Meso-Zeaxanthin: One of Important Carotenoids for Human Health

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1 Sep Journal of Northeast Agricultural University (English Edition) Vol. 17 No Meso-Zeaxanthin: One of Important Carotenoids for Human Health XU Xinde 1, JIANG Lianzhou 2, ZHANG Lihua 1, and SHAO Bin 1 1 Zhejiang Medicine Co., Ltd., Xinchang Pharmaceutical Factory, Xinchang , Zhejiang, China 2 College of Food Sciences, Northeast Agricultural University, Harbin , China Abstract:As one of optical isomers of zeaxanthin, meso-zeaxanthin is an important ingredient of macular pigment. Compared with lutein and zeaxanthin, meso-zeaxanthin may display strong functions as antioxidant and filtering short-wavelength, for example, the blue light. Comparisons among lutein, zeaxanthin and meso-zeaxanthin as well as functions and distributions together with the source of meso-zeaxanthin were discussed. The application as a supplement of diet and issues should be studied in the future for mesozeaxanthin were also analyzed. Key words:meso-zeaxanthin, function, distribution, source, application CLC number: TS202.3 Document code: A Article ID: (2010) Introduction: Zeaxanthin (Z) and Mesozeaxanthin (MZ) Zeaxanthin belongs to a group of pigments known as xanthophylls which have no provitamin A activity. Zeaxanthin is an orange-red crystalline powder, with little or no odor. It is practically insoluble in water, sparingly soluble in chloroform giving a clear intensive orange-red solution. It would be bleached upon exposure to light or atmospheric oxygen. Its CAS number is ; the chemical formula is C 40 H 56 O 2 ; and the molecular weight is The chemical structure is shown in Fig. 1 [1]. The other kind of carotenoid which related to zeaxanthin is lutein (L). Zeaxanthin and lutein are isomers but not stereoisomers because they are both polyisoprenoids containing 40 carbon atoms and cyclic structures at each end of their conjugated chains. And they can show both optical (R- and S-stereo isomers) and geometrical isomers (trans, E-, and cis, Z-). The main difference between zeaxanthin and lutein is the location of a double bond in one of the end ring [2]. On one hand, the conjugated double bonds of zeaxanthin and lutein contribute to the distinctive color of each pigment and also influence the ability to quench singlet oxygen, on the other hand, this difference gives lutein three chiral centers whereas zeaxanthin has two. While lutein has three chiral centers, but only (3R, 3'R, 6'R)-lutein was detected in nature, human blood and retina. Theoretically, zeaxanthin which has two chiral centers should be four stereoisomers, because of symmetry, the (3R, 3'S) and (3S, 3'R) stereoisomers of zeaxanthin are identical; therefore, zeaxanthin has only three stereoisomeric forms, namely (3R, 3'R)-, (3R, 3'S)-, (3S, 3'S)-zeaxanthin [3]. The (3R, 3'S)- stereoisomer is called meso-zeaxanthin [4]. Zeaxanthin, either chemically synthesized or naturally existed, is exclusively the 3R, and 3'R-zeaxanthin. The chemical structure of lutein and three stereoisomeric forms of zeaxanthin are shown in Fig. 2. Received 9 October 2009 XU Xinde (1976-), male, Ph. D, senior engineer, engaged in the research of functional food additives. xuxinde-2000@hotmail.com xuebaoenglish@neau.edu.cn

2 XU Xinde et al. Meso-Zeaxanthin: One of Important Carotenoids for Human Health 77 Zeaxanthin, C 40 H 56 O 2 Lutein, C 40 H 56 O 2 Fig. 1 Structural formulas of zeaxanthin and lutein ' 13' 11' (3R, 3'R, 6'R)-lutein (3R, 3'R, 6'R)-β, ε-carotene-3, 3'-diol 9' H 7' 5' 6' 4' 3' 1' 2' (3R, 3'R)-zeaxanthin (3R, 3'R)-β, β-carotene-3, 3'-diol (3R, 3'S, meso)-zeaxanthin (3R, 3'S)-β, β-carotene-3, 3'-diol (3R, 3'S)-zeaxanthin (3R, 3'S)-β, β-carotene-3, 3'-diol Fig. 2 Chemical structure of lutein and stereoisomers of zeaxanthin Functions and Distributions of Meso- Zeaxanthin Zeaxanthin and lutein which are two major components of the macular pigment have an important role for eyes' health. The macula lutea or "yellow spot" in the retina is responsible for central vision and visual acuity. Macular pigment (MP) filters out and absorbs cell damaging, high-energy, blue wavelengths of light [5]. In addition, zeaxanthin and lutein are the strongest anti-oxidants in our bodies [6], which protect the central retina from oxidative damage caused by free radicals [7]. Lots of investigations in human beings and epidemiologic surveys showed that the increasement of macula pigment was correlated with a decreased risk of Age-related Macular Degeneration (AMD) [8-10], furthermore, high levels of lutein and zeaxanthin in either the diet or blood were correlated with high amounts of these carotenoids in the retina [11]. Besides prevention and treatment of AMD, zeaxanthin and lutein also could relieve eyestrain, correct chromatic aberration, better visual acuity, improve contrast sensitivity, and decrease the glare recovery time [12-13]. All of optical isomers of zeaxanthin were analyzed as a whole in the previous research. With the further http: //publish.neau.edu.cn

