- Mini Review
Interactions between canthaxanthin and lipid membranes — possible mechanisms of canthaxanthin toxicity
Cellular & Molecular Biology Letters volume 14, pages 395–410 (2009)
Canthaxanthin (β, β-carotene 4, 4′ dione) is used widely as a drug or as a food and cosmetic colorant, but it may have some undesirable effects on human health, mainly caused by the formation of crystals in the macula lutea membranes of the retina. This condition is called canthaxanthin retinopathy. It has been shown that this type of dysfunction of the eye is strongly connected with damage to the blood vessels around the place of crystal deposition. This paper is a review of the experimental data supporting the hypothesis that the interactions of canthaxanthin with the lipid membranes and the aggregation of this pigment may be the factors enhancing canthaxanthin toxicity towards the macula vascular system. All the results of the experiments that have been done on model systems such as monolayers of pure canthaxanthin and mixtures of canthaxanthin and lipids, oriented bilayers or liposomes indicate a very strong effect of canthaxanthin on the physical properties of lipid membranes, which may explain its toxic action, which leads to the further development of canthaxanthin retinopathy.
age-related macular degeneration
egg yolk phosphatidylcholine
Fourier transform ultra red
glutathione S-transferase, zeaxanthin-binding protein
nuclear magnetic resonance
retinal pigment epithelial cell
Harnois, C., Samson, J., Malenfant, M. and Rousseau, A. Canthaxanthin retinopathy. Anatomic and functional reversibility. Arch. Ophtalmol. 107 (1989) 538–540.
Bloomenstein, M.R. and Pinkert, R.B. Canthaxanthine retinopathy. J. Am. Optom. Assoc. 67 (1996) 690–692.
McGuinnes, R. and Beaumont, P. Gold dust retinopathy after the ingestion of canthaxanthin to produce skin-bronzing. Med. J. 143 (1985) 622–623.
Daicker, B., Schiedt, K., Adnet, J.J. and Bermond, P. Canthaxanthin retinopathy. An investigation by light and electron microscopy and physicochemical analysis. Graefes Arch. Clin. Exp. Ophtalmol. 222 (1987) 189–197.
White, G.L.J., Beesley, R., Thiese, S.M. and Murdock, R.T. Retinal crystals and oral tanning agents. Am. Fam. Physician 37 (1988) 125–126.
Arden, G.B., Oluwole, J.O., Polkinghorne, P., Bird, A.C., Barker, F.M., Norris, P.G. and Haek, J.L. Monitoring of patients taking canthaxanthin and β-carotene: an electroetinographic and ophtalmologic survey. Hum. Toxicol. 8 (1989) 439–450.
Bopp, S., el-Hifnawi, E.L. and Laqua, H. Canthaxanthin retinopathy and macular pucker. J. Fr. Ophtalmol. 12 (1989) 891–896.
Weber, U., Michaelis, L., Kern, W. and Goerz, G. Experimental carotenoid retinopathy. II. Functional and morphological alterations of the rabbit retina after canthaxanthin application with small unilamellar phospholipid liposomes. Graefes Arch. Clin. Exp. Ophtalmol. 225 (1987) 346–450.
Hennekes, R. Peripheral retinal dystrophy following administration of canthaxanthin? Fortschr. Ophtalmol. 83 (1986) 600–601.
Bluhm, R., Branch, R., Johnston, P. and Stein, R. Aplastic anaemia associated with canthaxanthin ingested for ‘tanning’ purposes. JAMA 264 (1990) 1141–1142.
Chew, B.P., Park, J.S., Wong, M.W. and Wong, T.S. A comparison of the anticancer activities of dietary β-carotene, canthaxanthin and astaxanthin in mice in vivo. Anticancer Res. 19 (1999) 1849–1853.
Mathews-Roth, M.M. Antitumor activity of beta-carotene, canthaxanthin and phytoene. Oncology 39 (1982) 33–37.
Mayne, S.T. and Parker, R.S. Antioxidant activity of dietary canthaxanthin. Nutr. Cancer 12 (1989) 225–236.
Palozza, P., Maggiano, N., Calviello, G., Lanza, P., Piccioni, E., Ranelletti, F.O. and Bartoli, G.M. Canthaxanthin induces apoptosis in human cancer cell lines. Carcinogenesis 19 (1998) 373–376.
