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Department of Biochemistry, School of Medicine, U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111-1837
2To whom correspondence should be addressed. E-mail: norman.krinsky{at}tufts.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONLITERATURE CITED |
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KEY WORDS: • lutein • zeaxanthin • age-related macular degeneration • antioxidation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONLITERATURE CITED |
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) dissected the foveal region of four human retinas, extracted the yellow pigment with petroleum ether, and reported that the absorption spectrum of the yellow pigment agreed quite well with the estimate of the macular pigment, derived from the differences in the spectral sensitivity of peripheral and foveal cones. Furthermore, the spectrum resembled that of a preparation of leaf xanthophyll, or lutein; on the basis of this property as well as its solubility, Wald concluded that the macula pigment was the xanthophyll, lutein. Wald had already established the central role in vision of vitamin A aldehyde (retinal) as the ligand associated with the protein, opsin, to form the visual pigment, rhodopsin (2
). With the identification of the macular pigment as a member of the carotenoid family that also included the precursors of retinal, he had involved carotenoids and their metabolites in both the visual function of the retina and the color property of the fovea, explaining the chemical basis of the term "macular" region of the retina. It would be another 50 years before carotenoids were also identified in the lens of the eye (3
) and 56 years before carotenoids were identified in virtually all of the tissues of the eye (4
).
The first careful chromatographic characterization of the macular pigment was made by Bone et al. (5
,6
) who used an HPLC analysis to demonstrate that there were actually two xanthophylls present in the macula, i.e., lutein and zeaxanthin. Shortly thereafter, Handelman et al. (7
) confirmed this observation, and also noticed that there was a different ratio of lutein to zeaxanthin between the central fovea and the more peripheral regions. Subsequently, Bone et al. (8
) identified mesozeaxanthin as an important component of the macular pigment. The structures of the major macular pigments are shown in Figure 1
. More recently, Khachik et al. (9
) reported that some of the minor peaks observed in the HPLC analysis of the macular pigment consist of oxidation products of both lutein and zeaxanthin, such as 3'-epilutein and 3-hydroxy-ß,
-caroten-3'-one, as well as geometric isomers of the major pigments. The presence of cis-isomers in the retina is not surprising because the macula is exposed to bright light, which is know to isomerize carotenoids. However, the presence of oxidized metabolites would suggest that the pigments are susceptible to oxidation in the tissue, or that an active metabolic process takes place, with some potential interconversions from among the reported intermediates. As discussed by Jandacek (10
), the levels of carotenoids in tissues may be a reflection of the extent of oxidative stress, and the presence of oxidation products would also reflect oxidative stress.
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- structure of lutein means that there are 10 conjugated double bonds in the molecule, whereas zeaxanthin, with the ß,ß-structure, has 11 conjugated double bonds. As such, lutein absorbs at slightly shorter wavelengths than does zeaxanthin. This difference is depicted in Figure 2
, from the excellent review by Landrum and Bone (11
). Both lutein and zeaxanthin are effective in filtering blue light (400–475 nm), but zeaxanthin is much more effective in absorbing blue-green light at 500 nm and slightly above.
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). ß-Carotene, lycopene or ß-cryptoxanthin, also present in human plasma at concentrations equivalent to that of lutein and zeaxanthin (13
), would also serve as effective filters of blue light, but they have not been selected for this action. Therefore, it must be some specific property of these xanthophylls that might help explain their presence in the primate retina. One such property is their disposition in biological membranes.
