. Researchers have found that Haematococcus pluvialis is a good source of natural astaxanthin by analyzing and measuring the astaxanthin content in different biological resources [9]. Astaxanthin accounts for about 4% to 5% of the dry weight of algal powder; astaxanthin in red fava yeast accounts for about 0.12% of the dry weight [10]; the total astaxanthin content in several other common aquatic resources is shown in Figure 2. The data show that the total astaxanthin content in Antarctic krill is about 120 mg/kg, in shrimp and sweet shrimp about 30 mg/kg to 60 mg/kg, in crab about 30 mg/kg, and in salmon about 15 mg/kg to 20 mg/kg [11-12] (all calculated on a dry weight basis).

1.2.2 Forms of astaxanthin

The main forms of astaxanthin in nature are the free form and the esterified form (monoester and diester, as shown in Figure 3), and there are significant species differences. Studies have shown that astaxanthin is mainly present in the free state in salmon trout and red yeast [13-14], while it is mainly present in the esterified state in algae, shrimp and crab, with relatively low levels of free astaxanthin [15-17]. Miao Fengping [17] reported that the free astaxanthin, astaxanthin monoesters and diesters in Haematococcus pluvialis accounted for about 5%, 70% and 25% respectively. Gladis and Bjerkeng [16] studied  the pigment components of the rock crab, the results showed that among the total carotenoids, free astaxanthin accounted for about 10%, astaxanthin monoesters accounted for about 12%, and astaxanthin diesters accounted for about 70%. The relative percentages of free astaxanthin and esterified astaxanthin in several common aquatic resources are shown in Figure 4.

In addition, the fatty acid chains linked to astaxanthin are mostly long-chain fatty acids. Among them, the fatty acids in the astaxanthin ester structure from Haematococcus pluvialis are mainly octadecanoic acid and hexadecanoic acid. In the case of white shrimp, Antarctic krill, and swimming crab, the fatty acid chains of astaxanthin esters mostly exist in the form of C20:5 and C22:6. It is worth noting that animals cannot synthesize astaxanthin and astaxanthin esters [18] and can only obtain them from food. Astaxanthin is mainly found in the esterified form in aquatic organisms such as shrimp, but in fish  are mostly in the free state, indicating that the absorption, conversion and accumulation of astaxanthin in animals is highly selective. From a biomimetic perspective, this provides new ideas for studying and improving the utilization of astaxanthin in the human body.

On the other hand, free astaxanthin in nature mostly exists in the geometric configurations of all-trans-astaxanthin and 13-cis-astaxanthin, but the optical configurations of astaxanthin in different organisms vary significantly. The authors searched for relevant domestic and foreign research [10, 17, 19] and summarized the optical isomer composition of astaxanthin in different species (as shown in Figure 5). The data show that the astaxanthin in Haematococcus pluvialis, salmon and Antarctic krill mainly exists in the 3 S, 3 'S configuration, while astaxanthin in Rhodopseudomonas palustris is all in the 3R, 3'R configuration. In prawns and crabs, the relative content of the 3S, 3 'S and 3S, 3 'R configurations is relatively high, and synthetic astaxanthin is a mixture of the three astaxanthin forms (3S, 3 'S 25%, 3R, 3 'R 25%, 3S, 3 'R 50%) [9, 10, 16, 20-21].

2 Research on the biological function and absorption and metabolism of astaxanthin.

2. Biological function of astaxanthin

The special β-ionone ring and long-chain conjugated  alkene structure in the molecular structure of astaxanthin  give it the function of effectively quenching active oxygen. It is by far the strongest natural antioxidant in nature, and its ability to scavenge free radicals is 500 times that of vitamin E and other carotenoids (lutein, lycopene and beta-carotene) by 500 times [22]. Astaxanthin is currently the only carotenoid found to be able to penetrate the blood-brain and blood-retina barriers [4]. Many of its structures and properties make astaxanthin exhibit excellent biological functions.

A large number of animal experiments have shown that astaxanthin has anti-tumor [23], anti-inflammatory [24], anti-diabetic [25], reduces oxidative damage [26], enhances immunity [27], improves motor function [28], and prevents cardiovascular and cerebrovascular diseases [29] and other functions. Current research reports on the biological activity of astaxanthin are summarized in Table 1. In addition, domestic and foreign studies have shown that the biological functions exhibited by different astaxanthin isomers are different. 3S,3'S astaxanthin has better biological functions and stronger antioxidant activity than 3R,3'R and 3S,3 R have better biological functions and stronger antioxidant activities [9]; Liu et al. [30] proved through various in vitro simulation tests that compared with all-trans astaxanthin, 9-cis- and 13-cis-astaxanthin exhibit higher antioxidant capacity in multiple simulated systems.

