The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK

• Published in: Cancer letters Vol. 159; no. 1; pp. 63 - 71
• Main Authors: Abdel-Rahman, Sherif Z, El-Zein, Randa A
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 16-10-2000; Elsevier
• Subjects: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone; Adult; Alleles; Biological and medical sciences; Biomarkers; Cancer; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - pharmacology; Chemical agents; Cytogenetic; DNA - genetics; DNA Repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Dose-Response Relationship, Drug; Female; Gene Frequency; Genetic susceptibility; Genotoxicity; Genotype; Glutamine - genetics; Humans; Lymphocytes - cytology; Lymphocytes - drug effects; Lymphocytes - metabolism; Male; Medical sciences; Metabolism; Middle Aged; Nitrosamines - pharmacology; Polymorphism; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Sister Chromatid Exchange - drug effects; Sister chromatid exchanges; Smoking; Tumors; X-ray Repair Cross Complementing Protein 1; XRCC1; Genetic susceptibility; 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone; Genotoxicity; Cytogenetic; Biomarkers; XRCC1; Sister chromatid exchanges; Metabolism; DNA repair; Polymorphism; Cancer; Smoking; Human; Toxicity; Sister chromatid exchange; Nitrosamine; Genotype; Malignant tumor; Mutagen; Carcinogenesis; In vitro; Blood; Non smoker; Carcinogen; Tobacco; Gene; DNA; Predisposition; Genetics; Repair; Lymphocyte
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/S0304-3835(00)00532-2

DNA repair plays a critical role in protecting the genome of the cell from the insults of cancer-causing agents such as those found in tobacco smoke. Reduced DNA repair capacity would, therefore, constitute a significant risk factor for smoking-related cancers. Recently, a number of polymorphisms in several DNA repair genes have been discovered, and it is possible that these polymorphisms may affect DNA repair capacity and thus modulate cancer susceptibility in exposed populations. In the current study, we explored the relationship between two polymorphisms in the DNA repair gene
XRCC1 (polymorphisms in codons 194 and 399) and the genotoxic response induced by the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The sister chromatid exchange (SCE) assay was used as a marker of genetic damage. Our results, using whole blood cultures from 47 volunteers, indicated that treatment of cells with 0.24, 0.72 and 1.44 mM of NNK induced a concentration-dependent increase in the mean number of SCE (
P<0.001). There was a significant difference (
P<0.05) in response to NNK treatment between cells from individuals with the
399Gln allele (either homozygous or heterozygous) and cells from individuals with the homozygous 399
Arg/
Arg genotype. Treatment of cells that have the
399Gln allele with 0.24, 0.72 and 1.44 mM NNK resulted in 22.8, 35.8 and 52.8% increases in NNK-induced SCE, respectively. Treatment of cells with the 399
Arg/
Arg genotype using the same NNK concentrations resulted in 16.0, 15.5 and 32.6% increases in NNK-induced SCE, respectively. In contrast, no significant difference in NNK-induced SCE was observed between cells with the codon 194
Arg/
Arg genotype and cells with the codon 194
Arg/
Trp genotype at all concentrations of NNK tested. These data suggest that the Arg399Gln amino acid change may alter the phenotype of the XRCC1 protein, resulting in deficient DNA repair. Our study underscores the important role of polymorphisms in DNA repair genes in influencing the genotoxic responses to environmental mutagens, and justifies additional studies to investigate their potential role in susceptibility to cancer.