Bone and Landrum (14
) studied the dichroic properties of lutein in an attempt to explain the yellow brush or tufts known as Haidinger’s brushes, observed in the macula when the eye is illuminated with polarized light. They made suspensions of lutein in a mixture of natural phosphatidylethanolamine and phosphatidylcholine (PC), and thus containing multiple polyunsaturated fatty acids, comparable to biological membranes. They concluded that lutein was located perpendicular to the plane of the bilayer membrane. Using a 1H NMR technique, Gabrielska and Gruszecki (15
) concluded that zeaxanthin resides primarily perpendicular to the plane of the membrane, whereas the hydrocarbon, ß-carotene, has no preferred orientation. An additional study from Gruszecki’s group (16
), using a linear dichroism analysis of either lutein or zeaxanthin in egg yolk PC membranes, led to the conclusion that these two xanthophylls adopt slightly different conformations in these bilayer membranes. Zeaxanthin was found to adopt a roughly perpendicular orientation to the plane of the membrane, whereas lutein appeared to exist in two distinct pools in these membranes. One pool followed the orientation of zeaxanthin, whereas the second pool was parallel with respect to the membrane. That latter observation is quite unusual, and raises the question concerning what type of lutein would be parallel to the bilayer membrane. One possibility is that a dehydration of some of the lutein had occurred in their experimental system, which would result in the formation of anhydrolutein, with only a single 
OH group, and much less likely to assume a vertical orientation in a bilayer membrane. Another possibility is that they were had some cis-isomers of lutein in their preparations, and this might explain the linear dichroism analysis. The potential orientations of zeaxanthin and lutein in a bilayer membrane are depicted in Figure 3
(15
).
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) apparently first formulated this concept in a review detailing the possible protective role of carotenoids in eyes and photoreceptor cells. He suggested that the "macular pigment could also provide protection by quenching excited states of sensitizing pigments and/or singlet oxygen." This idea was picked up by Haegerstrom-Portnoy (18
) who viewed the macular pigment as "a destroyer of free radicals formed on exposure to light" as well as by Weiter et al. (19
) who proposed that the carotenoids in the macula region "may also have a direct antioxidant effect." This idea that the macular pigment protects the retina from light-initiated oxidative damage is now very widely accepted, and usually is qualified by the statement that carotenoids are antioxidants. If that were so, then it would offer a second, valid explanation for the role of xanthophylls as protective agents in the retina.
But we should probably examine the basis for the claim that carotenoids such as lutein and zeaxanthin are antioxidants, particularly in vivo. The literature spans many years, and has been reviewed periodically (20
–24
). In fact, not only are antioxidant properties presented, but those associated with prooxidation have also been reviewed (25
,26
). The general consensus is that lutein and zeaxanthin are effective antioxidants in vitro, and may also demonstrate this action in ex vivo systems, primarily those associated with evaluating their effects on LDL oxidation. However, how does one adequately evaluate whether these xanthophylls are functioning as antioxidants in vivo?
One conclusion drawn by several investigators is that if oxidation products of these carotenoids are found in a tissue such as the macula, this constitutes adequate evidence that these compounds are acting as antioxidants in that tissue (4
,9
). However, carotenoids are not very stable compounds, and the mere presence of oxidation products cannot be considered evidence that they are acting as antioxidants, as opposed to reflecting the oxidant stress in any given tissue (10
).
What is the effect of supplementing subjects with lutein or other carotenoids on biomarkers of oxidation? Collins et al. (27
) treated volunteers with a variety of carotenoids, including lutein, and employed the "comet assay" (single-cell alkaline gel electrophoresis) to measure strand breaks, oxidized pyrimidines and altered purines in the DNA of lymphocytes. The carotenoid supplementation did not have a significant effect on endogenous oxidative damage. Torbergsen and Collins (28
) continued these studies by administering 15 mg/d of ß-carotene, lutein or lycopene to volunteers for 1 wk and utilizing the comet assay to determine DNA strand breaks after treating isolated lymphocytes with H2O2 for up to 24 h. They reported substantially faster rejoining of strand breaks after the ß-carotene administration, but no such effect was observed with lutein. Although plasma levels of both ß-carotene and lutein increased two- to threefold after 1 wk of supplementation, they did not report the values in the isolated lymphocytes. This is a problem with their results because we would have to know that the lymphocyte level increased as well as the plasma level. Thus, these reports are not adequate to allow us to conclude that lutein is an effective antioxidant in either the in vivo or ex vivo experiments.
