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J. Liu, W. Lu, A.M. Laties, C.H. Mitchell; Tamoxifen Elevates Lysosomal pH in RPE Cells . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1384.
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An acid pH is essential for optimal function of lysosomal enzymes. Elevation of lysosomal pH in RPE cells is linked to a loss of enzyme activity and decreased clearance of phagocytosed outer segments, and may contribute to the development of macular degeneration. Tamoxifen is known to increase lysosomal pH in other cells, and to decrease the activity of cathepsin D in RPE cells. We thus asked whether tamoxifen increases lysosomal pH in RPE cells.
Lysosomal pH was measured in ARPE–19 cells using the ratiometric pH indicator Lysosensor Yellow/Blue. Microscopic examination localized the indicator to late endosomal and lysosomal vesicles. Optimal loading conditions for stable recordings were determined and the pH was calibrated for each trial.
Under control conditions, lysosomal pH was approximately 4.5 unit. Tamoxifen elevated lysosomal pH in a time and concentration dependent manner. A maximal effect was reached after 15 min with an EC50 of 30 µM. 17–ß–estrodiol did not alter lysosomal pH, indicating estrogen receptors were not involved in the response.
Tamoxifen increased lysosomal pH of RPE cells. This effect was not mediated by traditional receptors. Instead, tamoxifen may have acted in an A2E–like detergent manner. Although retinal disorders after tamoxifen treatment are rare, they do occur and are consistent with an RPE pathology related to lysosomal disfunction.
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