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Interindividual Variability in Response to Sodium Dichromate–Induced Oxidative DNA Damage: Role of the Ser³²⁶Cys Polymorphism in the DNA-Repair Protein of 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine DNA Glycosylase 1

School of Biosciences, The University of Birmingham, Birmingham, United Kingdom

Requests for reprints: Nikolas J. Hodges, School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 121-4145422; Fax: 121-4145925. E-mail: N.Hodges{at}bham.ac.uk

Although the genotoxic mechanism(s) of hexavalent chromium (CrVI) carcinogenicity remain to be fully elucidated, intracellular reduction of CrVI and concomitant generation of reactive intermediates including reactive oxygen species and subsequent oxidative damage to DNA is believed to contribute to the process of carcinogenesis. In the current study, substantial interindividual variation (7.19-25.84% and 8.79-34.72% tail DNA as assessed by conventional and FPG-modified comet assay, respectively) in levels of DNA strand breaks after in vitro treatment of WBC with sodium dichromate (100 µmol/L, 1 hour) was shown within a group of healthy adult volunteers (n = 72) as assessed by both comet and formamidopyrimidine glycosylase–modified comet assays. No statistically significant correlation between glutathione S-transferases M1 or T1, NADPH quinone oxidoreductase 1 (codon 187) and X-ray repair cross complementation factor 1 (codon 194) genotypes and individual levels of DNA damage were observed. However, individuals homozygous for the Cys³²⁶ 8-oxo 7,8-dihydro-2'-deoxyguanosine glycosylase 1 (OGG1) polymorphism had a statistically significant elevation of formamidopyrimidine glycosylase–dependent oxidative DNA damage after treatment with sodium dichromate when compared with either Ser³²⁶/Ser³²⁶ or Ser³²⁶/Cys³²⁶ individuals (P = 0.008 and P = 0.003, respectively). In contrast, no effect of OGG1 genotype on background levels of oxidative DNA damage was observed. When individuals were divided on the basis of OGG1 genotype, Cys³²⁶/Cys³²⁶ individuals had a statistically significant (P < 0.05, one-way ANOVA followed by Tukey test) higher ratio of oxidative DNA damage to plasma antioxidant capacity than either Ser³²⁶/Ser³²⁶ or Ser³²⁶/Cys³²⁶ individuals. The results of this study suggest that the Cys³²⁶/Cys³²⁶ OGG1 genotype may represent a phenotype that is deficient in the repair of 8-oxo-7,8-dihydro-2'-deoxyguanosine, but only under conditions of cellular oxidative stress. We hypothesize that this may be due to oxidation of the Cys³²⁶ residue. In conclusion, the homozygous Cys³²⁶ genotype may represent a biomarker of individual susceptibility of lung cancer risk in individuals that are occupationally exposed to CrVI.

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