title: Analysis of diepoxide-specific cyclic N-terminal globin adducts in mice and rats after inhalation exposure to 1,3-butadiene.
abstract: 1,3-Butadiene is an important industrial chemical used in the production of synthetic rubber and is also found in gasoline and combustion products. It is a multispecies, multisite carcinogen in rodents, with mice being the most sensitive species. 1,3-Butadiene is metabolized to several epoxides that form DNA and protein adducts. Previous analysis of 1,2,3-trihydroxybutyl-valine globin adducts suggested that most adducts resulted from 3-butene-1,2-diol metabolism to 3,4-epoxy-1,2-butanediol, rather than from 1,2;3,4-diepoxybutane. To specifically examine metabolism of 1,3-butadiene to 1,2;3,4-diepoxybutane, the formation of the 1,2;3,4-diepoxybutane-specific adduct N,N-(2,3-dihydroxy-1,4-butadiyl)-valine was evaluated in mice treated with 3, 62.5, or 1250 ppm 1,3-butadiene for 10 days and rats exposed to 3 or 62.5 ppm 1,3-butadiene for 10 days, or to 1000 ppm 1,3-butadiene for 90 days, using a newly developed immunoaffinity liquid chromatography tandem mass spectrometry assay. In addition, 2-hydroxy-3-butenyl-valine and 1,2,3-trihydroxybutyl-valine adducts were determined. The analyses of several adducts derived from 1,3-butadiene metabolites provided new insight into species and exposure differences in 1,3-butadiene metabolism. Mice formed much higher amounts of N,N-(2,3-dihydroxy-1,4-butadiyl)-valine than rats. The formation of 2-hydroxy-3-butenyl-valine and N,N-(2,3-dihydroxy-1,4-butadiyl)-valine was similar in mice exposed to 3 or 62.5 ppm 1,3-butadiene, whereas 2-hydroxy-3-butenyl-valine was 3-fold higher at 1250 ppm. In both species, 1,2,3-trihydroxybutyl-valine adducts were much higher than 2-hydroxy-3-butenyl-valine and N,N-(2,3-dihydroxy-1,4-butadiyl)-valine. Together, these data show that 1,3-butadiene is primarily metabolized via the 3-butene-1,2-diol pathway, but that mice are much more efficient at forming 1,2;3,4-diepoxybutane than rats, particularly at low exposures. This assay should also be readily adaptable to molecular epidemiology studies on 1,3-butadiene-exposed workers.
authors.affiliation: Department of Environmental Sciences and Engineering, School of Public Health, The University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Boysen
authors.forename: Nadia I
authors.initials: NI
authors.lastname: Georgieva
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Upton
authors.forename: Karupiah
authors.initials: K
authors.lastname: Jayaraj
authors.forename: Yutai
authors.initials: Y
authors.lastname: Li
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Walker
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002070:Butadienes / Q000378:metabolism* / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D002853:Chromatography, Liquid; D004852:Epoxy Compounds / Q000378:metabolism*; D005260:Female; D005914:Globins / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D019570:Inhalation Exposure; D013058:Mass Spectrometry; D051379:Mice; D011759:Pyrrolidines / Q000032:analysis / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D014633:Valine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism
chemical_list: D002070:Butadienes; D002273:Carcinogens; D004852:Epoxy Compounds; C101917:N,N-(2,3-dihydroxybuta-1,4-diyl)valine; D011759:Pyrrolidines; C007366:diepoxybutane; D005914:Globins; D014633:Valine; C031763:1,3-butadiene