All-trans-retinal dimer formation alleviates the cytotoxicity of all-trans-retinal in human retinal pigment epithelial cells
All-trans-retinal dimer formation alleviates the cytotoxicity of all-trans-retinal in human retinal pigment epithelial cells
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全反式视网膜二聚体的形成减轻了全反式视网膜对人视网膜色素上皮细胞的细胞毒性
DOI：
10.1016/j.tox.2016.10.005
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发表时间：
2016-09-14
期刊：
影响因子：
4.5
通讯作者：
Wu, Yalin
中科院分区：
文献类型：
--
作者：
Li, Jie;Zhang, Yanli;Wu, Yalin
从视网膜色素上皮 (RPE) 细胞中有效清除全反式视网膜 (atRAL) 对于避免其细胞毒性非常重要。然而，atRAL 在 RPE 细胞中的代谢尚不清楚。本研究旨在分析 atRAL 的代谢产物，并比较 atRAL 与其衍生物全反式视网膜二聚体 (atRAL-dimer) 在人 RPE 细胞中的细胞毒性。我们发现，RPE细胞与atRAL孵育6小时后，产生了全反式视黄醇（atROL）以及atRAL缩合代谢物（包括atRAL-二聚体和A2E）的混合物，并且atRAL-二聚体的量显着高于A2E。在Rdh8（-/-）Abca4（-/-）小鼠（具有类视黄醇循环缺陷的小鼠模型，表现出年龄相关性黄斑变性（AMD）的一些象征性特征）的眼中，atRAL-二聚体的水平比野生型小鼠有所增加，甚至远高于A2E和异构体的水平。与其前体atRAL相比，atRAL-二聚体的细胞毒性降低。后者可能引起细胞内活性氧 (ROS) 过量产生，增加几种氧化应激相关基因（Nrf2、HO-1 和 gamma-GCSh）的 mRNA 表达，并诱导 RPE 细胞中 Delta psi m 损失。相比之下，atRAL-二聚体诱导细胞内ROS和氧化应激的能力比浓度匹配的atRAL弱得多，并且atRAL-二聚体在较高浓度下对线粒体功能没有表现出毒性作用。总之，atRAL代谢过程中atRAL二聚体的形成通过减少氧化应激改善了atRAL的细胞毒性。 (C) 2016 Elsevier Ireland Ltd. 保留所有权利。
Effective clearance of all-trans-retinal (atRAL) from retinal pigment epithelial (RPE) cells is important for avoiding its cytotoxicity. However, the metabolism of atRAL in RPE cells is poorly clarified. The present study was designed to analyze metabolic products of atRAL and to compare the cytotoxicity of atRAL versus its derivative all-trans-retinal dimer (atRAL-dimer) in human RPE cells. We found that all-transretinol (atROL) and a mixture of atRAL condensation metabolites including atRAL-dimer and A2E were generated after incubating RPE cells with atRAL for 6 h, and the amount of atRAL-dimer was significantly higher than that of A2E. In the eyes of Rdh8(-/-) Abca4(-/-) mice, a mouse model with defects in retinoid cycle that displays some symbolic characteristics of age-related macular degeneration (AMD), the level of atRAL-dimer was increased compared to wild-type mice, and was even much greater than that of A2E & isomers. The cytotoxicity of atRAL-dimer was reduced compared with its precursor atRAL. The latter could provoke intracellular reactive oxygen species (ROS) overproduction, increase the mRNA expression of several oxidative stress related genes (Nrf2, HO-1, and gamma-GCSh), and induce Delta psi m loss in RPE cells. By contrast, the abilities of atRAL-dimer to induce intracellular ROS and oxidative stress were much weaker versus that of concentration-matched atRAL, and atRAL-dimer exhibited no toxic effect on mitochondrial function at higher concentrations. In conclusion, the formation of atRAL-dimer during atRAL metabolic process ameliorates the cytotoxicity of atRAL by reducing oxidative stress. (C) 2016 Elsevier Ireland Ltd. All rights reserved.