The Hydroxyl Radical in Lens Nuclear Cataractogenesis

Fu, Shanlin; Dean, Roger T.; Southan, Michael; Truscott, Roger J.W.

doi:10.1074/jbc.273.44.28603

Cited by 161 publications

(107 citation statements)

References 53 publications

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“…diTyr may be produced via myeloperoxidase activity and its increase in complex lesions is consistent with a recent study showing increased numbers of myeloperoxidase-expressing macrophages in advanced, but not early, atherogenesis. 54 However an increase in the content of Tyr modification, particularly diTyr, appeared to be present in even early lesions compared to those values derived for normal iliac tissue, 21 normal aorta, 51 and normal LDL 55 (Table 5). Thus, our results do not exclude the possibility that specific Tyr modifications may be early disease events and that such oxidation could contribute to the initiation of atherogenesis.…”

Section: Discussionmentioning

confidence: 63%

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Upston

Niu

Brown

et al. 2002

The American Journal of Pathology

126

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Oxidative modification of low-density lipoprotein is thought to promote arterial lipid accumulation and atherogenesis. Previous studies reported on the presence of certain lipid or protein oxidation products in lesions, although a systematic investigation measuring several oxidation parameters and the accumulation of nonoxidized lipids and antioxidants at various stages of atherosclerosis has not been performed in the same tissue. Using the intimal lipoprotein-containing fraction of human aortic lesions, we demonstrate here that cholesterol accumulated with lesion development and that this increase was already significant at the fatty streak stage. By comparison, cholesterylesters increased significantly only in fibrofatty and more complex lesions that also contained significantly increased amounts of cholesterylester hydro(pero)xides and 27-hydroxycholesterol. Cholesterylester hydroxides were the major lipid oxidation product detected. Despite accumulation of oxidized lipid, ␣-tocopherol was also present and maintained at a comparable level over the disease process. Of the oxidized protein moieties measured only o,o-dityrosine increased with disease, although chlorotyrosines were present at relatively high levels in all lesions compared to healthy vessels. Our data show that accumulation of nonoxidized lipid precedes that of oxidized lipid in human aortic lesions. The development of atherosclerosis to clinical manifestations is a protracted process that spans several decades. It is well established that lipids, specifically cholesterol, accumulate as the disease progresses 1 and that these lipids are derived from plasma low-density lipoprotein (LDL). Aberrant uptake of LDL and its associated lipids by intimal monocytes that have infiltrated from the blood is believed to generate foam cells and thereby initiate atherosclerosis. 2 Foam cells are the hallmark of the fatty streak/early lesion from which the more advanced and complicated lesions derive. In advanced lesions, a fibrous cap is formed from collagen and a lipid-rich necrotic core. Vessel lumen narrowing because of the enlarged fibrous cap and plaque rupture lead to clinical manifestations.The definitive mechanisms leading to the initiation and development of atherosclerosis are unknown. However, retention of LDL in the vessel wall because of interaction and complex formation with extracellular matrix components is well-documented 3 and is thought to be important. Further, a bulk of evidence suggests that oxidative modifications to LDL contribute to its retention. 4 -6 Both arterial wall retention and oxidative modification of LDL are thought to contribute to foam cell formation.In vitro studies with plasma LDL have shown that oxidative modifications proceed in different stages and involve changes to LDL's antioxidants, lipids, and protein components. The nature and extent of these alterations vary depending on the type of oxidant involved, the oxidant to lipoprotein ratio used, and the extent to which oxidation is allowed to proceed. Originally 4 the pa...

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Section: Discussionmentioning

confidence: 63%

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Upston

Niu

Brown

et al. 2002

The American Journal of Pathology

126

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“…Preparation of Biological Samples for Analysis of Chlorinated Tyrosines-Samples of normal human iliac vessels and advanced carotid atherosclerotic plaques (54), of normal and stage IV cataractous human lenses (55), and of peritoneal abscesses from the mouse, were extracted to provide materials ready for protein hydrolysis. 4WT/BL and BALB/c mice were injected with 2 ϫ 10 7 colony-forming units/ml Escherichia coli, 5 ϫ 10 9 colony-forming units/ml Bacteroides fragilis, and 10 mg/ml bran (100 l per animal, intraperitoneal), as described in detail previously (56).…”

Section: Methodsmentioning

confidence: 99%

Reactions of Hypochlorous Acid with Tyrosine and Peptidyl-tyrosyl Residues Give Dichlorinated and Aldehydic Products in Addition to 3-Chlorotyrosine

Fu¹,

Wang²,

Davies³

et al. 2000

Journal of Biological Chemistry

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The toxicity of hypochlorous acid (HOCl) generated from activated neutrophils has been associated with several pathological processes such as atherosclerosis. Formation of 3-chlorotyrosine (Cl-Tyr) has been used as a marker for assessing the involvement of HOCl in such processes. In this study, we aimed to investigate the formation of Cl-Tyr from reaction of HOCl with tyrosine (both free and peptide-bound) and the fate of Cl-Tyr under such conditions. Tyrosine, N-acetyltyrosine, bovine serum albumin, and human low density lipoproteins were incubated with a range of reagent hypochlorite concentrations for varying periods in 10 mM phosphate buffer (pH 7.4) at 22°C. The reaction products, and several biological samples, were hydrolyzed (in the case of proteins), isolated, and purified by high pressure liquid chromatography and characterized or quantitated by mass spectrometry and NMR. A significant amount of 3,5-dichlorotyrosine (diCl-Tyr) was obtained from the bovine serum albumin, low density lipoprotein, and some biological samples, in addition to Cl-Tyr, indicating that Cl-Tyr competes effectively for HOCl even when tyrosine is present in great excess. Cl-Tyr and diCl-Tyr were also formed from free tyrosine but then reacted further with HOCl. This finding differs from a claim in the literature that Cl-Tyr was not formed in such a system. The further reaction products of ClTyr and diCl-Tyr with HOCl were elucidated as their corresponding mono-and dichlorinated 4-hydroxyphenylacetaldehydes. These results indicate the importance of assessing other products of HOCl action in addition to Cl-Tyr.

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“…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).…”

mentioning

confidence: 99%

Human Lens Coloration and Aging

Hood

Garner

Truscott

1999

Journal of Biological Chemistry

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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The Hydroxyl Radical in Lens Nuclear Cataractogenesis

Cited by 161 publications

References 53 publications

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis

Reactions of Hypochlorous Acid with Tyrosine and Peptidyl-tyrosyl Residues Give Dichlorinated and Aldehydic Products in Addition to 3-Chlorotyrosine

Human Lens Coloration and Aging

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