Biochemistry and Pharmacology of the Macular Carotenoids

描述（由申请人提供）：越来越多的人认识到叶黄素和玉米黄质可能是防止年龄相关性黄斑变性（AMD）视力丧失的重要保护因素，AMD是发达国家不可逆失明的主要原因。这些叶黄素类胡萝卜素完全来自饮食，它们在人类黄斑中以非常高的水平浓缩，具有非常高的特异性。它们被认为通过抗氧化和遮光机制来保护黄斑免受与年龄相关的损伤。 每当一个组织表现出选择性摄取的化合物，该过程很可能是通过特定的结合蛋白介导的，和类胡萝卜素的氧化产物在眼睛中的详细分析表明，视网膜是一个网站的饮食叶黄素和玉米黄质及其代谢物的活性代谢相互转化。参与这些途径的酶和结合蛋白将从人类供体眼睛中进行表征和分离。特别强调的是，将被放置在谷胱甘肽S-转移酶（GSTP 1），最近在本实验室确定的酶的pi亚型很可能是参与在人眼中的叶黄素玉米黄质的转换。类胡萝卜素结合和代谢途径的缺陷可能对正常黄斑功能产生严重后果。 稳定同位素方法将用于研究小动物模型眼中类胡萝卜素摄取、清除和代谢的药理学。这些研究可能会导致改善和更合理的策略，提高黄斑类胡萝卜素水平的个人在风险的视力丧失从AMD。 共振拉曼光谱已被证明是一个强大的客观的方法，黄斑类胡萝卜素水平的非侵入性评估。该技术的成像模式将用于绘制类胡萝卜素在人类供体眼睛和灵长类动物视网膜中的分布，具有以前无法获得的分辨率和特异性。这些信息将为正常眼睛中黄斑色素的生理学提供有价值的见解，并更好地了解可能与衰老和退行性过程相关的变化。

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.