Carcinogenesis, Vol 19, 1879-1887, Copyright © 1998 by Oxford University Press
CJ Saranko, LJ Pluta and L Recio
1,3-Butadiene (BD) is a genotoxic carcinogen that is bioactivated to at
least two mutagenic metabolites: 1,2-epoxybutene (EB) and 1,2:3,4-
diepoxybutane (DEB). We reported previously that lacI transgenic mice
exposed to BD had an increased frequency of specific base substitution
mutations in the bone marrow and spleen relative to unexposed controls. In
the experiments described here, we determined the mutagenicity and
mutational spectrum of EB in Rat2 lacI transgenic fibroblasts as a means of
assessing the contribution of this metabolite to the lacI mutational
spectrum of BD. Rat2 cells were exposed to 0, 0.4, 0.6, 0.8 or 1.0 mM EB
for 24 h, resulting in a range of cell survival from 100 to 15%,
respectively. Mutagenicity was assessed at 0, 0.6 and 1.0 mM EB. Unexposed
controls had a background mutant frequency of 6 +/- 1 +/- 10(-5), while the
mutant frequency in cells exposed to 0.6 and 1.0 mM EB was increased 2- and
3-fold, respectively. DNA sequence analysis of 154 lacI mutants recovered
in these experiments revealed an increase in the frequency of specific base
substitution mutations in cells exposed to 1.0 mM EB compared with
controls. These included G:C-->A:T transitions at non-CpG sites,
G:C-->T:A transversions and A:T-->T:A transversions, which have all
been observed in lacI mutants isolated from transgenic mice exposed to BD.
These results suggest that EB causes mutation primarily by base
substitution and that the spectrum of these mutations closely resembles
that of BD. These data, along with previous findings from our laboratory,
suggest that EB is more likely than DEB to be primarily responsible for the
lacI mutational spectrum observed in lacI transgenic mice exposed to BD.
ARTICLES
Molecular analysis of lacI mutants from transgenic fibroblasts exposed to 1,2-epoxybutene
Department of Toxicology, North Carolina State University, Raleigh, USA.
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