An Impediment to Glutathione Diffusion in Older Normal Human Lenses: a Possible Precondition for Nuclear Cataract

Sweeney, Matthew; Truscott, Roger J.W.

doi:10.1006/exer.1998.0549

Cited by 211 publications

(203 citation statements)

References 40 publications

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“…However, this reduction does not appear to be sufficient to account for the marked age-dependent decline in GSH levels in the lens core (19). For example, in advanced stages of cataract when GSH levels in the nucleus decline significantly, the anti-oxidant levels remain sufficiently high in the outer cortex (42).…”

Section: Discussionmentioning

confidence: 99%

“…An alternative view is that GSH diffuses from the outer cortex to the nucleus via gap junction channels. This view was based on a study that followed the movement of 35 S-labeled cysteine in the lens (18,19). Movement of the label, which was incorporated into GSH, occurred in the equatorial plane along the length of fiber cells where gap junctions are abundantly expressed.…”

mentioning

confidence: 99%

“…Movement of the label, which was incorporated into GSH, occurred in the equatorial plane along the length of fiber cells where gap junctions are abundantly expressed. A barrier to diffusion of GSH was shown to develop with age, leading to a decrease in GSH delivery to the lens core (19). Diffusion of anionic GSH through gap junctions is driven by the large concentration gradient from the surface to the center as well as by the relatively depolarized resting membrane potential of inner fiber cells (V m ϳϪ50 mV) compared with outer fiber cells (V m ϳϪ70 mV) (14).…”

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confidence: 99%

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Connexin 46 (Cx46) Gap Junctions Provide a Pathway for the Delivery of Glutathione to the Lens Nucleus

Slavi

Rubiños

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Connexin 46 (Cx46) Gap Junctions Provide a Pathway for the Delivery of Glutathione to the Lens Nucleus

Slavi

Rubiños

et al. 2014

Journal of Biological Chemistry

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“…The observed increase in the extent of binding of 3-OHKG to lens protein after the age of 40 -50 (Fig. 2) may result in part from a diminished concentration of reduced GSH in the nuclear region of the lens (23,24). This feature may result from the development of a barrier to the diffusion of GSH, from its site of synthesis (or reduction) in the lens cortex to the interior of the lens (23).…”

Section: Lens Coloration and Aging 32549mentioning

confidence: 93%

“…2) may result in part from a diminished concentration of reduced GSH in the nuclear region of the lens (23,24). This feature may result from the development of a barrier to the diffusion of GSH, from its site of synthesis (or reduction) in the lens cortex to the interior of the lens (23). Because other UV filters present in the human lens, such as kynurenine and 3-hydroxykynurenine (7,8), contain the same amino acid side chain as 3-OHKG, it would be expected that these would also bind to lens proteins.…”

Section: Lens Coloration and Aging 32549mentioning

confidence: 99%

Human Lens Coloration and Aging

Hood

Garner

Truscott

1999

Journal of Biological Chemistry

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108

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The human lens becomes increasingly yellow with age and thereby reduces our perception of blue light. This coloration is associated with lens proteins (crystallins), but its molecular basis was unknown. Here we show that the coloration occurs because of the interaction of crystallins with a UV filter compound, 3-hydroxykynurenine glucoside (3-OHKG). Crystallin modification results from deamination of the 3-OHKG amino acid side chain, yielding an unsaturated ketone that is susceptible to nucleophilic attack by cysteine, histidine, and lysine residues. This novel protein modification contributes to age-related lens coloration and may play a role in human nuclear cataractogenesis.As part of the normal process of aging, the human lens becomes progressively more yellow and fluorescent (1-3), leading to a concomitant increase in light absorption in the 300 -500 nm range (1) and thus diminishes our perception of violet and blue light. The age-related increase in lens coloration and fluorescence is associated with the major proteins of the lens, the crystallins, and is particularly prominent in the lens nucleus (2, 3). Because there is little or no protein turnover in the lens nucleus (4), the proteins are as old as the individual. The post-translational modifications that result in crystallin coloration, therefore, accumulate throughout life and may eventually contribute to age-related nuclear cataract. The latter condition is characterized by a brown coloration of the lens nucleus and extensive protein oxidation (5, 6). The human lens also contains a family of Trp-derived UV filter compounds, of which 3-OHKG 1 is present at the highest concentration (Ϸ500 M) (7, 8). These UV filters are thought to play a protective role by preventing potentially damaging UV light from reaching the retina. Several investigators have considered the possibility that the UV filters could covalently modify lens crystallins with deleterious consequences, including alteration of protein conformation and increased sensitivity to UV light (9 -11). However, the mechanism leading to crystallin modification by 3-OHKG was not determined nor was there any evidence that 3-OHKG induces protein modification in vivo.We have recently elucidated a novel pathway that leads to the formation of a glutathione (GSH) adduct of 3-OHKG in the human lens (12). The GSH-3-OHKG adduct was formed via deamination of the 3-OHKG amino acid side chain to form an ␣, ␤-unsaturated carbonyl that was highly susceptible to nucleophilic attack by the cysteine of GSH (12). The aim of the present studies is to assess the relevance of analagous reactions in the modification of crystallins and also to probe for evidence of crystallin-3-OHKG adducts in human lenses. EXPERIMENTAL PROCEDURESMaterials-All organic solvents were HPLC grade (Ajax, Unichrom, Auburn, NSW, Australia). Poly-L-lysine was from Sigma, trifluoroacetic acid (Ͼ99% pure) was from Aldrich, and acetic acid (Ͼ99.8% pure) from BDH (Poole, UK). 3-hydroxykynurenine O-␤-D-glucoside (3-OHKG) and 2-amino-3-hydroxyacetopheno...

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Eye Lens Crystallins: Remarkable Long‐Lived Proteins

Grosas

Carver

2021

Long‐lived Proteins in Human Aging and Disease

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An Impediment to Glutathione Diffusion in Older Normal Human Lenses: a Possible Precondition for Nuclear Cataract

Cited by 211 publications

References 40 publications

Connexin 46 (Cx46) Gap Junctions Provide a Pathway for the Delivery of Glutathione to the Lens Nucleus

Connexin 46 (Cx46) Gap Junctions Provide a Pathway for the Delivery of Glutathione to the Lens Nucleus

Human Lens Coloration and Aging

Eye Lens Crystallins: Remarkable Long‐Lived Proteins

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