1,2,3,4-Diepoxybutane (DEB), an oxidant product of the carcinogen butadiene, has been shown to cause glutathione (GSH)-dependent enhanced base-pair substitution mutations in Salmonella typhimurium TA1535 (Chem. Res. Toxicol. 23, 1544 (2010)) and Escherichia coli TRG8 cells (Chem. Res. Toxicol. 25, 1522 (2012)). In order to define the role of GSH conjugation in the in vivo mutagenicity of DEB, Big Blue transgenic mice (?LIZ shuttle vector) were treated under the following conditions: corn oil (control), DEB, or butathione sulfoximine (BSO) prior to DEB (to decrease GSH levels). Treatment with BSO significantly decreased the levels of GSH in livers and kidneys (P < 0.0005). The cII mutant frequency in mice treated with DEB was higher than that in control (P < 0.0001). Further, the cII mutant frequency in mice treated with BSO prior to DEB was decreased to a similar extent as the GSH level (P < 0.01). These results, along with the strong enhancement of mutagenicity of DEB by GSH in bacterial assays, demonstrate the significance of the GSH-containing adducts. (Supported in part by USPHS grants R01 ES010546 and P30 ES000267)

In vivo mutagenicity of butadiene diepoxide-glutathione conjugate

246th National Meeting (2013)

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