Induction of sister chromatid exchange by 1,2-epoxy-3-butene in cultured human lymphocytes: influence of GSTT1 genotype.
The influence of glutathione S-transferase T1 (GSTT1) genotype on the genotoxicity of 1,2-epoxy-3-butene (MEB), a metabolite of 1,3-butadiene, was assessed by the analysis of sister chromatid exchanges (SCEs) in 72-h human whole-blood lymphocyte cultures. The cultures were from 18 donors, representing both GSTT1 'positive' genotype (with at least one undeleted GSTT1 allele; GSTT1 activity present) and GSTT1 'null' genotype (homozygous deletion of the GSTT1 gene; no GSTT1 activity). As we have previously observed that allelism of glutathione S-transferase M1 (GSTM1) affects SCE induction by MEB in cultured lymphocytes, only individuals with the GSTM1 null genotype were included in this study. At 125 and 250 microM MEB (treatment at 24 h for 48 h), the mean frequencies of MEB-induced SCEs per cell (control level subtracted) were 4.5 (SD 1.8) and 8.9 (SD 1.0) for GSTT1 positive cell cultures (n = 13) and 5.3 (SD 1.2) and 12.5 (SD 1.1) for GSTT1 null cell cultures (n = 5) respectively, and the difference between the genotypes was statistically significant (P < 0.001) at the higher dose. All individual mean frequencies of SCEs induced by 250 microM MEB were higher in the GSTT1 null group (range 11.2-13.9) than in the GSTT1 positive group (range 7.2-10.8). The findings suggest that GSTT1, in addition to GSTM1, is involved in the detoxification of MEB in human whole-blood lymphocyte cultures. The deletion of the GSTT1 gene results in reduced erythrocytic detoxification capacity, thereby increasing the genotoxic effects of MEB.
Bernardini
S
S
Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki.
Hirvonen
A
A
Pelin
K
K
Norppa
H
H
D000704:Analysis of Variance; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000494:pharmacology*; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D009153:Mutagens / Q000494:pharmacology; D011110:Polymorphism, Genetic; D012854:Sister Chromatid Exchange / Q000187:drug effects*
D004852:Epoxy Compounds; D009153:Mutagens; C024370:3,4-epoxy-1-butene; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase