Biochemistry and Pharmacology of the Macular Carotenoids

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DESCRIPTION (provided by applicant): There is growing awareness that lutein and zeaxanthin may be 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 anti-oxidant and light-screening mechanisms. Whenever a tissue exhibits selective uptake of a compound, the process is likely to be mediated through specific binding proteins, and detailed analysis of carotenoid oxidation products in the eye suggests that the retina is a site for active metabolic interconversions of dietary lutein and zeaxanthin and their metabolites. The enzymes and binding proteins involved in these pathways will be characterized and isolated from human donor eyes. Particular emphasis will be placed on the pi isoform of glutathione S-transferase (GSTP1), an enzyme recently identified in this laboratory as likely to be involved in the conversion of lutein to zeaxanthin in the human eye. Defects in carotenoid binding and metabolic pathways could have severe consequences on normal macular function. Stable isotope methods will be used to study the phamacokinetics of carotenoid uptake, clearance, and metabolism in the eyes of small animal models. 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 has proven to be a powerful objective method for the noninvasive assessment of macular carotenoid levels. An imaging mode of this technique will be used to map the distribution of carotenoids in human donor eyes and in the primate retina with previously unobtainable resolution and specificity. This information will provide valuable insights into the physiology of the macular pigments in the normal eye and a greater understanding of the alterations that may occur in association with aging and degenerative processes.