Effect of the XRCC1 codon 399 polymorphism on the repair of vinyl chloride metabolite-induced DNA damage.
Li-Y; Long-C; Lin-G; Marion-MJ; Freyer-G; Santella-RM; Brandt-Rauf-PW
J Carcinog 2009 Oct; 8:14
Background: Recent epidemiologic evidence suggests that the common polymorphism at amino acid residue 399 of the x-ray cross complementing-1 (XRCC1) protein, a key component of the base excision repair (BER) pathway for DNA damage, plays a significant role in the genetic variability of individuals in terms of the mutagenic damage they experience following exposure to the carcinogen vinyl chloride (VC). The aim of this study was to provide support for the biological plausibility of these epidemiologic observations with experimental data derived from cell lines in culture from individuals who were either homozygous wild-type or homozygous variant for this XRCC1 polymorphism following exposure to chloroethylene oxide (CEO), the active metabolite of VC, with measurement of the induced etheno-DNA adducts before and after repair. Materials and Methods: Immortalized lymphoblast cell lines from seven VC workers (four homozygous wild-type and three homozygous variant for the 399 XRCC1 polymorphism) were exposed to CEO, and etheno-adenosine (eA) adduct levels were determined by enzyme-linked immunosorbent assay (ELISA) pre-exposure and at 0, 4, 8 and 24 h following exposure. Results: The average eA adduct levels were statistically significantly higher in the variant cells compared to the wild-type cells at 8 and 24 h following exposure (P<0.05) with an overall average repair efficiency of 32% in the variant cells compared to 82% in the wild-type cells. Conclusion: These results are consistent with the epidemiologic findings of the types of VC-induced biomarkers observed in exposed individuals and the mutational spectra found in the resultant tumors as well as the key role that BER, especially XRCC1, plays in this carcinogenic pathway.
Epidemiology; Amino-acids; Proteins; Genetics; Genetic-factors; Genes; Mutagens; Biological-effects; Exposure-levels; Statistical-analysis;
Author Keywords: Base excision repair; chloroethylene oxide; etheno adducts
Paul W Brandt-Rauf, School of Public Health, University of Illinois at Chicago, 1603 West Taylor Street, Room 1145, Chicago, IL 60612
Journal of Carcinogenesis
University of Illinois