Lober, C.W. Canthaxanthin - the ‘tanning’ pill. J. Am. Acad. Dermatol. 13 (1985) 660.
Baker, R. and Gunther, C. The role of carotenoids in consumer choice and the likely benefits from their inclusion into products for human consumption. Trends Food Sci. Technol. 15 (2004) 484–488.
Goralczyk, R., Barker, F.M., Buser, S., Liechti H. and Bausch, J. Dose dependency of canthaxanthin crystals in monkey retina and spatial distribution of its metabolites. Invest. Ophthalmol. Vis. Sci. 41 (2000) 1513–1522.
Macdonald, K., Holti, G. and Marks, J. Is there a place for carotene/canthaxanthin in photochemoterapy for psoriasis? Dermatologica 169 (1984) 41–46.
Futterman, S. and Kupfer, C. The fatty acid composition of the retinal vasculature of normal and diabetic human eyes. Invest. Ophthalmol. Vis. Sci. 7 (1968) 105–108.
Landrum, J.T. and Bone, R.A. Lutein, zeaxanthin, and the macular pigment. Arch. Biochem. Biophys. 385 (2001) 28–40.
Handelman, G.J., Drarz, E.A., Reay, C.C. and van Kuijk, F.J.G.M. Carotenoids in the human macula and whole retina. Invest. Ophthalmol. Vis. Sci. 29 (1988) 850–855.
Bone, R.A., Landrum, J.T., Fernandez, L. and Tarsis, S.L. Analysis of the macular pigment by HPLC: retinal distribution and age study. Invest. Ophthalmol. Vis. Sci. 29 (1988) 843–849.
Bernstein, P.S., Yoshida, M.D., Katz, M.B., McClane, R.W. and Gellermann, W. Raman detection of macular carotenoid pigments in intact human retina. Invest. Ophthalmol. Vis. Sci. 39 (1998) 2003–3011.
Bernstein, P.S., Khachik, F., Carvalho, L.S., Muir, G.J., Zhao, D.-Y. and Katz, N.B. Identification and quantization of carotenoids and their methabolites in the tissues of the human eye. Exp. Eye Res. 72 (2001) 215–223.
Sujak, A., Gabrielska, J., Grudzinski, W., Borc, R., Mazurek, P. and Gruszecki, W.I. Lutein and zeaxanthin as protectors of lipid membranes against oxidative damage: the structural aspects. Arch. Biochem. Biophys. 371 (1999) 301–307.
Schalch, W. Carotenoids in the retina in: Free Radicals and Ageing (Emerit, I. and Chence, B., Eds) Birkhauser-Verlag, Basel 1992.
Landrum, J.T. Serum and macular pigment response to 2.4 mg dosage of lutein (Abstract). Assoc. Res. Vis. Ophtalmol. 41 (2000) S60.
Landrum, J.T., Bone, R.A., Jos, H., Kilburn, M.D., Moore, L.L. and Sprague, K.E. A 1 year study of the macular pigment: the effect of 140 days of a lutein supplement. Exp. Eye Res. 65 (1997) 57–62.
Kopcke, W., Barker, F.M. and Schalch, W. Canthaxanthin deposition in the retina - a biostatistical evaluation of 411 patients. J. Toxicol. Cutan Ocul. Toxicol. 14 (1995) 8089–8104.
Espaillat, A., Aiello, L.P., Arrigg, P.G., Villalobos, R., Silver, P.M. and Cavicchi, R.W. Canthaxanthine retinopathy. Arch. Ophthalmol. 117 (1999) 412–413.
Chang, T.S., Aylward, W. and Gass, J.D. Asymmetric canthaxanthin retinopathy. Am. J. Ophthalmol. 119 (1995) 801–802.
Oosterhuis, J.A., Remky, H., Nijman, N.M., Craandijk, A. and de Wolff, F.A. Canthaxanthin retinopathy without intake of canthaxanthin. Klin. Monatsbl. Augenheilkd 194 (1989) 110–116.
Audouy, D., Bord, G. and Audouy, R. Maculopathy with golden paillettes. Bull. Soc. Ophthalmol. Fr. (1987) 191–193.