2.1 Current research on the absorption and metabolism of astaxanthin

As a carotenoid, the key factor in whether astaxanthin can exert biological activity after ingestion is the proportion of it that is absorbed and utilized or stored in the body. Its utilization rate is mainly affected by factors such as molecular structure, physical binding in food, fat content in the diet, and the content of pancreatic enzymes and bile salts in the gastrointestinal tract [49].

At present, there is relatively little research on the metabolic processes of astaxanthin absorption in the body, and there is little reporting on the digestion and absorption of astaxanthin compounds with different molecular structures in the body. Ranga et al. [20, 32] and Olson et al. [50] reported that the bioavailability of astaxanthin can be effectively improved by adding lipids to the diet, suggesting that the type and content of lipids in the food matrix are important factors affecting the bioavailability of astaxanthin in the body.

Østerlie et al. [51] and Coral et al. [52] studied the presence of astaxanthin in human serum after oral intake of astaxanthin and astaxanthin esters . The results showed that after ingestion of free astaxanthin, it binds to lipoproteins in the blood; after ingestion of astaxanthin esters, only free astaxanthin was detected in the blood, and no esterified astaxanthin was detected. The response value in the blood was 4–5 times lower than that of ingesting the same amount of free astaxanthin. it is speculated that free astaxanthin can be directly absorbed and utilized by the human body, while esterified astaxanthin needs to be hydrolyzed into free astaxanthin in the digestive tract, and then absorbed by the human body in the form of free astaxanthin. This study provides some evidence that astaxanthin esters exert the same biological efficacy as free astaxanthin in the body, but there is a lack of intuitive and systematic research data to prove the accuracy of this speculation.

Fukami et al. [53] synthesized astaxanthin mono- and diesters using chemical methods and studied their pharmacokinetics using a rat model. The results showed that the bioavailability of the presumed medium-chain astaxanthin ester was better than that of the long-chain astaxanthin ester. The bioavailability of astaxanthin monoester with octanoic acid in rats was higher than that of astaxanthin diester with octanoic acid, and higher than that of the commercial Haematococcus pluvialis-derived astaxanthin extract (mixture of astaxanthin and astaxanthin ester). In addition, the maximum metabolic concentration of astaxanthin in the liver was about three times that in the serum. According to Fuka- mi's inference, astaxanthin esters with medium-chain fatty acid chains have higher bioavailability. The results of this study show that there is a correlation between the fatty acid chain composition of astaxanthin esters and their bioavailability. However, the structure-bioavailability relationship between astaxanthin esters is currently unclear and requires further research.

3 Conclusion

Natural astaxanthin is of great practical significance for improving human health, but it is extremely unstable and easily oxidized and degraded by external factors such as light, heat, and oxygen, which leads to a decrease in the appearance and nutritional value of the food. Therefore, astaxanthin added to food must exist in a relatively stable molecular state with high biological potency.

In addition, the stability and bioavailability of astaxanthin are affected not only by the molecular structure, but also by external factors such as the food system. However, the current understanding of the influence and mechanism of different molecular forms of astaxanthin structure and food systems on its stability and absorption and metabolism is still unclear. Therefore, the development of such research work in the future is particularly important.

 It not only has important theoretical significance for revealing the factors, laws and mechanisms affecting the stability and bioavailability of astaxanthin, but also provides a basis for screening astaxanthin molecular forms with high stability and bioavailability, as well as the design of food products with high bioavailability of astaxanthin esters. Finally, it explores new strategies and solutions for the high-value utilization of astaxanthin resources and scientific nutritional diets.

