title: Hemoglobin adducts and micronuclei in rodents after treatment with isoprene monoxide or butadiene monoxide.
abstract: 1,3-Butadiene and isoprene (2-methyl-1,3-butadiene) are chemically related substances that are carcinogenic to rodents. The overall aim of this work is to elucidate the role of the genotoxic action of diepoxide metabolites in the carcinogenesis of the dialkenes. In vivo doses of the diepoxide metabolites were measured through reaction products with hemoglobin (Hb adducts) in studies of induced micronuclei (MN) in rodents. In the reaction with N-terminal valine in Hb, diepoxybutane and isoprenediepoxide form ring-closed adducts, pyrrolidines [N,N-(2,3-dihydroxy-1,4-butadiyl)valine and N,N-(2,3-dihydroxy-2-methyl-1,4-butadiyl)valine, respectively]. The method applied for Hb-adduct measurement is based on tryptic degradation of the protein and liquid chromatography electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS) analysis. Mice were given single i.p. injections of the monoepoxides of butadiene and isoprene, 1,2-epoxy-3-butene or 1,2-epoxy-2-methyl-3-butene, respectively. Rats were treated in the same way with 1,2-epoxy-3-butene. In mice pyrrolidine adduct levels increased with increasing administered doses of the monoepoxides. The in vivo dose of diepoxybutane was on average twice as high (0.29+/-0.059 mMh) as the in vivo dose of isoprenediepoxide (0.15+/-0.053 mMh) per administered dose (mmol/kg body weight) of the monoepoxides. In mice the genotoxic effects of the two monoepoxides, measured as the increase in the frequencies of micronuclei (MN), were approximately linearly correlated to the in vivo doses of the diepoxides (except at the highest dose of diepoxybutane). In rats the pyrrolidine-adduct levels from diepoxybutane were below the limit of quantification at all administered doses of 1,2-epoxy-3-butene and no significant increase was observed in the frequency of MN. Measurement of the ring-closed adducts to N-termini in Hb by the applied method permits analysis of in vivo doses of diepoxybutane and isoprenediepoxide, which may be further used for the elucidation of the mechanisms of carcinogenesis of butadiene and isoprene.
authors.affiliation: Department of Environmental Chemistry, Stockholm University, SE-106 91 Stockholm, Sweden.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Fred
authors.forename: Jan
authors.initials: J
authors.lastname: Grawé
authors.forename: Margareta
authors.initials: M
authors.lastname: Törnqvist
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D002070:Butadienes / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects; D045782:Hemiterpenes / Q000378:metabolism / Q000633:toxicity*; D006454:Hemoglobins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048629:Micronuclei, Chromosome-Defective; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity; D010420:Pentanes / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002070:Butadienes; D004852:Epoxy Compounds; D045782:Hemiterpenes; D006454:Hemoglobins; D009153:Mutagens; D010420:Pentanes; C503271:isoprene monoxide; C005059:isoprene; C024370:3,4-epoxy-1-butene