Abstract
Polymorphisms in chemical metabolizing genes are known to influence individual susceptibility to environmental cancer. We investigated the role of GSTM1 and GSTT1 polymorphisms in modifying the genotoxicity of a tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) using the sister chromatid exchange (SCE), and the tandem-probe fluorescence in situ hybridization chromosome aberration (CA) assays. NNK (0.24, 0.72 or 1.44 mM) induced a significant concentration-dependent increase in the mean number of SCE regardless of genotypes. In comparing the effects between genotypes, significant increase was observed in GSTM1 null cells compared with GSTM1 positive cells only at the low concentration of NNK (0.24 mM). No significant difference was observed between cells with the null and positive GSTT1 genotypes. Using the CA assay, treatment with NNK (0.12, 0.24 or 0.72 mM) induced a significant concentration-dependent increase in the frequency of CA. In addition, cells with the null GSTM1 genotype had significantly increased CA compared with cells with GSTM1 positive genotype at the three concentrations of NNK. Regarding GSTT1 polymorphism, no significant effect was observed between the null and the positive genotypes. Treatment of the cells with 1 mM glutathione monoethyl ester (GSHME) significantly reduced NNK-induced CA in all cells regardless of their genotypes. The effect was clearly more evident in cells with the GSTM1 positive genotype. Therefore, GSHME is protective against NNK-induced CA with more dominant effect in cells with the GSTM1 positive genotype. Our study indicates that GSTM1 may influence NNK-induced genotoxicity and subsequent tobacco-related health effects.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 735-743 |
| Number of pages | 9 |
| Journal | Pharmacogenetics |
| Volume | 9 |
| Issue number | 6 |
| State | Published - 1999 |
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Keywords
- Chromosome aberrations
- FISH
- Genetic polymorphism
- Genetic susceptibility
- GSH
- GST
- Metabolism
- NNK
- Sister chromatid exchanges
ASJC Scopus subject areas
- Genetics
- Pharmacology, Toxicology and Pharmaceutics(all)
Cite this
Role of polymorphic GSTM1 and GSTT1 genotypes on NNK-induced genotoxicity. / Salama, S. A.; Abdel-Rahman, Sherif; Sierra-Torres, C. H.; Hamada, F. A.; Au, William W.
In: Pharmacogenetics, Vol. 9, No. 6, 1999, p. 735-743.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Role of polymorphic GSTM1 and GSTT1 genotypes on NNK-induced genotoxicity
AU - Salama, S. A.
AU - Abdel-Rahman, Sherif
AU - Sierra-Torres, C. H.
AU - Hamada, F. A.
AU - Au, William W.
PY - 1999
Y1 - 1999
N2 - Polymorphisms in chemical metabolizing genes are known to influence individual susceptibility to environmental cancer. We investigated the role of GSTM1 and GSTT1 polymorphisms in modifying the genotoxicity of a tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) using the sister chromatid exchange (SCE), and the tandem-probe fluorescence in situ hybridization chromosome aberration (CA) assays. NNK (0.24, 0.72 or 1.44 mM) induced a significant concentration-dependent increase in the mean number of SCE regardless of genotypes. In comparing the effects between genotypes, significant increase was observed in GSTM1 null cells compared with GSTM1 positive cells only at the low concentration of NNK (0.24 mM). No significant difference was observed between cells with the null and positive GSTT1 genotypes. Using the CA assay, treatment with NNK (0.12, 0.24 or 0.72 mM) induced a significant concentration-dependent increase in the frequency of CA. In addition, cells with the null GSTM1 genotype had significantly increased CA compared with cells with GSTM1 positive genotype at the three concentrations of NNK. Regarding GSTT1 polymorphism, no significant effect was observed between the null and the positive genotypes. Treatment of the cells with 1 mM glutathione monoethyl ester (GSHME) significantly reduced NNK-induced CA in all cells regardless of their genotypes. The effect was clearly more evident in cells with the GSTM1 positive genotype. Therefore, GSHME is protective against NNK-induced CA with more dominant effect in cells with the GSTM1 positive genotype. Our study indicates that GSTM1 may influence NNK-induced genotoxicity and subsequent tobacco-related health effects.
AB - Polymorphisms in chemical metabolizing genes are known to influence individual susceptibility to environmental cancer. We investigated the role of GSTM1 and GSTT1 polymorphisms in modifying the genotoxicity of a tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) using the sister chromatid exchange (SCE), and the tandem-probe fluorescence in situ hybridization chromosome aberration (CA) assays. NNK (0.24, 0.72 or 1.44 mM) induced a significant concentration-dependent increase in the mean number of SCE regardless of genotypes. In comparing the effects between genotypes, significant increase was observed in GSTM1 null cells compared with GSTM1 positive cells only at the low concentration of NNK (0.24 mM). No significant difference was observed between cells with the null and positive GSTT1 genotypes. Using the CA assay, treatment with NNK (0.12, 0.24 or 0.72 mM) induced a significant concentration-dependent increase in the frequency of CA. In addition, cells with the null GSTM1 genotype had significantly increased CA compared with cells with GSTM1 positive genotype at the three concentrations of NNK. Regarding GSTT1 polymorphism, no significant effect was observed between the null and the positive genotypes. Treatment of the cells with 1 mM glutathione monoethyl ester (GSHME) significantly reduced NNK-induced CA in all cells regardless of their genotypes. The effect was clearly more evident in cells with the GSTM1 positive genotype. Therefore, GSHME is protective against NNK-induced CA with more dominant effect in cells with the GSTM1 positive genotype. Our study indicates that GSTM1 may influence NNK-induced genotoxicity and subsequent tobacco-related health effects.
KW - Chromosome aberrations
KW - FISH
KW - Genetic polymorphism
KW - Genetic susceptibility
KW - GSH
KW - GST
KW - Metabolism
KW - NNK
KW - Sister chromatid exchanges
UR - http://www.scopus.com/inward/record.url?scp=0033408385&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033408385&partnerID=8YFLogxK
M3 - Article
C2 - 10634136
AN - SCOPUS:0033408385
VL - 9
SP - 735
EP - 743
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
SN - 1744-6872
IS - 6
ER -