Reference:

[1]   HIGUERA-CIAPARA I,FELIX-VALENZUELA L,GOYCOOLEA F  M. Astaxanthin：a review of its chemistry and applications[J]. Criti- cal reviews in food science and nutrition,2006,46(2):185-196

[2]    AMBATI R R,PHANG S M,RAVI S,et al. Astaxanthin：Sources,ex- traction,stability,biological  activities  and  its  commercial  applica-  tions—A review[J]. Marine drugs,2014,12(1):128-152

[3]    GUERIN M,HUNTLEY M E,OLAIZOLA M. Haematococcus astax- anthin：applications for human health and nutrition[J]. TRENDS in Biotechnology,2003,21(5):210-216

[4]    JYONOUCHI H,SUN S,IIJIMA K,et al. Antitumor activity of astax- anthin and its mode of action  [J]. Nutrition and cancer,2000,36(1): 59-65

[5] Hu Jinjin, Jin Yuanxiang, Fu Zhengwei. Research progress on structural modification of astaxanthin [J]. Food Science, 2008, 28(12): 531-534

[6] Lei Feng'ai. Separation and purification of astaxanthin from Haematococcus pluvialis and analysis of isomers [D]. Hohhot: Inner Mongolia Agricultural University, 2009

[7]    QIU D,WU Y C,ZHU W L,et al. Identification of Geometrical Iso- mers and Comparison of Different Isomeric Samples of Astaxanthin [J]. Journal of Food Science,2012,77(9):934-940

[8]   HOLTIN K,KUEHNLE M,REHBEIN J,et al. Determination of astax - anthin and astaxanthinesters in the microalgae Haematococcus plu- vialis  by  LC -(APCI) -MS  and  characterization  of predominant  carotenoid isomers by NMR spectroscopy  [J]. Analytical and Bio-  analytical Chemistry,2009,395(6):1613-1622

[9]    LORENZ R T,CYSEWSKI G R. Commercial potential for Haemato- coccus microalgae as a natural  source  of astaxanthin   [J].  Trends Biotechnol,2000,18(4):160-167

[10]  TETENS I. EFSA NDA Panel   (EFSA Panel on Dietetic Products,   Nutrition and Allergies）,2014 Scientific Opinion on the safety of as-  taxanthin-rich ingredients (AstaREAL A1010 and AstaREAL L10） as novel food ingredients[R]. London：Europen Food Safety Author-  ity,2014

[11] Yang Shu. Study on the change of astaxanthin compounds during storage and processing of white leg shrimp [D]. Qingdao: Ocean University of China, 2015

[12]  CORRÊA N C F,DA SILVA MACEDO C,DE FC MORAES J,et al.  Characteristics of the extract of Litopenaeus vannamei shrimp ob- tained from the cephalothorax using pressurized CO2[J]. The Journal  of Supercritical Fluids,2012,66：176-180

[13]  ANDREWES A G,STARR M P.   (3R,3 ’R）-Astaxanthin from the yeast Phaffia rhodozyma[J]. Phytochemistry,1976,15(6):1009-1011

[14]  SHEEHAN E M,OCONNOR T P,SHEEHY P J A,et al. Stability of astaxanthin and canthaxanthin in raw and smoked Atlantic salmon (Salmo salar）during frozen storage  [J]. Food Chemistry,1998,63(3): 313-317

[14]  SHAHIDI F,SYNOWIECKI J. Isolation and characterization of nu - trients  and  value -added  products  from  snow  crab (Chionoecetes opilio）and shrimp (Pandalus borealis）processing discards[J]. Jour- nal of Agricultural and Food Chemistry,1991,39(8):1527-1532

[16]  CORAL-HINOSTROZA G N,BJERKENG B. Astaxanthin from the  red crab langostilla (Pleuroncodes planipes):optical R/S isomers and fatty acid moieties of astaxanthin esters  [J]. Comparative Biochem - istry and Physiology Part B：Biochemistry and Molecular Biology, 2002,133(3):437-444

[17] Miao Fengping. Identification of astaxanthin esters and fatty acids and analysis of differentially expressed genes in Haematococcus pluvialis [D]. Wuhan: Graduate University of the Chinese Academy of Sciences (Wuhan Botanical Garden), 2007

[18]  BURRI B J,CHANG J S T,NEIDLINGER T R.  β -Cryptoxanthin - and  α -carotene -rich  foods have  greater  apparent  bioavailability than β-carotene-rich foods in Western diets  [J]. British Journal of Nutrition,2011,105(2):212-219

[19]  BREITHAUPT D E. Identification and quantification of astaxanthin  esters in shrimp   (Pandalus borealis) and in a microalga (Haemato- coccus pluvialis) by liquid chromatography-mass spectrometry us- ing negative ion atmospheric pressure chemical ionization  [J]. Jour- nal of Agricultural and Food Chemistry,2004,52(12):3870-3875

[20]  RANGA R A,RAGHUNATH REDDY  R L,BASKARAN V,et al. Characterization of microalgal carotenoids by mass spectrometry and their  bioavailability  and  antioxidant properties elucidated in rat model  [J]. Journal of Agricultural and Food Chemistry,2010,58(15): 8553-8559

