MUTAGENICITY OF BUTADIENE AND ITS EPOXIDE METABOLITES .2. MUTATIONAL SPECTRA OF BUTADIENE, 1,2-EPOXYBUTENE AND DIEPOXYBUTANE AT THE HPRT LOCUS IN SPLENIC T-CELLS FROM EXPOSED B6C3F1 MICE

The mutagenic potential and mutational spectra of butadiene (BD), 1,2- epoxybutene (EB), and diepoxybutane (DEB) were determined in splenic T cells from exposed B6C3F1 mice. Mice exposed by inhalation to 625 p.p .m. BD for 2 weeks displayed an average hprt(-) mutation frequency of 6.2 x 10(-6) compared to 1.2x10(-6) in controls. Mice were also given three daily i.p. doses of 60, 80 and 100 nag EB/kg or 7, 14 and 21 mg DEB/kg. Average hprt(-) frequencies of 5.4 x 10(-6) 4.1x10(-6) and 8.6 x10(-6) were seen in the EB groups, respectively, while average freque ncies of 4.6x10(-6) 9.4x10(-6) and 13x10(-6) were seen in the DEB grou ps. DNA sequencing revealed that approximately half of the mutations i nduced in vivo by BD, EB and DEB were frameshift mutations. A +1 frame shift 'hotspot' in six consecutive guanine bases in exon 3 was observe d with all three compounds. The remaining mutations produced by BD, EB and DEB were transition and transversion mutations at both AT and GC base pairs. Base pair substitutions induced by BD were biased in favor of mutation at AT base pairs. The mutational spectra produced by BD, EB and DEB were very similar to that observed previously with ethylene oxide, suggesting that these epoxide agents may be working through a similiar mutagenic mechanism.