3,4‐Epoxy‐1‐butene, a reactive metabolite of 1,3‐butadiene, induces somatic mutations in Xpc‐null mice

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.

Metabolite identification studies on amiodarone in in vitro (rat liver microsomes, rat and human liver S9 fractions) and in vivo (rat feces, urine, plasma) matrices by using liquid chromatography with high‐resolution mass spectrometry and multiple‐stage mass spectrometry: Characterization of the diquinone metabolite supposedly responsible for the drug's hepatotoxicity

“…The targeted ortho ‐diquinone metabolite was formed in all likelihood through the dihydrodiol intermediate, which was also observed in this study as metabolite M4. It is hypothesized that M4 itself was formed through an epoxide intermediate, which incidentally was not observed in our study, perhaps due to its rapid conversion into M4 or its highly reactive nature, which is a well‐known phenomenon for epoxides . The epoxide intermediate is thus shown in a dotted box in Fig.…”

“…It is hypothesized that M4 itself was formed through an epoxide intermediate, [44] which incidentally was not observed in our study, perhaps due to its rapid conversion into M4 or its highly reactive nature, which is a well-known phenomenon for epoxides. [45] The epoxide intermediate is thus shown in a dotted box in Fig. 14. Also, no para-dihydrodiol was observed, so the formation of para-diquinone is shown direct from the drug in the figure.…”

XPC: Going where no DNA damage sensor has gone before

“…Interestingly, knockdown of XPC, but not of XPA, in HeLa cells leads to mild sensitivity to etoposide, a topoisomerase II inhibitor known to cause double-strand breaks (DSBs) [59]. Moreover, XPC is involved in repair of butadiene epoxide induced DNA lesions through an unidentified pathway [60]. Also implicating XPC in DSB repair is increased XPC transcription in response to ionizing radiation and to cyanotoxin cylindrospermopsin [61, 62].…”

Nucleotide Excision Repair and Cancer

“…XPC functioning has been implied in other DNA repair pathways like base excision repair and non-homologous end joining or might be involved in redox homeostasis (D'Errico et al,2006;Despras et al,2007;Liu et al,2010;Okamoto et al,2008;Rezvani et al,2010;Shimizu et al,2003;Uehara et al,2009). Chemical exposures to B[a]P (Wickliffe et al,2006), 3,4-epoxy-1-butene (EB) (Wickliffe et al,2006), DMBA (Wijnhoven et al,2001) and UV-B (Ikehata et al,2007) also showed significantly enhanced mutant frequencies compared to wild type mice in several tissues. Direct comparisons to Xpa mice in these studies have not been made, however when Xpa and Xpc mice were exposed to pro-oxidants (DEHP and paraquat) for 39 weeks, Xpc again exhibited a higher mutant frequency than Xpa.…”