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Oxidative deoxyribonucleic acid damage in the eyes of glaucoma patients

      Abstract

      Background

      Little is known about the molecular mechanisms responsible for the development of glaucoma, the leading cause of irreversible blindness worldwide. Some investigators have hypothesized that oxidative damage may be involved. We evaluated oxidative deoxyribonucleic acid (DNA) damage, in terms of 8-hydroxy-2′-deoxyguanosine (8-OH-dG), in the eyes of glaucoma patients.

      Methods

      Levels of 8-OH-dG were measured in the trabecular meshwork region from 42 patients with glaucoma and 45 controls of similar age and sex. Genotypes of glutathione S-transferase isoenzymes (GSTM1 and GSTT1) were assessed by polymerase chain reaction in the same DNA samples.

      Results

      Levels of 8-OH-dG were significantly higher in glaucoma patients than in controls. Oxidative DNA damage in patients with glaucoma correlated significantly with intraocular pressure; in patients with primary open-angle glaucoma, it also correlated with visual field defects. GSTT1 was similar in the two groups, and had no effect on 8-OH-dG levels. Conversely, 8-OH-dG levels were significantly higher in GSTM1-null than in GSTM1-positive subjects. The GSTM1-null genotype was significantly more common in patients with primary open-angle glaucoma than in controls.

      Conclusion

      Oxidative DNA damage is significantly increased in the trabecular meshwork of glaucoma patients. GSTM1 gene deletion, which has been associated with an increased risk of cancer at various sites and molecular lesions in atherosclerosis, predisposes to more severe oxidative DNA damage in glaucoma patients. These findings may contribute to understanding the pathogenesis of glaucoma and may be useful in the prevention and treatment of this disease.
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      References

