Can Xanthophyll-Membrane Interactions Explain Their Selective Presence in the Retina and Brain?

Abstract

Epidemiological studies demonstrate that a high dietary intake of carotenoids may offer protection against age-related macular degeneration, cancer and cardiovascular and neurodegenerative diseases. Humans cannot synthesize carotenoids and depend on their dietary intake. Major carotenoids that have been found in human plasma can be divided into two groups, carotenes (nonpolar molecules, such as β-carotene, α-carotene or lycopene) and xanthophylls (polar carotenoids that include an oxygen atom in their structure, such as lutein, zeaxanthin and β-cryptoxanthin). Only two dietary carotenoids, namely lutein and zeaxanthin (macular xanthophylls), are selectively accumulated in the human retina. A third carotenoid, meso-zeaxanthin, is formed directly in the human retina from lutein. Additionally, xanthophylls account for about 70% of total carotenoids in all brain regions. Some specific properties of these polar carotenoids must explain why they, among other available carotenoids, were selected during evolution to protect the retina and brain. It is also likely that the selective uptake and deposition of macular xanthophylls in the retina and brain are enhanced by specific xanthophyll-binding proteins. We hypothesize that the high membrane solubility and preferential transmembrane orientation of macular xanthophylls distinguish them from other dietary carotenoids, enhance their chemical and physical stability in retina and brain membranes and maximize their protective action in these organs. Most importantly, xanthophylls are selectively concentrated in the most vulnerable regions of lipid bilayer membranes enriched in polyunsaturated lipids. This localization is ideal if macular xanthophylls are to act as lipid-soluble antioxidants, which is the most accepted mechanism through which lutein and zeaxanthin protect neural tissue against degenerative diseases.

Keywords: age-related macular degeneration (AMD); age-related neurodegenerative diseases; carotenoids; lipid antioxidants; lutein; macular xanthophylls; neural tissue; zeaxanthin.

Figure 1

Chemical structures of carotenoids (xanthophylls and carotenes) abundant in food, blood plasma and neural tissue.

Figure 2

(A) Preferential accumulation of xanthophylls in the brain and retina tissues expressed as a percent of xanthophylls in the total carotenoid pool; (B) preferential accumulation of zeaxanthin over lutein in the brain and retina tissues expressed as the zeaxanthin-to-lutein ratio. Data adapted from [1,2,4,9,10,11,12].

Figure 3

Schematic drawing showing the location of the xanthophyll molecule in the cholesterol-rich and cholesterol-poor membrane domains. An unfavorable interaction with cholesterol in the cholesterol-rich domain is indicated.

Figure 4

Schematic drawing explaining the physical stability of dipolar xanthophylls in the lipid-bilayer membranes. A hydrophobic barrier across the lipid bilayer is indicated. To remove the dipolar xanthophyll molecule from the bilayer, one of its polar −OH groups has to cross the hydrophobic (energy) barrier. ΔE_H is the energy needed to pull the polar −OH group of the dipolar xanthophyll across this barrier.

Figure 5

Partition coefficient of dipolar xanthophylls (lutein and zeaxanthin), monopolar xanthophyll (β-cryptoxanthin) and nonpolar carotenoid (β-carotene) between the bulk (unsaturated) domain and the raft (saturated) domain in the membrane made of the raft-forming mixture and in the model of photoreceptor outer segment (POS) membranes. The unsaturated domain in the model of POS membranes is abundant in DHA, with six double bonds. For more details, see [100,101].

Figure 6

Diagram illustrating processes through which xanthophylls are protecting membranes against oxidative damage. Photo-related and dark processes are actively involved in protecting the retina, while only dark processes are assumed to be active in the protection of brain tissue. The broken rectangles indicate processes that are not yet fully confirmed as involved in protecting the eye retina and are included here as purported processes.