[21] Yang Shu, Zhang Ting, Xu Jie, et al. Analysis of astaxanthin optical isomers in organisms by high performance liquid chromatography chiral resolution[J]. Food Science, 2015, 36(8): 139-144

[22]   NAGUIB  Y  M.  Antioxidant  activities  of  astaxanthin  and  related carotenoids[J]. Journal of Agricultural and Food Chemistry,2000,48(4):1150-1154

[23] Pei Lingpeng. Experimental study on the antitumor and immunomodulatory effects of astaxanthin in vivo [J]. Shanghai Journal of Traditional Chinese Medicine, 2009, 43(6): 68-69

[24]  CHEW W,MATHISON B D,KIMBLE L L,et al. Astaxanthin decreas - es inflammatory biomarkers associated with cardiovascular disease  in human umbilical vein endothelial cells  [J]. American Journal of  Advances in Food Science and Technology,2013,1：1-17

[25]  UCHIYAMA K,NAITO Y,HASEGAWA G,et al. Astaxanthin pro - tects β-cells against glucose toxicity in diabetic db/db mice[J]. Re-  dox Report,2002,7(5):290-293

[26] Cao Xiuming, Yang Guiqun, Yang Feifei. Protective effect of astaxanthin on mitochondrial oxidative damage and decreased viability of HepG2 cells caused by hydrogen peroxide [J]. Chinese Journal of Oceanic Drugs, 2010, 5: 26-32

[27]  PARK J S,CHYUN J H,KIM Y K,et al. Astaxanthin decreased oxida - tive stress and inflammation and enhanced immune response in hu- mans[J]. Nutrition and Metabolism,2010,7：1-10

[28]  IKEUCHI M,KOYAMA T,TAKAHASHI J,et al. Effects of astaxan - thin supplementation on exercise-induced fatigue in mice  [J]. Bio - logical and Pharmaceutical Bulletin,2006,29(10):2106-2110

[29]  PASHKOW F J,WATUMULL D G,CAMPBELL C L. Astaxanthin：a novel potential treatment for oxidative stress and inflammation in cardiovascular  disease   [J].  The  American  Journal  of  Cardiology, 2008,101(10):58-68

[30]  LIU X,OSAWA T. Cis astaxanthin and especially 9-cis astaxanthin exhibits a higher antioxidant activity in vitro compared to the all - trans isomer  [J]. Biochemical and Biophysical Research Communi - cations,2007,357(1):187-193

[31]  RANGA A R,SINDHUJA H N,DHARMESH S M,et al. Effective in - hibition of skin cancer,tyrosinase,and antioxidative properties by as - taxanthin and astaxanthin esters from the green alga Haematococcus pluvialis[J]. Journal of Agricultural and Food Chemistry,2013,61(16):  3842-3851

[32]  RANGA A R,BASKARAN V,SARADA R,et al. In vivo bioavailabil - ity and antioxidant activity of carotenoids from microalgal biomass -  A repeated dose study  [J]. Food Research International,2013,54(1):  711-717

[33]  SILA A,AYED-AJMI Y,SAYARI N,et al. Antioxidant and anti-pro - liferative activities of astaxanthin extracted from the shell waste of deep-water pink shrimp   (Parapenaeus longirostris）[J]. Journal of Natural Products,2013,3：82-89

[34]  YANG Y,SEO J M,NGUYEN A,et al. Astaxanthin-rich extract from  the green alga Haematococcus pluvialis lowers plasma lipid concen- trations  and  enhances  antioxidant  defense  in  apolipoprotein  E  knockout mice[J]. The Journal of Nutrition,2011,141(9):1611-1617

[35]  MAOKA T,TOKUDA H,SUZUKI N,et al. Anti -oxidative,anti -tu - mor-promoting,and anti-carcinogensis activities of nitroastaxanthin and nitrolutein,the reaction products of astaxanthin and lutein with peroxynitrite[J]. Marine Drugs,2012,10(6):1391-1399

[36]  HUANGFU J,LIU J,SUN Z,et al. Antiaging effects of astaxanthin - rich  alga  Haematococcus pluvialis  on  fruit  flies under oxidative stress  [J]. Journal of Agricultural and Food Chemistry,2013,61(32): 7800-7804