Bone, R.A. and Landrum, J.T. Distribution of macular pigment components, zeaxanthin and lutein, in human retina. Methods Enzymol. 213 (1992) 360–366.
Stevens Andrews, J. and Leonard-Martin, T. Total lipid and membrane lipid analysis of normal animal and human lenses. Invest. Ophthalmol. Vis. Sci. 21 (1981) 39–45.
Boudreault, G., Cortin, P., Corriveau, L.A., Rousseau, A.P., Tardif Y. and Malenfant, M. Canthaxanthin retinopathy: 1. Clinical study in 51 consumers. Can. J. Ophtalmol. 18 (1983) 325–328.
Gruszecki, W.I. and Strzalka, K. Carotenoids as modulators of lipid membrane physical properties. Biochim. Biophys. Acta 1740 (2005) 108–115.
Bendich, A. and Olson, J.A. Biological actions of carotenoids. Fed. Am. Soc. Exp. Biol. J 3 (1989) 1927–1932.
Gruszecki, W.I. Carotenoids in Membranes in: The Photochemistry of Carotenoids (Frank, H.A., Young, A.J., Britton, G., Cogdell, R.J., Eds), Kluwer Academic Publ., Dordrecht 1999.
Sujak, A., Gabrielska, J., Milanowska, J., Mazurek, P., Strzalka, K. and Gruszecki, W.I. Studies on canthaxanthin in lipid membranes. Biochim. Biophys. Acta 1712 (2005) 17–28.
Linden, A., Bürgi, B. and Eugster, C.H. Confirmation of the structures of lutein and zeaxanthin. Helvetica Chim. Acta 87 (2004) 1254–1269.
Bart J.C. and MacGillavry, C.H. The crystal and molecular structure of canthaxanthin. Acta Crystallogr. B 24 (1968) 1587–1606.
Sujak, A., Okulski, W. and Gruszecki, W.I. Organisation of xanthophyll pigments lutein and zeaxanthin in lipid membranes formed with dipalmitoylphosphatidylcholine. Biochim. Biophys. Acta 1509 (2000) 255–263.
Sujak, A., Mazurek, P. and Gruszecki, W.I. Xanthophyll pigments lutein and zeaxanthin in lipid multibilayers formed with dimyristoylphosphatidylcholine. J. Photochem. Photobiol. B 68 (2002) 39–44.
Birge, R.R., Zgierski, M.Z., Serrano-Andres, L. and Hudson, B.S. Transition Dipole orientation of linear polyenes: semiempirical models and extrapolation to the infinite chain limit. J. Phys. Chem. 103 (1999) 2251–2255.
Dulley, P. Ocular adverse reactions to tamoxifen-a review. Optal. Physiol. Opt. 19 (1999) S2–S9.
Berson, E.L. Acute toxic effects of chloroquine on the cat retina. Invest. Ophthalmol. Vis. Sci. 9 (1970) 618–628.
Olson, J.A. Absorption, transport, and metabolism of carotenoids in humans. Pure Appl. Chem. 66 (1994) 1011–1016.
Snodderly, D.M., Brown, P.K., Delori, F.C. and Auran, J.D. The macular pigment. I. Absorbance spectra, localization, and discrimination from other yellow pigments in primate retinas. Invest. Ophthalmol. Vis. Sci. 25 (1984) 660–673.
Billsten, H.H., Bhosale, P., Yemelyanov, A., Bernstein, P.S. and Polivka, T. Photophysical properties of xanthophylls in carotenoproteins from human retina. Photochem. Photobiol. 78 (2003) 138–145.
Yemelyanow, A.Y., Katz, N.B. and Bernstein, P.S. Ligand-binding characterization of xantophyll carotenoids to solubilized membrane proteins derived from the human retina. Exp. Eye Res. 71 (2001) 381–392.
Bhosale, P., Larson, J.M., Frederick, K., Southwick, K., Thulin, C.D. and Bernstein, P.S. Identification and characterization of a Pi isoform of glutathione S-transferase (GSTP1) as a zeaxanthin-binding protein in the macula of the human eye. J. Biol. Chem. 279 (2004) 49447–49454.
