Mutational spectrum of 1,3-butadiene and metabolites 1,2-epoxybutene and 1,2,3,4-diepoxybutane to assess mutagenic mechanisms

1,3-Butadiene (BD) is a multisite carcinogen and is mutagenic in multiple t issues of B6C3F1 mice. BD is bioactivated to at least three directly mutage nic metabolites: 1,2-epoxy-butene (EB), 1.2-epoxy-3,4-butanediol (EBD), and 1,2,3,4-diepoxybutane (DEB). However, the contribution of these individual metabolites to the carcinogenicity and in vivo mutatidnal spectrum of BD i s uncertain. To assess the role of two BD metabolites EB and DEB in the in vivo mutagenicity of the parent compound BD. we examined the in vitro mutat ional spectra of EB and DEB in human and rodent cells, We also examined the in vivo mutagenicity and mutational spectrum of inhaled EB in the lung. In the bone marrow and spleen of B6C3F1 laci transgenic mice, BD-induced an i ncreased frequency of the identical class of point mutations at A:T base pa irs: AT --> GC transitions and AT --> TA transversions. BD exposure also in duced an increased frequency of GC --> AT transitions in the spleen that wa s not observed in bone marrow, demonstrating tissue-specific differences in mutation spectrum. Exposure of Rat2 laci transgenic cells and human TK6 ly mphoblasts to EB-induced an increased frequency of AT --> TA transversions. DEB exposure induced an increased frequency of AT --> TA transversions and partial deletions at hprt in human cells. In Rat laci transgenic cells, DE B was not mutagenic at laci but induced an increased frequency of micronucl ei. In contrast to inhaled BD, inhaled DEB and EB were not mutagenic in the bone marrow or spleen. However, EB was mutagenic in the lungs. In the lung of mice, EB-induced specific increases in GC --> AT transitions, AT --> TA transversions. and deletion events. AT --> TA transversions are the most c onsistent mutation observed across biological systems following in vivo exp osure to BD or in vitro exposures to EB and DEB. Although, BD exposure in m ice induces chromosomal alterations and single base substitutions, the spec ific BD metabolite that induces the genetic events leading to tumors is unc ertain. At present, it appears that only DEB can effectively induce this ra nge of mutagenic events at levels of this metabolite that occur in the bloo d of mice exposed to BD. Detailed investigations to identify relevant bioma rkers of BD exposure and response, particularly DNA adducts or lesions, tha t can be biologically linked to the range of genotoxic events known to occu r in mice exposed to BD are needed. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.