title: UVA light-excited kynurenines oxidize ascorbate and modify lens proteins through the formation of advanced glycation end products: implications for human lens aging and cataract formation.
abstract: Advanced glycation end products (AGEs) contribute to lens protein pigmentation and cross-linking during aging and cataract formation. In vitro experiments have shown that ascorbate (ASC) oxidation products can form AGEs in proteins. However, the mechanisms of ASC oxidation and AGE formation in the human lens are poorly understood. Kynurenines are tryptophan oxidation products produced from the indoleamine 2,3-dioxygenase (IDO)-mediated kynurenine pathway and are present in the human lens. This study investigated the ability of UVA light-excited kynurenines to photooxidize ASC and to form AGEs in lens proteins. UVA light-excited kynurenines in both free and protein-bound forms rapidly oxidized ASC, and such oxidation occurred even in the absence of oxygen. High levels of GSH inhibited but did not completely block ASC oxidation. Upon UVA irradiation, pigmented proteins from human cataractous lenses also oxidized ASC. When exposed to UVA light (320-400 nm, 100 milliwatts/cm(2), 45 min to 2 h), young human lenses (20-36 years), which contain high levels of free kynurenines, lost a significant portion of their ASC content and accumulated AGEs. A similar formation of AGEs was observed in UVA-irradiated lenses from human IDO/human sodium-dependent vitamin C transporter-2 mice, which contain high levels of kynurenines and ASC. Our data suggest that kynurenine-mediated ASC oxidation followed by AGE formation may be an important mechanism for lens aging and the development of senile cataracts in humans.
authors.affiliation: From the Departments of Chemistry, Ophthalmology and Visual Sciences, mdl78@case.edu.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Linetsky
authors.affiliation: Ophthalmology and Visual Sciences.
authors.forename: Cibin T
authors.initials: CT
authors.lastname: Raghavan
authors.affiliation: the Iladevi Cataract and IOL Research Center, Gurukul Road, Memnagar, Ahmedabad, Gujarat-380052, India.
authors.forename: Kaid
authors.initials: K
authors.lastname: Johar
authors.affiliation: Pathology, and.
authors.forename: Xingjun
authors.initials: X
authors.lastname: Fan
authors.affiliation: Pathology, and Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106 and.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Monnier
authors.affiliation: the Iladevi Cataract and IOL Research Center, Gurukul Road, Memnagar, Ahmedabad, Gujarat-380052, India.
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Vasavada
authors.affiliation: Ophthalmology and Visual Sciences, ram.nagaraj@case.edu.
authors.forename: Ram H
authors.initials: RH
authors.lastname: Nagaraj
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism*; D002386:Cataract / Q000378:metabolism*; D003459:Crystallins / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism / Q000528:radiation effects*; D007908:Lens, Crystalline / Q000254:growth & development / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D010084:Oxidation-Reduction; D014466:Ultraviolet Rays
chemical_list: D003459:Crystallins; D017127:Glycation End Products, Advanced; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D001205:Ascorbic Acid
keywords: Aging; Ascorbic Acid; Cataract; Glycation; Lens; Tryptophan