Bhosale, P. and Bernstein, P.S. Vertebrate and invertebrate carotenoid-binding proteins. Arch. Biochem. Biophys. 458 (2007) 121–127.
Stahl, W. and Sies, H. Bioactivity and protective effects of natural carotenoids. Biochim. Biophys. Acta 1740 (2005) 101–105.
Furr, H.C. and Clark, R.M. Intestinal absorption and tissue distribution of carotenoids. Nutr. Biochem. 8 (1997) 364–377.
Wisniewska, A., Widomska, J. and Subczynski, W.K. Carotenoid-membrane interactions in liposomes: effect of dipolar, monopolar, and nonpolar carotenoids. Acta Biochim. Pol. 53 (2006) 475–484.
Sujak, A., Strzalka, K. and Gruszecki, W.I. Thermotropic phase behaviour of lipid bilayers containing carotenoid pigment canthaxanthin: a differential scanning calorimetry study. Chem. Phys. Lipids 145 (2007) 1–12.
Jones, M.N. and Chapman, D. Micelles, monolayers and biomembranes. Wiley-Liss, New York, 1995.
Shafaa, M.W.I., Diehl, H.A. and Socaciu, C. The solubilization pattern of lutein, zeaxanthin, canthaxanthin and b-carotene differ characteristically in liposomes, liver microsomes and retinal epithelial cells. Biophys. Chem. 129 (2007) 111–119.
Sujak, A., Gagos, M., Dalla Serra, M. and Gruszecki, W.I. Organization of two-component monomolecular layers formed with dipalmitoylphosphatidylcholine and the carotenoid pigment, canthaxanthin. J. Mol. Biol. 24 (2007) 431–444.
Subczynski, W.K., Markowska, E., Gruszecki, W.I. and Sielewiesiuk, J. Effects of polar carotenoids on dimyristoylphosphatidylcholine membranes: a spin-label study. Biochim. Biophys. Acta 1105 (1992) 97–108.
Jezowska, I., Wolak, A., Gruszecki, W.I. and Strzalka, K. Effect of betacarotene on structural and dynamic properties of model phosphatidylcholine membranes. II. A 31P-NMR and 13C-NMR study. Biochim. Biophys. Acta 1194 (1994) 143–148.
Strzalka, K. and Gruszecki, W.I. Effect of beta-carotene on structural and dynamic properties of model phosphatidylcholine membranes. I. An EPR spin label study. Biochim. Biophys. Acta 1194 (1994) 138–142.
Gabrielska, J. and Gruszecki, W.I. Zeaxanthin (dihydroxy-beta-carotene) but not beta-carotene rigidifies lipid membranes: A 1H-NMR study of carotenoid-egg phosphatidylcholine liposomes. Biochim. Biophys. Acta 1285 (1996) 167–174.
Castelli, F., Caruso, S. and Giuffrida, N. Different effects of two structurally similar carotenoids, lutein and beta-carotene, on the thermotropic behaviour of phosphatidylcholine liposomes. Calorimetric evidence of their hindered transport through biomembranes. Thermochim. Acta 327 (1999) 125–131.
Suwalsky, M., Hidalgo, P., Strzałka, K. and Kostecka-Gugała, A. Comparative X-ray studies on the interaction of carotenoids with a model phosphatidylcholine membrane. Z. Naturforsch. 57C (2002) 129–134.
Jemiola-Rzeminska, M., Pasenkiewicz-Gierula, M. and Strzalka, K. The behaviour of beta-carotene in the phosphatidylcholine bilayer as revealed by a molecular simulation study. Chem. Phys. Lipids 135 (2005) 27–37.
Kostecka-Gugala, A., Latowski, D. and Strzalka, K. Thermotropic phase behaviour of alpha-dipalmitoylphosphatidylcholine multibilayers is influenced to various extents by carotenoids containing different structural features-evidence from differential scanning calorimetry. Biochim. Biophys. Acta 1609 (2003) 193–202.
About this article
Cite this article
Sujak, A. Interactions between canthaxanthin and lipid membranes — possible mechanisms of canthaxanthin toxicity. Cell Mol Biol Lett 14, 395–410 (2009). https://doi.org/10.2478/s11658-009-0010-8
- Macula lutea
- Model lipid membranes
- Molecular interactions