Radu Roxana A, Mata Nathan L, Bagla Aarti, Travis Gabriel H
Jules Stein Eye Institute and Department of Biological Chemistry, School of Medicine, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5928-33. doi: 10.1073/pnas.0308302101. Epub 2004 Apr 5.
Recessive Stargardt's macular degeneration is a blinding disease of children caused by mutations in the ABCA4 (ABCR) gene. Mice with a knockout mutation in abcr accumulate toxic lipofuscin pigments in ocular tissues, similar to affected humans. The major fluorophore of lipofuscin is the bis-retinoid, N-retinylidene-N-retinylethanolamine (A2E). In the current study, we sought to define the effect of increasing light on A2E accumulation. We crossed the abcr(-/-) mutation onto an albino background. The retinoid profiles in albino mice indicated higher retinal illuminance than in pigmented mice exposed to similar ambient light. Unexpectedly, A2E levels were not higher in the albino mice. Also, A2E levels in abcr(-/-) mice reared under cyclic light at 30, 120, or 1,700 lux were similar. Thus, increased retinal illuminance was not correlated with higher A2E. A2E has been shown to undergo light-dependent oxidation to yield a series of A2E epoxides or oxiranes. These oxiranes react with DNA in vitro, suggesting a potential mechanism for A2E cytotoxicity. We analyzed ocular tissues from abcr(-/-) mice for A2E oxiranes by mass spectrometry. Unlike A2E, the oxiranes were more abundant in albino vs. pigmented abcr(-/-) mice, and in abcr(-/-) mice exposed to increasing ambient light. These observations suggest that both the biosynthesis of A2E and its conversion to oxiranes are accelerated by light. Finally, we showed that the formation of A2E oxiranes is strongly suppressed by treating the abcr(-/-) mice with Accutane (isotretinoin), an inhibitor of rhodopsin regeneration.
隐性Stargardt黄斑变性是一种由ABCA4（ABCR）基因突变引起的儿童致盲性疾病。abcr基因发生敲除突变的小鼠在眼部组织中积累有毒的脂褐素色素，这与患病的人类相似。脂褐素的主要荧光团是双视黄醛，即N-视黄叉-N-视黄基乙醇胺（A2E）。在本研究中，我们试图确定光照增加对A2E积累的影响。我们将abcr（-/-）突变引入白化背景。白化小鼠的视黄醛谱显示，其视网膜照度高于暴露于相似环境光下的有色小鼠。出乎意料的是，白化小鼠的A2E水平并不更高。此外，在30、120或1700勒克斯的循环光照下饲养的abcr（-/-）小鼠的A2E水平相似。因此，视网膜照度增加与更高的A2E水平无关。已证明A2E会发生光依赖性氧化，生成一系列A2E环氧化物或环氧乙烷。这些环氧乙烷在体外与DNA反应，提示了A2E细胞毒性的潜在机制。我们通过质谱分析了abcr（-/-）小鼠眼部组织中的A2E环氧乙烷含量。与A2E不同的是，环氧乙烷在白化与有色abcr（-/-）小鼠中以及暴露于环境光增加的abcr（-/-）小鼠中更为丰富。这些观察结果表明光照会加速A2E的生物合成及其向环氧乙烷的转化。最后我们发现，用维甲酸（异维甲酸）（一种视紫红质再生抑制剂）处理abcr（-/-）小鼠可强烈抑制A2E环氧乙烷的形成。
