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

Sherif Abdel-Rahman, Randa A. El-Zein

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Abstract

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. (C) 2000 Published by Elsevier Science Ireland Ltd.

Original languageEnglish (US)
Pages (from-to)63-71
Number of pages9
JournalCancer Letters
Volume159
Issue number1
DOIs
StatePublished - Oct 16 2000

Fingerprint

Nitrosamines
DNA Repair
Tobacco
Sister Chromatid Exchange
Lymphocytes
Genes
Genotype
Codon
Neoplasms
Alleles
DNA Repair-Deficiency Disorders
Mutagens
Therapeutics
Genetic Markers
Smoke
Volunteers
Smoking
Genome
Phenotype
Amino Acids

Keywords

  • 4-(Methylnitrosamino)-1-(3-pyridyl)-1- butanone
  • Biomarkers
  • Cancer
  • Cytogenetic
  • DNA repair
  • Genetic susceptibility
  • Genotoxicity
  • Metabolism
  • Polymorphism
  • Sister chromatid exchanges
  • Smoking
  • XRCC1

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology
  • Oncology

Cite this

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title = "The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK",
abstract = "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. (C) 2000 Published by Elsevier Science Ireland Ltd.",
keywords = "4-(Methylnitrosamino)-1-(3-pyridyl)-1- butanone, Biomarkers, Cancer, Cytogenetic, DNA repair, Genetic susceptibility, Genotoxicity, Metabolism, Polymorphism, Sister chromatid exchanges, Smoking, XRCC1",
author = "Sherif Abdel-Rahman and El-Zein, {Randa A.}",
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T1 - The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK

AU - Abdel-Rahman, Sherif

AU - El-Zein, Randa A.

PY - 2000/10/16

Y1 - 2000/10/16

N2 - 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. (C) 2000 Published by Elsevier Science Ireland Ltd.

AB - 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. (C) 2000 Published by Elsevier Science Ireland Ltd.

KW - 4-(Methylnitrosamino)-1-(3-pyridyl)-1- butanone

KW - Biomarkers

KW - Cancer

KW - Cytogenetic

KW - DNA repair

KW - Genetic susceptibility

KW - Genotoxicity

KW - Metabolism

KW - Polymorphism

KW - Sister chromatid exchanges

KW - Smoking

KW - XRCC1

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U2 - 10.1016/S0304-3835(00)00532-2

DO - 10.1016/S0304-3835(00)00532-2

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SP - 63

EP - 71

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

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