Biochemistry and Pharmacology of the Macular Carotenoids

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DESCRIPTION (provided by applicant): There is growing awareness that lutein and zeaxanthin are important protective factors against visual loss from age-related macular degeneration (AMD), the leading cause of irreversible blindness in the developed world. These xanthophyll carotenoids are derived exclusively from the diet, and they are concentrated at very high levels in the human macula with extraordinarily high specificity. They are thought to protect against age-related damage to the macula through antioxidant and light-screening mechanisms. Whenever a tissue exhibits selective uptake of a compound, the process is likely to be mediated through specific binding proteins. A major long-term goal of this project is the identification and characterization of xanthophyll-binding proteins and enzymes in the primate eye. We have identified GSTP1 as the major zeaxanthin-binding protein in the human macula, and we have initial evidence that a specific lutein-binding protein is present as well. Defects in carotenoid binding and metabolic pathways could have severe consequences on normal macular function. Stable isotope methods will be used to study the pharmacokinetics of carotenoid uptake, clearance, and metabolism in the eyes of small animal models such as Japanese quail and transgenic mice overexpressing xanthophyll-binding proteins in their retinas. These studies may lead to improved and more rational strategies for raising macular carotenoid levels in individuals at risk for visual loss from AMD. Resonance Raman spectroscopy and lipofuscin autofluorescence attenuation have proven to be powerful objective methods for the noninvasive assessment of macular carotenoid levels. Imaging modes of these techniques will be refined to map the distributions of carotenoids in human donor eyes and in the primate retina with previously unobtained resolution and specificity, and integral modes will be used to perform noninvasive pharmacokinetics in small animal models. Public Health Relevance: The National Eye Institute has devoted considerable resources to the clinical study of carotenoids' roles in protection against AMD in the recently initiated AREDS II study. This grant proposal will provide valuable insights into the physiology of the macular carotenoid pigments in the normal eye and a greater understanding of the alterations that may occur with aging and degenerative processes.