        • Goldberg I
        How common is glaucoma worldwide?.
        in: Weinreb R.N Kitazawa J Krieglestein G.K Glaucoma in the 21st Century. Mosby, Landau, Germany2000: 1-8
        • Quigley H.A
        The search for glaucoma genes—implications for pathogenesis and disease detection.
        N Engl J Med. 1998; 338: 1063-1064
        • Tomarev S.I
        Eyeing a new route along an old pathway.
        Nat Med. 2001; 7: 294-295
        • Wang N
        • Chintala S.K
        • Fini M.E
        • Schuman J.S
        Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype.
        Nat Med. 2001; 7: 304-309
        • Alward W.L.M
        • Fingert J.H
        • Coote M.A
        • et al.
        Clinical features associated with mutations in the chromosome 1 open angle glaucoma gene (GLC1A).
        N Engl J Med. 1998; 338: 1022-1027
        • Gugleta K
        • Orgul S
        • Flammer J
        Should and can vasospasms be treated?.
        in: Orgul S Flammer J Pharmaco-therapy in Glaucoma. Verlag Hans Huber, Bern, Switzerland2000: 197-206
        • Craig J.E
        • Mackey D.A
        Glaucoma genetics.
        Curr Opin Ophthalmol. 1999; 10: 126-134
        • Flammer J
        • Haefliger I.O
        • Orgul S
        • Resink T
        Vascular dysregulation.
        J Glaucoma. 1999; 8: 212-219
        • Alvarado J.A
        • Murphy C.G
        • Polansky J.R
        • Juster R
        Age-related changes in human trabecular meshwork cellularity.
        Invest Ophthalmol Vis Sci. 1981; 21: 714-727
        • Alvarado J.A
        • Murphy C.G
        • Juster R
        Trabecular meshwork cellularity in primary open-angle glaucoma and nonglaucomatous normals.
        Ophthalmology. 1984; 91: 564-579
        • Kahn M.G
        • Giblin F.J
        • Epstein D.L
        Glutathione in calf trabecular meshwork and its relation to aqueous humor outflow facility.
        Invest Ophthalmol Vis Sci. 1983; 24: 1283-1287
        • Zhou L
        • Li Y
        • Yue B.Y
        Oxidative stress affects cytoskeletal structure and cell-matrix interactions in cells from an ocular tissue.
        J Cell Physiol. 1999; 180: 182-189
        • Ko M.L
        • Hu D.N
        • Ritch R
        • Sharma S.C
        The combined effect of brain-derived neurotrophic factor and a free radical scavenger in experimental glaucoma.
        Invest Ophthalmol Vis Sci. 2000; 41: 2967-2971
        • Ames B.N
        • Gold L.S
        Endogenous mutagens and the causes of aging and cancer.
        Mutat Res. 1991; 250: 3-16
        • Seidegård J
        • Vorachek W.R
        • Pero R.W
        • Pearson W.R
        Hereditary differences in the expression of the human glutathione transferase active on tranS-stilbene oxide are due to a gene deletion.
        Proc Natl Acad Sci USA. 1988; 85: 7293-7297
        • Caprioli J
        Clinical evaluation of the optic nerve in glaucoma.
        Trans Am Ophthalmol Soc. 1994; 92: 589-641
        • Aulhorn E
        • Karmeyer H
        Frequency distribution in early glaucomatous visual field defects.
        Doc Ophthalmol. 1977; 14: 75-83
        • Saccà S.C
        • Rolando M
        • Marletta A
        • Macri A
        • Cerqueti P
        • Ciurlo G
        Fluctuations of intraocular pressure during the day in open-angle glaucoma, normal-tension glaucoma and normal subjects.
        Ophthalmologica. 1998; 212: 115-119
        • Asrani S
        • Zeimer R
        • Wilensky J
        • Gieser D
        • Vitale S
        • Lindenmuth K
        Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma.
        J Glaucoma. 2000; 9: 134-142
        • Izzotti A
        • Balansky R.M
        • D’Agostini F
        • et al.
        Modulation of biomarkers by chemopreventive agents in smoke-exposed rats.
        Cancer Res. 2001; 61: 2472-2479
        • Izzotti A
        • Cartiglia C
        • Taningher M
        • De Flora S
        • Balansky R
        Age-related increases of 8-hydroxy-2′-deoxyguanosine and DNA protein crosslinks in mouse organs.
        Mutat Res. 1999; 446: 215-223
        • Izzotti A
        • Orlando M
        • Gasparini L
        • et al.
        In vitro inhibition by N-acetylcysteine of oxidative DNA modifications detected by 32P-postlabeling.
        Free Radic Res. 1998; 28: 165-178
        • Izzotti A
        • Cartiglia C
        • Lewtas J
        • De Flora S
        Increased DNA alterations in atherosclerotic lesions of individuals lacking the GSTM1 genotype.
        FASEB J. 2001; 15: 752-757
        • Zhong S
        • Wyllie A.H
        • Barnes D
        • Wolf C.R
        • Spurr N.K
        Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer.
        Carcinogenesis. 1993; 14: 1821-1824
        • To-Figueras J
        • Gené M
        • Gòmez-Catàlan J
        • et al.
        Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms and lung cancer risk among Northwestern Mediterraneans.
        Carcinogenesis. 1997; 18: 1529-1533
        • Ritch R
        • Shields M.B
        • Krupin T
        Classifications of the glaucomas.
        in: Ritch R Shields M.B Krupin T The Glaucomas. 2nd ed. Mosby, St. Louis, MO1996: 717-725
        • Alvarado J.A
        • Murphy C.G
        Outflow obstruction in pigmentary and primary open angle glaucoma.
        Arch Ophthalmol. 1992; 110: 1769-1778
        • De Flora S
        • Izzotti A
        • Randerath K
        • et al.
        DNA adducts and chronic degenerative diseases. Pathogenetic relevance and implications in preventive medicine.
        Mutat Res. 1996; 366: 197-238
        • Schuler D
        • Ottender M
        • Sagelsdorff P
        • Eder E
        • Gupta R.C
        • Lutz W.K
        Comparative analysis of 8-oxo-2′-deoxyguanosine in DNA by 32P postlabelling and electrochemical detection.
        Carcinogenesis. 1997; 18: 2367-2371
        • Lutgerink J.T
        • de Graaf E
        • Hoebee B
        • Stavenuitez H.F.C
        • Westra J.G
        • Kriek E
        Detection of 8-hydroxyguanosine in small amounts by 32P postlabelling.
        Anal Biochem. 1992; 201: 127-133
        • Eaton J.W
        UV-mediated cataractogenesis.
        Doc Ophthalmol. 1994; 88: 233-242
        • Solberg Y
        • Rosner M
        • Belkin M
        The association between cigarette smoking and ocular diseases.
        Surv Ophthalmol. 1998; 42: 535-547
        • Lütjen-Drecoll E
        • Rohen J.W
        Morphology of aqueous outflow pathways in normal and glaucomatous eyes.
        in: Rich R Shields M.B Krupin T The Glaucomas. Mosby, St. Louis, MO1986: 89-123
        • Tschumper R.C
        • Johnson D.H
        Trabecular meshwork cellularity. Differences between fellow eyes.
        Invest Ophthalmol Vis Sci. 1990; 31: 1327-1331
        • Giblin F.J
        • McCready J.P
        • Kodama T
        • Reddy V.N
        A direct correlation between the levels of ascorbic acid and H2O2 in aqueous humor.
        Exp Eye Res. 1984; 38: 87-93
        • De la Paz M.A
        • Epstein D.L
        Effect of age on superoxide dismutase activity of human trabecular meshwork.
        Invest Ophthalmol Vis Sci. 1996; 37: 1849-1853
        • Richer S.P
        • Rose R.C
        Water soluble antioxidants in mammalian aqueous humor.
        Vision Res. 1998; 38: 2881-2888
        • Ketterer B
        • Harris J.M
        • Talaska G
        • et al.
        The human glutathione S-transferase supergene family, its polymorphism, and its effect on susceptibility to lung cancer.
        Environ Health Perspect. 1992; 98: 87-94
        • Coca Prados M
        • Escribano J
        • Ortego J
        Differential gene expression in the human ciliary epithelium.
        Prog Retin Eye Res. 1999; 18: 403-429
        • Nguyen K.P
        • Weiss H
        • Karageuzian L.N
        • Anderson P.J
        • Epstein D.L
        Glutathione reductase of calf trabecular meshwork.
        Invest Ophthalmol Vis Sci. 1985; 26: 887-890
        • Yang J
        • Tezel G
        • Patil R.V
        • Romano C
        • Wax M.B
        Serum autoantibody against glutathione S-transferase in patients with glaucoma.
        Invest Ophthalmol Vis Sci. 2001; 42: 1273-1276
        • Taningher M
        • Malacarne D
        • Izzotti A
        • Ugolini D
        • Parodi S
        Drug polymorphisms as modulators of cancer susceptibility.
        Mutat Res. 1999; 436: 227-261
        • De Flora S
        • Izzotti A
        • Walsh D
        • Degan P
        • Petrilli G.L
        • Lewtas J
        Molecular epidemiology of atherosclerosis.
        FASEB J. 1997; 11: 1021-1031