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Yalin Wu; The Visual Chromophore All-Trans-Retinaldehyde in Retinal Pigment Epithelial Cells: An Alternative Metabolic Pathway. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4037.
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During the visual (retinoid) cycle, clearance of all-trans-retinaldehyde (atRAL) released from photoactivated rhodopsin involves reisomerization of it back to 11-cis-retinaldehyde, the chromophore binding with opsin to regenerate rhodopsin, in retinal pigment epithelial (RPE) cells. Given that disrupted atRAL clearance will cause severe RPE/photoreceptor dystrophy as well as the production of toxic atRAL condensation byproducts that constitute RPE lipofuscin, free atRAL and RPE lipofuscin are both considered to implicate the etiology of age-related macular degeneration (AMD). As the precursor of bisretinoid constituents of RPE lipofuscin, free atRAL exhibits higher cytotoxicity to RPE cells than bisretinoids A2E and all-trans-retinaldehyde dimer (atRAL-dimer), thereby revealing that the conversion of free atRAL to bisretinoid fluorophores is likely an antidotal process at the start. Only when accumulated beyond a critical level, A2E and atRAL-dimer have the ability to trigger the death of RPE cells. In the present study, an alternative metabolic pathway of the visual chromophore atRAL in RPE cells is elucidated.
Primary porcine RPE cells laden with atRAL, and irradiated atRAL or atRAL-dimer in RPE cells and cell-free systems were analyzed by high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). Cellular toxicity was evaluated by MTS assays.
By using primary porcine RPE cells, we found that, after treatment with atRAL, atRAL-dimer readily formed and accumulated in a concentration- and time-dependent manners. Moreover, atRAL-dimer was highly vulnerable to light, and HPLC analysis revealed that irradiation of atRAL-dimer by light produced a series of hydrophilic products that might be relatively easy to be metabolically eliminated. More importantly, exposure of primary porcine RPE cells fed with atRAL-dimer to light showed no cytotoxic effects.
We proposed an alternative metabolic pathway of atRAL in RPE cells: atRAL that evades the visual (retinoid) cycle enters into RPE cells, and undergoes the condensation reaction to generate atRAL-dimer. Light will facilitate the removal of atRAL-dimer without causing RPE cell death. This is the first report on a new concept regarding how atRAL is metabolized in RPE cells.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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