3 78 Journal of Northeast Agricultural University (English Edition) Vol. 17 No development of investigations, more and more people have realized the uniqueness of optical isomers of zeaxanthin and lutein, especially the specific action of meso-zeaxanthin to eyes' health of human. Our bodies do not manufacture zeaxanthin and lutein which must be obtained from the diet [14]. Zeaxanthin was abundant in yolk of eggs, and many fruit and vegetables, particularly maize, kiwis, spinach, Targets erect red flowers, Lycium barbarum and orange peppers [15]. Whereas the highest concentrations of lutein were found in dark green, leafy vegetables (spinach, kale, collard greens and other), corn, and egg yolks [14]. Chemically synthesis of lutein is very difficult because of the asymmetry in its molecular structure, so lutein commonly was extracted from plants especially marigold flowers. However, zeaxanthin could be produced synthetically by the Wittig reaction or by extracting and subsequent purifying after the saponification and crystallization of oleoresin from Targets erect red flowers or obtained from the isomerization of lutein with natural source as marigold flowers [1, 16-17]. As has been stated before that lutein had three chiral centers, but only (3R, 3'R, 6'R)-lutein was detected in nature, human blood and eye tissues. But zeaxanthin is different from lutein. In human plasma and liver, (3R, 3'R)-zeaxanthin and (3R, 3'R, 6'R)-lutein are detected [18-19]. (3R, 3'S)-zeaxanthin and (3S, 3'S)- zeaxanthin are absent or are not detected in plant tissue, human plasma and liver [20-21]. Whereas, (3R, 3'R)-zeaxanthin, (3R, 3'R, 6'R)-lutein and mesozeaxanthin are found throughout the whole retina. Moreover, meso-zeaxanthin is found in the retina especially in the fovea. Zeaxanthin, meso-zeaxanthin and lutein form the macular pigment, and nearer to the central macula, more zeaxanthin and meso-zeaxanthin but less lutein could be found, within the peripheral retina, the results are opposite [22]. Table 1 showed the proportional distribution of lutein, zeaxanthin and meso-zeaxanthin in the plant extracts, human blood and different areas of the human eye tissues [23]. From Table 1, meso-zeaxanthin represents approximately 25% of the total amount of zeaxanthin in fovea of retina, whereas 15% in the whole retina. Fig. 3 also shows the ratios of lutein, zeaxanthin and meso-zeaxanthin in different areas of retina [24]. It is particularly worth noting that meso-zeaxanthin is not present in the human blood or other organ tissues. Table 1 Ratios of L, Z and MZ in plant extracts and different areas of human bodies Position L : Z : MZ Marigold flowers : 1 : 0 Blood 3-5 : 1 : 0 The whole retina 2 : 1 : 0.5 L : Z Fovea 1 : 2 : 1 Outer Medial Inner MZ : Z Fig. 3 Ratios of L, Z and MZ in different areas of retina Within the central macula, zeaxanthin and mesozeaxanthin are the dominant components, whereas in the peripheral retina, lutein predominates. The macula might be expected to derive benefit from the greater protection afforded by zeaxanthin and mesozeaxanthin compared with lutein. Besides (3R, 3'R)-zeaxanthin and (3R, 3'S)-zeaxanthin, (3S, 3'S)-zeaxanthin, which is the same as (3R, 3'S)-zeaxanthin for not being detected in nature and human blood, presents in the macula with a much small amount as about five per thousand of the total pigment [25]. Where is Meso-zeaxanthin from? Meso-zeaxanthin is not found in the diet and human xuebaoenglish@neau.edu.cn

