title: Influence of GSTM1, GSTT1, GSTP1, NAT1, NAT2, EPHX1, MTR and MTHFR polymorphism on chromosomal aberration frequencies in human lymphocytes.
abstract: We have studied the influence of genetic polymorphisms in the xenobiotic-metabolizing genes GSTM1, GSTP1, GSTT1, EPHX1, NAT1 and NAT2 and the folate-metabolizing genes MTR and MTHFR on the frequencies of cells with chromosomal aberrations (CAs) in peripheral lymphocytes of Norwegian men. Log-linear Poisson regression models were applied on 357 subjects of whom data on all the polymorphisms examined were available. Total CAs and chromosome-type aberrations (CSAs) were significantly increased by higher age alone, whereas chromatid-type aberrations (CTAs) were elevated by the GSTT1-null genotype and MTHFR codon 222 variant allele and chromatid gaps (CTGs) by EPHX1 high activity genotype and occupational exposure. Stratification by smoking and age (<40 and ≥40 years) showed that the effect of the GSTT1 null and EPHX1 high activity genotypes only concerned (older) smokers, in agreement with the roles of the respective enzymes in detoxification and metabolic activation. The MTHFR codon 222 variant allele was associated with high CTGs in smokers, the MTR codon 919 variant allele with high CTAs in older smokers and the NAT2 fast acetylator genotype with high CTGs in older subjects. Among younger nonsmokers, however, carriers of the MTHFR codon 222 and MTR codon 919 variant alleles showed a decrease in the level of CTGs and total CAs, respectively. In conclusion, polymorphisms of GSTT1, EPHX1, MTHFR, MTR and NAT2 differentially affect the frequency of CTAs, CSAs and CTGs, showing interaction with smoking and age. It appears that CA subtypes rather than total CAs should be considered in this type of studies.
authors.affiliation: Department of Laboratory Medicine, Section of Medical Genetics, Telemark Hospital, Skien, Norway. skcf@sthf.no
authors.forename: Camilla Furu
authors.initials: CF
authors.lastname: Skjelbred
authors.forename: Marit
authors.initials: M
authors.lastname: Svendsen
authors.forename: Vera
authors.initials: V
authors.lastname: Haugan
authors.forename: Anette Kildal
authors.initials: AK
authors.lastname: Eek
authors.forename: Kjell Oskar
authors.initials: KO
authors.lastname: Clausen
authors.forename: Elin H
authors.initials: EH
authors.lastname: Kure
authors.forename: Jarno T
authors.initials: JT
authors.lastname: Tuimala
authors.forename: Martin Veel
authors.initials: MV
authors.lastname: Svendsen
authors.forename: Hannu
authors.initials: H
authors.lastname: Norppa
authors.forename: Inger-Lise
authors.initials: IL
authors.lastname: Hansteen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D002869:Chromosome Aberrations; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D004851:Epoxide Hydrolases / Q000235:genetics*; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D016273:Occupational Exposure; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D012907:Smoking / Q000009:adverse effects; D050053:TRPM Cation Channels / Q000235:genetics*; D014166:Transferases / Q000235:genetics*; D055815:Young Adult
chemical_list: D001191:Arylamine N-Acetyltransferase; D004247:DNA; D004851:Epoxide Hydrolases; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D050053:TRPM Cation Channels; D014166:Transferases; C404409:TRPM5 protein, human; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human; C522330:EPHX1 protein, human