title: In vivo roles of conjugation with glutathione and O6-alkylguanine DNA-alkyltransferase in the mutagenicity of the bis-electrophiles 1,2-dibromoethane and 1,2,3,4-diepoxybutane in mice.
abstract: Several studies with bacteria and in vitro mammalian systems have provided evidence of the roles of two thiol-based conjugation systems, glutathione (GSH) transferase and O(6)-alkylguanine DNA-alkyltransferase (AGT), in the bioactivation of the bis-electrophiles 1,2-dibromoethane and 1,2,3,4-diepoxybutane (DEB), the latter an oxidation product of 1,3-butadiene. The in vivo relevance of these conjugation reactions to biological activity in mammals has not been addressed, particularly with DEB. In this work, we used transgenic Big Blue mice, utilizing the cII gene, to examine the effects of manipulation of conjugation pathways on liver mutations arising from dibromoethane and DEB in vivo. Treatment of the mice with butathionine sulfoxime (BSO) prior to dibromoethane lowered hepatic GSH levels, dibromoethane-GSH DNA adduct levels (N(7)-guanyl), and the cII mutation frequency. Administration of O(6)-benzylguanine (O(6)-BzGua), an inhibitor of AGT, did not change the mutation frequency. Depletion of GSH (BSO) and AGT (O(6)-BzGua) lowered the mutation frequency induced by DEB, and BSO lowered the levels of GSH-DEB N(7)-guanyl and N(6)-adenyl DNA adducts. Our results provide evidence that the GSH conjugation pathway is a major in vivo factor in dibromoethane genotoxicity; both GSH conjugation and AGT conjugation are major factors in the genotoxicity of DEB. The latter findings are considered to be relevant to the carcinogenicity of 1,3-butadiene.
authors.affiliation: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-0146, United States.
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Cho
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
mesh_terms: D000818:Animals; D002070:Butadienes / Q000737:chemistry / Q000633:toxicity; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000032:analysis; D004252:DNA Mutational Analysis; D004852:Epoxy Compounds / Q000737:chemistry* / Q000633:toxicity; D015946:Ethylene Dibromide / Q000737:chemistry* / Q000633:toxicity; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009152:Mutagenicity Tests; D009154:Mutation; D059645:Mutation Rate; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D002070:Butadienes; D018736:DNA Adducts; D004852:Epoxy Compounds; C064976:O(6)-benzylguanine; D015946:Ethylene Dibromide; D019328:Buthionine Sulfoximine; D006147:Guanine; C007366:diepoxybutane; D019853:O(6)-Methylguanine-DNA Methyltransferase; D005982:Glutathione Transferase; D005978:Glutathione; C031763:1,3-butadiene