[37]  BHUVANESWARI S,YOGALAKSHMI B,SREEJA S,et al. Astaxan - thin reduces hepatic endoplasmic reticulum stress and nuclear fac -  tor-κB -mediated inflammation in high fructose and high fat diet -  fed mice[J]. Cell Stress and Chaperones,2014,19(2):183-191

[38]  PARK J S,MATHISON B D,HAYEK M G,et al. Astaxanthin modu - lates age-associated mitochondrial dysfunction in healthy dogs [J].  Journal of Animal Science,2013,91(1):268-275

[39]  GAL A F,ANDREI S,CERNEA C,et al. Effects of astaxanthin sup - plementation on chemically induced tumorigenesis in Wistar rats[J].  Acta VeterinariaScandinavica,2012,54：1-6

[40]  WIBRAND K,BERGE K,MESSAOUDI M,et al. Enhanced cognitive  function and antidepressant-like effects after krill oil supplementa - tion in rats[J]. Lipids in Health and Disease,2013,12(6):1-13

[41]  BENNEDSEN M,WANG X,WILLÉN R,et al. Treatment of H. pylori infected mice with antioxidant astaxanthin reduces gastric inflam - mation,bacterial load and modulates cytokine release by splenocytes [J]. Immunology Letters,2000,70(3):185-189

[42]  TURKEZ H,GEYIKOGLU F,YOUSEF M I. Beneficial effect of as -  taxanthin on 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced liver in - jury in rats  [J]. Toxicology and Industrial Health,2013,29  (7):591-  599

[43]  CHAN K,PEN P J,YIN M. Anticoagulatory and antiinflammatory ef- fects of astaxanthin in diabetic rats  [J]. Journal of Food Science,  2012,77(2):76-80

[44]  DONG L Y,JIN J,LU G,et al. Astaxanthin attenuates the apoptosis of retinal ganglion cells in db/db mice by inhibition of oxidative stress [J]. Marine Drugs,2013,11(3):960-974

[45]  IIZUKA M,AYAORI M,UTO -KONDO  H,et  al. Astaxanthin  en-hances ATP -binding  cassette transporter A1/G1  expressions  and  cholesterol efflux from macrophages  [J]. Journal of Nutritional Sci - ence and Vitaminology,2012,58(2):96-104

[46]  YOSHIDA H,YANAI H,ITO K,et al. Administration of natural astax - anthin increases serum HDL -cholesterol and adiponectin in sub-  jects with mild hyperlipidemia[J]. Atherosclerosis,2010,209(2):520-  523

[47]  PARK J S,MATHISON B D,HAYEK M G,et al. Astaxanthin stimu - lates cell-mediated and humoral immune responses in cats  [J]. Vet- erinary Immunology and Immunopathology,2011,144(3):455-461

[48]  LU Y P,LIU S Y,SUN H,et al. Neuroprotective effect of astaxanthin  on H2O2 -induced neurotoxicity in vitro  and on focal  cerebral  is- chemia in vivo[J]. Brain Research,2010,1360：40-48

[49]  FAILLA M L,CHITCHUMRONCHOKCHAI C,FERRUZZI M G,et al. Unsaturated fatty acids promote bioaccessibility and basolateral secretion of carotenoids and α-tocopherol by Caco-2 cells  [J]. Food & Function,2014,5(6):1101-1112

[50]  OLSON J A. Absorption,transport and metabolism of carotenoids in humans[J]. Pure and Applied Chemistry,1994,66(5):1011-1016

[51]  ØSTERLIE M,BJERKENG B,LIAAEN-JENSEN S. Plasma appear- ance and distribution of astaxanthin E/Z and R/S isomers in plasma lipoproteins of men after single dose administration of astaxanthin  [J]. The Journal of Nutritional Biochemistry,2000,11(10):482-490

[52]  CORAL -HINOSTROZA  G  N,YTRESTØYL  T,RUYTER  B,et  al. Plasma appearance of unesterified astaxanthin geometrical E/Z and optical R/S isomers in men given single doses of a mixture of optical3 and 3 ‘R/S isomers of astaxanthin fatty acyl diesters[J]. Compara- tive Biochemistry and Physiology Part C：Toxicology & Pharmacol- ogy,2004,139(1):99-110

[53]  FUKAMI H,NAMIKAWA K,SUGIURA-TOMIMORI N,et al. Chem - ical synthesis of astaxanthin n-octanoic acid monoester and diester  and evaluation of their oral absorbability[J]. Journal of Oleo Science,  2006,55(12):653-656