4 XU Xinde et al. Meso-Zeaxanthin: One of Important Carotenoids for Human Health 79 blood but found in the retina and particularly in the fover with the highest concentration. That suggested that meso-zeaxanthin might come into being in eyes rather than other organ tissues. More and more evidence showed that the presence of meso-zeaxanthin was the result of transformation from retinal lutein in eyes especially within the retina. Conversion of lutein into meso-zeaxanthin would require only the migration of the 4', 5' double bonds in lutein to the 5', 6' positions to form meso-zeaxanthin (leaving the spatial configuration of the hydroxyl groups unaltered). That might be seen in Fig. 4. Aside from the photochemical transformation of the lutein to meso-zeaxanthin, there were no known pathways in human bodies for the synthesis of meso-zeaxanthin [3, 24-25]. It could also be proved by changes of (L+MZ) : Z ratio in the inner, medial and outer regions of the retinas. The average values of (L+MZ) : Z for the inner, medial and outer regions of the retinas were 2.16±0.60, 2.32±0.77 and 2.91±1.21, respectively. These figures were consistent with various analyses of blood carotenoids which indicated L : Z ratios in the range of about 2 : 1 to 4 : 1 [24]. It indicated that lutein within blood was transported into eye tissues, some of lutein is then converted into meso-zeaxanthin in the inner of the retina, and this conversion was lower in the outer region. It also suggested that meso-zeaxanthin was more benefitial to eyes' health compared with lutein ' 13' 11' Lutein (3R, 3'R, 6'R)-β, ε-carotene-3, 3'-diol 9' H 7' 5' 6' 4' 3' 1' 2' Meso-zeaxanthin (3R, 3'S)-β, β-carotene-3, 3'-diol Fig. 4 Conversion of lutein into meso-zeaxanthin Further support regarding the retinal lutein converted into meso-zeaxanthin including: (1) when macaque (non-human primate, unique animal has macular region) was feed with feedstuffs removing carotenoids for some time [26], its eyes lacked of macular pigment. Later, macaque was feed with feedstuffs only containing lutein for a period, then lutein and meso-zeaxanthin were presented in the macular, while if macaque was feed with feedstuffs containing zeaxanthin, only zeaxanthin presented in the macular region. (2) The average mass ratio of L : Z and MZ : Z in the whole adult retinas and 0-7-month-old infants' retinas were given in Table 2 [24]. Here, that a somewhat higher L : Z and a lower MZ : Z ratio in 0-7-month- old infants' whole retina compared with adults, which indicated the conversion of a part of retinal lutein into meso-zeaxanthin in the adult retina. The isomerization process of the lutein into mesozeaxanthin had been proved in vitro and there were many researches about it [3, 16, 24-25]. Table 2 Ratios of L, Z and MZ in the retina of adult and 0-7 month-old infants [24] Groups L : Z MZ : Z Adult 1.86± ± month-old infants 3.30± ± 0.28 http: //publish.neau.edu.cn

