Deuterium Enrichment of Vitamin A at the C20 Position Slows the Formation of Detrimental Vitamin A Dimers in Wild-type Rodents
Deuterium Enrichment of Vitamin A at the C20 Position Slows the Formation of Detrimental Vitamin A Dimers in Wild-type Rodents
复制标题
DOI：
10.1074/jbc.m110.178640
复制
发表时间：
2011-03-11
影响因子：
4.8
通讯作者：
Washington, Ilyas
中科院分区：
文献类型：
--
作者：
Kaufman, Yardana;Ma, Li;Washington, Ilyas
退行性眼病是导致无法治愈的失明的最常见原因。视网膜色素上皮（RPE）中脂褐素（颗粒沉积物）的积累是主要退行性眼病如Stargardt病、Best病和年龄相关性黄斑变性的标志。维生素A的固有反应性导致其二聚化和形成色素如A2 E，并且被认为在眼部脂褐素的形成中起关键作用。我们寻求一种临床实用的方法来减缓维生素A二聚化，作为阐明黄斑变性发病机制和开发治疗干预的手段。我们制备了富含稳定同位素氘的维生素A（C20-D-3-维生素A）。结果表明，氘富集的维生素A的二聚反应比在体外测量的天然丰度的维生素A的二聚反应慢得多。对在维生素A加工中没有明显遗传缺陷的野生型啮齿动物施用C20-D-3-维生素A，减缓了A2 E的生物合成。这项研究阐明了A2 E生物合成的机制，并表明给予C20-D-3-维生素A可能是一种可行的，长期的方法来延缓维生素A二聚化，并通过扩展，可以减缓脂褐质沉积和常见退行性眼病的进展。
Degenerative eye diseases are the most common causes of untreatable blindness. Accumulation of lipofuscin (granular deposits) in the retinal pigment epithelium (RPE) is a hallmark of major degenerative eye diseases such as Stargardt disease, Best disease, and age-related macular degeneration. The intrinsic reactivity of vitamin A leads to its dimerization and to the formation of pigments such as A2E, and is believed to play a key role in the formation of ocular lipofuscin. We sought a clinically pragmatic method to slow vitamin A dimerization as a means to elucidate the pathogenesis of macular degenerations and to develop a therapeutic intervention. We prepared vitamin A enriched with the stable isotope deuterium at carbon twenty (C20-D-3-vitamin A). Results showed that dimerization of deuterium-enriched vitamin A was considerably slower than that of vitamin A at natural abundance as measured in vitro. Administration of C20-D-3-vitamin A to wild-type rodents with no obvious genetic defects in vitamin A processing, slowed A2E biosynthesis. This study elucidates the mechanism of A2E biosynthesis and suggests that administration of C20-D-3-vitamin A may be a viable, long-term approach to retard vitamin A dimerization and by extension, may slow lipofuscin deposition and the progression of common degenerative eye diseases.