Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: Role in mutagen sensitivity

Jarno Tuimala, Gabor Szekely, S. Gundy, Ari Hirvonen, Hannu Norppa

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Mutagen sensitivity, measuring the extent of chromosome damage induced by an in vitro treatment of peripheral lymphocytes with bleomycin, has been associated with an increased risk of various human cancers. Sensitivity to bleomycin appears to have high heritability and is usually considered to reflect individual capacity to repair DNA lesions. Another potential contributor to variation in bleomycin sensitivity could be inherited differences in the metabolism of bleomycin. We assessed whether genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes (XMEs) could explain bleomycin sensitivity. Frequencies of bleomycin-induced chromatid breaks per cell (b/c) were determined for 80 healthy Caucasians. Genotypes of DNA repair genes XRCC (X-ray repair cross-complementing) 1 and 3 and XME genes bleomycin hydrolase (BLHX), glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and N-acetyltransferase 2 (NAT2) were analyzed from leukocyte DNA using methods based on polymerase chain reaction. The mean number of chromatid b/c was increased in individuals with XRCC1 codon 280 variant allele (P = 0.002; two-sided Mann-Whitney test). Smokers carrying BLHX codon 1450 variant allele showed a decrease in the mean number of chromatid b/c (P = 0.036). In multiple linear regression models including adjustment for age, sex, smoking and genotype, the adjusted relative risks (and 95% confidence intervals) were 1.18 (0.98-1.41) and 0.84 (0.69-1.00) for carriers of XRCC1 codon 280 and BLHX codon 1450 variant alleles, respectively. XRCC1 codon 280 polymorphism had a significant effect (P = 0.012) in predetermining whether the individual was classified as non-sensitive, sensitive or hypersensitive to bleomycin. Although based on relatively few individuals, our results suggest that bleomycin sensitivity is partially explained by genetic polymorphisms affecting DNA repair (XRCC1) and in vitro metabolism of bleomycin (BLHX).

Original languageEnglish
Pages (from-to)1003-1008
Number of pages6
JournalCarcinogenesis
Volume23
Issue number6
Publication statusPublished - 2002

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Bleomycin
Mutagens
Xenobiotics
Genetic Polymorphisms
DNA Repair
Codon
Enzymes
Chromatids
Alleles
Linear Models
Genotype
Acetyltransferases
Genes
Leukocytes
Chromosomes
Smoking
X-Rays
Lymphocytes
Confidence Intervals
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research

Cite this

Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes : Role in mutagen sensitivity. / Tuimala, Jarno; Szekely, Gabor; Gundy, S.; Hirvonen, Ari; Norppa, Hannu.

In: Carcinogenesis, Vol. 23, No. 6, 2002, p. 1003-1008.

Research output: Contribution to journalArticle

Tuimala, J, Szekely, G, Gundy, S, Hirvonen, A & Norppa, H 2002, 'Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: Role in mutagen sensitivity', Carcinogenesis, vol. 23, no. 6, pp. 1003-1008.
Tuimala, Jarno ; Szekely, Gabor ; Gundy, S. ; Hirvonen, Ari ; Norppa, Hannu. / Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes : Role in mutagen sensitivity. In: Carcinogenesis. 2002 ; Vol. 23, No. 6. pp. 1003-1008.
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