5 80 Journal of Northeast Agricultural University (English Edition) Vol. 17 No Prospects for the Application of Meso- Zeaxanthin as Dietary Supplement and Its Research Orientation Besides (3R, 3'R, 6'R)-lutein and (3R, 3'R)-zeaxanthin, (3R, 3'S, meso)-zeaxanthin is one important composition of macular pigment, and meso-zeaxanthin must play an irreplaceable role in maintaining eyes' health, but the mechanism and type of action are worthwhile to depth study deeply, such as, which one is better to protect the retina for the formulation as zeaxanthin alone, lutein alone or a balanced mixture of lutein and zeaxanthin, is not known yet. Issues as what kinds of forms of zeaxanthin and lutein provide a greater protection to the retina as well as the mechanism of meso-zeaxanthin transformation and how to play an unique action, furthermore, if meso-zeaxanthin is directly intaken from food, how is it transported to eyes, and so on, which should be studied in more details. Formerly, zeaxanthin products in the market is all of chemosynthesis and appeared (3R, 3'R)-optical isomer. At present, industrialized products of (meso, 3R, 3'S)-zeaxanthin which is from the isomerization of lutein with natural source as marigold flower can be obtained in the market [16], and relative standard of zeaxanthin in FCC monograph has also been worked out. All these progresses provide possibilities for the further accurately evaluated relative roles of mesozeaxanthin in human health, especially in eyes' health. There are reasons to believe that the function of mesozeaxanthin can be adequately understood after plentiful researches and publicity and meso-zeaxanthin should be had more extensive applications in the future. References 1 Stankovic I. Zeaxanthin (Synthetic) and zeaxanthin-rich extract. Chemical and Technical Assessment [C]. 63rd JECIA, FAO, Landrum J T, Bone R A. Lutein, zeaxanthin, and the macular pigment [J]. Arch Biochem Biophys, 2001, 385: Bone R A, Landrum J T, Hime G W, et al. Stereochemistry of the human macular carotenoids [J]. Invest Ophthalmol Vis Sci, 1993, 34: Bone R A, Landrum J T, Friedes L M, et al. Distribution of lutein and zeaxanthin stereoisomers in the human retina [J]. Exp Eye Res, 1997, 64: Kirschfeld K. Carotenoid pigments: their possible role in protecting against photo-oxidation in eyes and photoreceptor cells [J]. Proc R Soc Lond B, 1982, 216: Chew B P, Park J S. Carotenoid action on the immune response [J]. J Nutr, 2004, 134(1): 257s-261s. 7 Foote C S, Chang Y C, Denny R W. Chemistry of singlet oxygen X. carotenoid quenching parallels biological protection [J]. J Am Chem Soc, 1970, 92: Landrum J T, Bone R A, Kilburn M D. The macular pigment: a possible role in protection from age-related macular degeneration [J]. Adv Pharmacol, 1997, 38: Bernstein P S, Zhao D Y, Wintch S W, et al. Resonance raman measurement of macular carotenoids in normal subjects and in agerelated macular degeneration patients [J]. Ophthalmology, 2002, 109: Massacesi A L, Faletra R, Gerosa F, et al. The effect of oral supplementation of macular carotenoids (lutein and zeaxanthin) on the prevention of age related macular degeneration: 18 months of follow up study [J]. Assoc Res Vision Ophthalmol, 2001, 42: S Bone, R A, Landrum, J T, Guerra, L H, et al. Lutein and zeaxanthin dietary supplements raise macular pigment density and serum concentrations of these carotenoids in humans [J]. J Nutr, 2003, 133: McLellan J S, Marcos S, Prieto P M, et a1. Imperfect optics may be the eye's defense against chromatic blur [J]. Nature, 2002, 417: Wooten B R, Hammond, B R. Macular pigment: influences on visual acuity and visibility [J]. Prog Retin Eye Res, 2002, 21: Sommerburg O, Keunen J E, Bird A C, et al. Fruit and vegetables that are sources for lutein and zeaxanthin: the macular pigment in human eyes [J]. Br J Ophthalmol, 1998, 82: Khachik F, Nir Z, Ausich R, Steck A, et al. Distribution of carotenoids in fruits and vegetables for the selection of appropriate chemopreventative factors [J]. Proceedings of the International Conference on Food Factors Chem Cancer Prev, 1995(5): xuebaoenglish@neau.edu.cn

6 XU Xinde et al. Meso-Zeaxanthin: One of Important Carotenoids for Human Health Xu X D, Zhang L H, Chen B C, et al. Preparation method for highcontent food-grade zeaxanthin [J]. US B2, EP , Swaminathan S, Bengalore, Priya K, et al. Isolation and purification of carotenoids from marigold flowers [J]. US B2, Khachik F, Beecher G R, Goli M B, et al. Separation and identification of carotenoids and their oxidation products in extracts of human plasma [J]. Anal Chem, 1992, 64: Khachik F, de Moura F F, Zhao D Y, et al. Transformations of selected carotenoids in plasma, liver, and ocular tissues of humans and in nonprimate animal models [J]. Invest Ophthalmol Vis Sci, 2002, 43: Shazia S, Ahmed M D, McGregor N, et al. The macular xanthophylls [J]. Survey of Ophthalmology, 2005, 50(2): Bone R A, Landrum J T, Fernandez L, et al. Analysis of the macular pigment by HPLC retinal distribution and age study [J]. Investigative Ophthalmology and Visual Science, 1988, 29(6): Frederick Khachi, F F. de Moura, ZHAO D Y, et al. Transformations of selected carotenoids in plasma, liver, and ocular tissues of humans and in nonprimate animal models [J]. IOVS, 1992, 43(11): Richer S. LAST & LAST Ⅱ temporal response data [C]. Beijing: Workshop on Lutein and Eye Health, 2009: Bone R A, Landrum J T, Friedes L M, et al. Distribution of lutein and zeaxanthin stereoisomers in the human retina [J]. Exp Eye Res, 1997, 64: Bone R A, Landrum J T, Hime G W, et al. Stereochemistry of the human macular carotenoids [J]. Invest Ophthalmol Vis Sci, 1993, 34: Johnson E J, Neuringer M, Russell R M, et al. Nutritional manipulation of primate retinas Ⅲ: effects of lutein or zeaxanthin supplementation on adipose tissue and retina of xanthophyll-free monkeys [J]. Invest Ophthalmol Vis Sci, 2005, 46: http: //publish.neau.edu.cn

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