Overview of Carotenoid Function in the

It has long been recognized that carotenoids may have an important role in ocular physiology. As far back as the 18th century anatomists noted that the primate fovea, the region of the retina responsible for high-resolution visual acuity, displayed a deep yellow coloration that they termed the "macula lutea" or "yellow spot" (2). In 1945, George Wald studied organic extracts of primate macular tissue and determined that the macular yellow pigment had spectro-scopic and chemical features characteristic of xanthophyll carotenoids, ubiquitous plant derived carotenoids containing at least one oxygen atom along the core C40H56 isoprenoid carotene structure (3). Several decades later, Bone and Landrum preliminarily identified the macular carotenoids as lutein and zeaxanthin (4), and in a follow-up investigation, they were able to demonstrate the stereochemical nature of the macular pigment as a mixture of dietary (3R,3'R,6'R)-lutein, dietary (3R,3'R)-zeaxanthin, and nondietary (3R,30 S-meso)-zeaxanthin (5). They suggested that meso-zeaxanthin may be derived from a metabolic conversion in the eye from dietary lutein, and subsequent studies seem to confirm this hypothesis (6).

Several groups have studied the distribution of lutein, zeaxanthin, and other carotenoids in the human and nonhuman primate eye using HPLC analysis or spectroscopic methods. In the foveal region of the retina, the concentration of lutein and zeaxanthin is enormously high, estimated to be in the range of 1 mM, by far the highest concentration of carotenoids anywhere in the human body (7). They are localized to the cone axons of the Henle fiber layer (8) or to the Muller cells of the fovea (9). The concentration per unit area declines rapidly with increasing eccentricity from the fovea, such that even a few millimeters away the retinal concentrations of lutein and zeaxanthin are approximately 100-fold lower than in the foveal center (10). At least a portion of these peripheral retinal carotenoids are associated with the photoreceptor outer segments (11,12). In the foveal area, the ratio of lutein to zeaxanthin and meso-zeaxanthin is in the range of 1: 1: 1, whereas in the periphery, lutein predominates over zeaxanthin by 3 : 1 and very little meso-zeaxanthin is present (13). In a comprehensive survey of all human ocular tissues, it is clear that uptake of lutein and zeaxanthin into the retina and the lens is highly specific since no other carotenoids except for a few closely related metabolites such as 3'-oxolutein and 3'-epilutein are detectable, whereas other ocular tissues contain a much more diverse carotenoid content similar to that of the serum (14). It is likely that the uptake of lutein and zeaxanthin into the retina (and possibly the lens) is mediated by saturable and specific xanthophyll-binding proteins (15). With the exception of the ciliary body, the total concentration of carotenoids per wet weight of tissue is generally lower than that of the peripheral retina.

The physiological role of the macular carotenoids has been the subject of considerable research interest. They are efficient antioxidants in a tissue composed of polyunsaturated lipids subject to significant oxidative stress from intense light and high oxygen levels (16,17). They absorb light with high efficiency in the 400-to 500-nm range, the region of the visible spectrum considered to be most phototoxic to the retina. Recent animal studies have indicated that lutein and/or zeaxanthin supplementation may provide protection in experimental models of retinal light damage (18). It is also possible that the macular carotenoids may help improve visual function by ameliorating chromatic aberration and haze caused by short-wavelength visible light (19).

The Eye Disease Case-Control (EDCC) study was the first large-scale study to provide epidemiological evidence that lutein and zeaxanthin may protect against age-related macular degeneration (ARMD), the leading cause of blindness among the elderly in the developed world. This study assessed participants' carotenoid levels through serum assays and food frequency questionnaires, and they reported that individuals who have high intakes of lutein and zeaxanthin have 43% lower rates of the wet form of ARMD (20,21). Subsequent studies by others have not confirmed such a large protective effect (22), but the EDCC data was compelling enough to launch a large-scale industry in the United States promoting supplements containing lutein and/or zeaxanthin to individuals at risk for visual loss from ARMD. The recent Age-Related Eye Disease Study (AREDS) has demonstrated that an antioxidant supplement combination containing high levels of zinc, vitamin E, vitamin C, and ^-carotene can slow the progression of moderate ARMD (23), but no similar large-scale prospective interventional studies of lutein and/or zeaxanthin have been performed.

While the EDCC provided intriguing information, their carotenoid assessment methods, food frequency questionnaires, and serum analyses are indirect measures of the carotenoid status of the eye. It is of paramount importance to have data on the levels of carotenoids in the relevant tissue, the macula of the human eye. Supportive evidence was supplied by Bone and Landrum in a study in which macular and peripheral retinal carotenoid levels were measured by HPLC in postmortem specimens of donors with and without a known history of ARMD. They found that lutein and zeaxanthin levels were 38% lower in the macula of ARMD eyes relative to controls with no known history of ARMD (24). However, postmortem studies have significant limitations because historical information on clinical history and risk factors of the donors is generally unavailable. Thus, it is clear that noninvasive methods of assessment of macular carotenoid levels in living humans could be powerful tools in epidemiological research on AMD, and these methods would be expected to be very useful for monitoring studies of dietary and/or nutritional interventions designed to raise macular carotenoid levels.

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