What do we know from the information available? Dietary lutein and zeaxanthin, either in the form of green, leafy vegetables or corn (29
,30
), or lutein supplements (31
,32
) can increase the amount of macular pigment. Under these circumstances, more blue light would be absorbed by the macular pigment, leading to a decrease in chromatic aberration. However, we still do not have direct evidence that there would be more antioxidant protection in the macula. Thus, we have a strong biologically plausible argument that xanthophylls may be protective with respect to the macula, but still lack convincing proof for this argument. Under these circumstances, several authors have advocated a "go slow" approach with respect to recommending lutein supplements either to inhibit the progression of age-related macular degeneration (33
) or to prevent cataract formation (34
).
Despite more than five decades of investigation into the biological actions of carotenoids, the comment made 30 years ago that except for their actions in photosynthesis, "the remaining functions outside of metabolites, must still be considered as speculative" (35
) remains valid.
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FOOTNOTES |
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONLITERATURE CITED |
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1.
Wald, G. (1945) Human vision and the spectrum. Science (Washington DC) 101:653-658.
2.
Wald, G. (1935) Carotenoids and the visual cycle. J. Gen. Physiol. 19:351-371.
3.
Yeum, K.-J., Taylor, A., Tang, G. & Russell, R. M. (1995) Measurement of carotenoids, retinoids, and tocopherols in human lenses. Investig. Ophthalmol. Vis. Sci. 36:2756-2761.
4. Bernstein, P. S., Khachik, F., Carvalho, L. S., Muir, G. J., Zhao, D.-Y. & Katz, N. B. (2001) Identification and quantitation of carotenoids and their metabolites in the tissues of the human eye. Exp. Eye Res. 72:215-223.[Medline]
5. Bone, R. A., Landrum, J. T. & Tarsis, S. L. (1985) Preliminary identification of the human macular pigment. Vis. Res. 25:1531-1535.[Medline]
6.
Bone, R. A., Landrum, J. T., Fernandez, L. & Tarsis, S. L. (1988) Analysis of the macular pigment by HPLC: retinal distribution and age study. Investig. Ophthalmol. Vis. Sci. 29:843-849.
7.
Handelman, G. J., Dratz, E. A., Reay, C. C. & van Kuijk, F.J.G.M. (1988) Carotenoids in the human macula and whole retina. Investig. Ophthalmol. Vis. Sci. 29:850-855.
8. Bone, R. A., Cains, A. & Zamor, J. (1992) Macular pigment revealed as a mixture of zeaxanthin, meso-zeaxanthin, and lutein by chiral column HPLC. Investig. Ophthalmol. Vis. Sci. 33:1010.
9.
Khachik, F., Bernstein, P. S. & Garland, D. L. (1997) Identification of lutein and zeaxanthin oxidation products in human and monkey retinas. Investig. Ophthalmol. Vis. Sci. 38:1802-1811.
10.
Jandacek, R. J. (2000) The canary in the cell: a sentinel role for ß-carotene. J. Nutr. 130:648-651.
11. Landrum, J. T. & Bone, R. A. (2001) Lutein, zeaxanthin, and the macular pigment. Arch. Biochem. Biophys. 385:28-40.[Medline]
12. Khachik, F., Spangler, C. J., Smith, J. C., Jr, Canfield, L. M., Steck, A. & Pfander, H. (1997) Identification, quantification, and relative concentrations of carotenoids and their metabolites in human milk and serum. Anal. Chem. 69:1873-1881.[Medline]
13. Krinsky, N. I., Russett, M. D., Handelman, G. J. & Snodderly, D. M. (1990) Structural and geometrical isomers of carotenoids in human plasma. J. Nutr. 120:1654-1661.
