The L84F and the I143V polymorphisms in the O6-methylguanine- DNA-methyltransferase (MGMT) gene increase human sensitivity to the genotoxic effects of the tobacco-specific nitrosamine carcinogen NNK

Courtney E. Hill, Jeffrey K. Wickliffe, Kevin J. Wolfe, Carla J. Kinslow, Mirtha S. Lopez, Sherif Abdel-Rahman

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

O6-Methylguanine-DNA-methyltransferase (MGMT) is a direct-reversal DNA repair protein that removes DNA adducts formed by alkylating mutagens found in tobacco smoke. Several coding single nucleotide polymorphisms (cSNPs) in the MGMT gene have been reported. However, their effect on the levels and types of genetic damage induced by specific environmental carcinogens remains to be fully elucidated. We developed two novel genotyping techniques and used them, in conjunction with the mutagen-sensitivity assay, to test the hypothesis that the L84F and I143V cSNPs in the MGMT gene confer increased sensitivity to genetic damage induced by the alkylating tobacco-specific nitrosamine carcinogen NNK. Lymphocytes from 114 healthy volunteers were exposed in vitro to NNK, and the genotoxic response was assessed by measuring chromosome aberration (CA) frequencies. A significant (P < 0.02) increase in NNK-induced CA was observed in cells from individuals with the 84F polymorphism compared to cells from individuals homozygous for the referent L84 allele. A significant positive interaction between this cSNP and smoking, gender and age was observed (P < 0.03). In subjects with the variant 143V allele, significantly higher levels of NNK-induced CA were observed in males and in young subjects (< 43 years old) compared to subjects homozygous for the referent I143 allele (P < 0.02). Individuals who inherited two cSNPs had significantly higher levels of NNK-induced CA compared to individuals with none or with one cSNP (P < 0.002). These new data suggest that the 84F and 143V cSNPs may alter the function characteristics of the MGMT protein, resulting in suboptimal repair of genetic damage induced by NNK.

Original languageEnglish (US)
Pages (from-to)571-578
Number of pages8
JournalPharmacogenetics and Genomics
Volume15
Issue number8
StatePublished - Aug 2005

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Nitrosamines
Methyltransferases
Carcinogens
Tobacco
Single Nucleotide Polymorphism
Chromosome Aberrations
DNA
Genes
Alleles
Mutagens
Genotyping Techniques
Protein Methyltransferases
Environmental Carcinogens
DNA Adducts
Smoke
DNA Repair
O-(6)-methylguanine
Healthy Volunteers
Smoking
Lymphocytes

Keywords

  • Alkyltransferase
  • Biomarkers
  • Cancer
  • Cytogenetics
  • DNA repair
  • MGMT
  • Mutagen sensitivity
  • NNK
  • Polymorphism
  • Smoking

ASJC Scopus subject areas

  • Genetics
  • Pharmacology

Cite this

The L84F and the I143V polymorphisms in the O6-methylguanine- DNA-methyltransferase (MGMT) gene increase human sensitivity to the genotoxic effects of the tobacco-specific nitrosamine carcinogen NNK. / Hill, Courtney E.; Wickliffe, Jeffrey K.; Wolfe, Kevin J.; Kinslow, Carla J.; Lopez, Mirtha S.; Abdel-Rahman, Sherif.

In: Pharmacogenetics and Genomics, Vol. 15, No. 8, 08.2005, p. 571-578.

Research output: Contribution to journalArticle

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abstract = "O6-Methylguanine-DNA-methyltransferase (MGMT) is a direct-reversal DNA repair protein that removes DNA adducts formed by alkylating mutagens found in tobacco smoke. Several coding single nucleotide polymorphisms (cSNPs) in the MGMT gene have been reported. However, their effect on the levels and types of genetic damage induced by specific environmental carcinogens remains to be fully elucidated. We developed two novel genotyping techniques and used them, in conjunction with the mutagen-sensitivity assay, to test the hypothesis that the L84F and I143V cSNPs in the MGMT gene confer increased sensitivity to genetic damage induced by the alkylating tobacco-specific nitrosamine carcinogen NNK. Lymphocytes from 114 healthy volunteers were exposed in vitro to NNK, and the genotoxic response was assessed by measuring chromosome aberration (CA) frequencies. A significant (P < 0.02) increase in NNK-induced CA was observed in cells from individuals with the 84F polymorphism compared to cells from individuals homozygous for the referent L84 allele. A significant positive interaction between this cSNP and smoking, gender and age was observed (P < 0.03). In subjects with the variant 143V allele, significantly higher levels of NNK-induced CA were observed in males and in young subjects (< 43 years old) compared to subjects homozygous for the referent I143 allele (P < 0.02). Individuals who inherited two cSNPs had significantly higher levels of NNK-induced CA compared to individuals with none or with one cSNP (P < 0.002). These new data suggest that the 84F and 143V cSNPs may alter the function characteristics of the MGMT protein, resulting in suboptimal repair of genetic damage induced by NNK.",
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T1 - The L84F and the I143V polymorphisms in the O6-methylguanine- DNA-methyltransferase (MGMT) gene increase human sensitivity to the genotoxic effects of the tobacco-specific nitrosamine carcinogen NNK

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AU - Wickliffe, Jeffrey K.

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AU - Abdel-Rahman, Sherif

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