Title: 3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice.

Authors: Wickliffe, J K; Galbert, L A; Ammenheuser, M M; Herring, S M; Xie, J; Masters 3rd, O E; Friedberg, E C; Lloyd, R S; Ward Jr, J B

Published In Environ Mol Mutagen, (2006 Jan)

Abstract: Xpc-null (Xpc-/-) mice, deficient in the global genome repair subpathway of nucleotide excision repair (NER-GGR), were exposed by intraperitoneal (i.p.) injection to a 300 mg/kg mutagenic dose of 3,4-epoxy-1-butene (EB), to investigate NER's potential role in repairing butadiene (BD) epoxide DNA lesions. Mutagenic sensitivity was assessed using the Hprt assay. Xpc-/- mice were significantly more sensitive to EB exposure, exhibiting an average 2.8-fold increase in Hprt mutant frequency (MF) relative to those of exposed Xpc+/+ (wild-type) mice. As a positive control for NER-GGR, additional mice were exposed by i.p. injection to a 150 mg/kg mutagenic dose of benzo[a]pyrene (B[a]P). The Xpc-/- mice had MFs 2.9-fold higher than those of exposed Xpc+/+ mice. These results suggest that NER-GGR plays a role in recognizing and repairing some of the DNA adducts formed following in vivo exposure to EB. Additional research is needed to examine the response of Xpc-/- mice, as well as other NER-deficient strains, to inhaled BD. Furthermore, it is likely that alternative DNA repair pathways also are involved in restoring genomic integrity compromised by BD-epoxide DNA damage. Collaborative studies are currently underway to address these critical issues.

PubMed ID: 16094661

MeSH Terms: Animals; Benzo(a)pyrene/toxicity; DNA Adducts*; DNA Repair; DNA-Binding Proteins/deficiency*; DNA-Binding Proteins/genetics; DNA/genetics; Epoxy Compounds/toxicity*; Genes, Reporter/genetics; Hypoxanthine Phosphoribosyltransferase/genetics*; Mice; Mice, Knockout; Mutagens/toxicity*; Mutation