14. Bone, R. A. & Landrum, J. T. (1984) Macular pigment in Henle fiber membranes: a model for Haidinger’s brushes. Vis. Res. 24:103-108.[Medline]
15. Gabrielska, J. & Gruszecki, W. I. (1996) Zeaxanthin (dihydroxy-ß-carotene) but not ß-carotene rigidifies lipid membranes: a 1H-NMR study of carotenoid-egg phosphatidylcholine liposomes. Biochim. Biophys. Acta 1285:167-174.[Medline]
16. Sujak, A., Gabrielska, J., Grudzinski, W., Borc, R., Mazurek, P. & Gruszecki, W. I. (1999) Lutein and zeaxanthin as protectors of lipid membranes against oxidative damage: the structural aspects. Arch. Biochem. Biophys. 371:301-307.[Medline]
17. Kirschfeld, K. (1982) Carotenoid pigments: their possible role in protecting against photooxidation in eyes and photoreceptor cells. Proc. R. Soc. Lond. B 216:71-85.[Medline]
18. Haegerstrom-Portnoy, G. (1988) Short-wavelength-sensitive-cone sensitivity loss with aging: a protective role for macular pigment?. J. Opt. Soc. Am. A 5:2140-2144.[Medline]
19. Weiter, J. J., Delori, F. & Dorey, C. K. (1988) Central sparing in annular macular degeneration. Am. J. Ophthalmol. 106:286-292.[Medline]
20. Krinsky, N. I. (1979) Carotenoid protection against oxidation. Pure Appl. Chem. 51:649-660.
21. Krinsky, N. I. (1989) Antioxidant functions of carotenoids. Free Radic. Biol. Med. 7:617-635.[Medline]
22. Palozza, P. & Krinsky, N. I. (1992) Antioxidant effects of carotenoids in vitro and in vivo: an overview. Methods Enzymol 213:403-420.[Medline]
23. Krinsky, N. I. (1998) The antioxidant and biological properties of the carotenoids. Ann. N.Y. Acad. Sci. 854:443-447.[Medline]
24. Krinsky, N. I. (2001) Carotenoids as antioxidants. Nutrition 17:815-817.[Medline]
25. Palozza, P. (1998) Prooxidant actions of carotenoids in biologic systems. Nutr. Rev. 56:257-265.[Medline]
26. Young, A. J. & Lowe, G. M. (2001) Antioxidant and prooxidant properties of carotenoids. Arch. Biochem. Biophys. 385:20-27.[Medline]
27.
Collins, A. R., Olmedilla, B., Southon, S., Granado, F. & Duthie, S. J. (1998) Serum carotenoids and oxidative DNA damage in human lymphocytes. Carcinogenesis 19:2159-2162.
28. Torbergsen, A. C. & Collins, A. R. (2000) Recovery of human lymphocytes from oxidative DNA damage; the apparent enhancement of DNA repair by carotenoids is probably simply an antioxidant effect. Eur. J. Nutr. 39:80-85.[Medline]
29.
Hammond, B. R., Jr, Johnson, E. J., Russell, R. M., Krinsky, N. I., Yeum, K.-J., Edwards, R. B. & Snodderly, D. M. (1997) Dietary modification of human macular pigment density. Investig. Ophthalmol. Vis. Sci. 38:1795-1801.
30.
Johnson, E. J., Hammond, B. R., Yeum, K.-J., Qin, J., Wang, X. D., Castaneda, C., Snodderly, D. M. & Russell, R. M. (2000) Relation among serum and tissue concentrations of lutein and zeaxanthin and macular pigment density. Am. J. Clin. Nutr. 71:1555-1562.
31. Landrum, J. T., Bone, R. A., Joa, H., Kilburn, M. D., Moore, L. L. & Sprague, K. E. (1997) A one year study of the macular pigment: the effect of 140 days of a lutein supplement. Exp. Eye Res. 65:57-62.[Medline]
32.
Berendschot, T.T.J.M., Goldbohm, R. A., Klöpping, W.A.A., van de Kraats, J., van Norel, J. & van Norren, D. (2000) Influence of lutein supplementation on macular pigment, assessed with two objective techniques. Investig. Ophthalmol. Vis. Sci. 41:3322-3326.
33.
Beatty, S., Boulton, M., Henson, D., Koh, H. H. & Murray, I. J. (1999) Macular pigment and age related macular degeneration. Br. J. Ophthalmol. 83:867-877.
34.
Mares-Perlman, J. A. (1999) Too soon for lutein supplements [editorial]. Am. J. Clin. Nutr. 70:431-432.
35. Krinsky, N. I. (1971) Function of carotenoids. Isler, O. eds. Carotenoids 1971:669-716 Birkhäuser Basel, Switzerland. .
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