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J. Biol. Chem., Vol. 280, Issue 48, 39732-39739, December 2, 2005

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Characterization of Peroxy-A2E and Furan-A2E Photooxidation Products and Detection in Human and Mouse Retinal Pigment Epithelial Cell Lipofuscin^*

Young P. Jang, Hiroko Matsuda, Yasuhiro Itagaki, Koji Nakanishi1, and Janet R. Sparrow¶2

From the Departments of Ophthalmology and ^¶Pathology, Columbia University, New York, New York 10032 and the Department of Chemistry, Columbia University, New York, New York 10027

The nondegradable pigments that accumulate in retinal pigment epithelial (RPE) cells as lipofuscin constituents are considered to be responsible for the loss of RPE cells in recessive Stargardt disease, a blindness macular disorder of juvenile onset. This autofluorescent material may also contribute to the etiology of age-related macular degeneration. The best characterized of these fluorophores is A2E, a compound consisting of two retinoid-derived side arms extending from a pyridinium ring. Evidence indicates that photochemical mechanisms initiated by excitation from the blue region of the spectrum may contribute to the adverse effects of A2E accumulation, with the A2E photooxidation products being damaging intermediates. By studying the oxidation products (oxo-A2E) generated using oxidizing agents that add one or two oxygens at a time, together with structural analysis by heteronuclear single quantum correlation-NMR spectroscopy, we demonstrated that the oxygen-containing moieties generated within photooxidized A2E include a 5,8-monofuranoid and a cyclic 5,8-monoperoxide. We have shown that the oxidation sites can be assigned to the shorter arm of A2E, to the longer arm, or to both arms by analyzing changes in the UV-visible spectrum of A2E, and we have observed a preference for oxidation on the shorter arm. By liquid chromatography-mass spectrometry, we have also detected both monofuran-A2E and monoperoxy-A2E in aged human RPE and in eye cups of Abca4/Abcr^–/– mice, a model of Stargardt disease. Because the cytotoxicity of endoperoxide moieties is well known, the production of endoperoxide-containing oxo-A2E may account, at least in part, for cellular damage ensuing from A2E photooxidation.

Received for publication, May 4, 2005 , and in revised form, August 11, 2005.

^* This work was supported in part by National Institutes of Health Grants EY 12951 (to J. R. S.) and GM 34509 (to K. N.) and the Macula Vision Research Foundation (to J. R. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Dept. of Chemistry, Columbia University, New York, NY 10027. Tel.: 212-854-2169; Fax: 212-932-8273; E-mail: kn5{at}columbia.edu. ² Recipient of an Alcon Research Institute award. To whom correspondence may be addressed: Dept. of Ophthalmology, Columbia University, New York, NY 10032. Tel.: 212-305-9944; Fax: 212-305-9638; E-mail: jrs88{at}columbia.edu.

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