Quantitative Investigation on the Metabolism of 1,3-Butadiene and of Its Oxidized Metabolites in Once-through Perfused Livers of Mice and Rats

Abstract

The industrial chemical 1,3-butadiene (BD) is a potent carcinogen in mice and a weak one in rats. This difference is generally related to species-specific burdens by the metabolites 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 3,4-epoxy-1,2-butanediol (EBD), which are all formed in the liver. Only limited data exist on BD metabolism in the rodent liver. Therefore, metabolism of BD, its epoxides, and the intermediate 3-butene-1,2-diol (B-diol) was studied in once-through perfused livers of male B6C3F1 mice and Sprague-Dawley rats. In BD perfusions, predominantly EB and B-diol were found (both species). DEB and EBD were additionally detected in mouse livers. Metabolism of BD showed saturation kinetics (both species). In EB perfusions, B-diol, EBD, and DEB were formed with B-diol being the major metabolite. Net formation of DEB was larger in mouse than in rat livers. In both species, hepatic clearance (Cl(H)) of EB was slightly smaller than the perfusion flow. In DEB perfusions, EBD was formed as a major metabolite. Cl(H) of DEB was 61% (mouse) and 73% (rat) of the perfusion flow. In the B-diol-perfused rat liver, EBD was formed as a minor metabolite. Cl(H) of B-diol was 53% (mouse) and 34% (rat) of the perfusion flow. In EBD-perfused rat livers, Cl(H) of EBD represented only 22% of the perfusion flow. There is evidence for qualitative species differences with regard to the enzymes involved in BD metabolism. The first quantitative findings in whole livers showing intrahepatic first-pass metabolism of BD and EB metabolites will improve the risk estimation of BD.

Use of Biomarker Data and Relative Potencies of Mutagenic Metabolites to Support Derivation of Cancer Unit Risk Values for 1,3-Butadiene from Rodent Tumor Data

“…BD is chemically inert, but is metabolized to several electrophilic epoxides that are capable of alkylating cellular macromolecules, to which the genotoxic and carcinogenic effects of BD are attributed (see Section 2.3 below). The metabolism of BD to reactive epoxide metabolites, including 2,3-epoxy-1-butene (EB), 1,2,3,4-diepoxybutane (DEB), and 3,4epoxybutane-1,2-diol (EBD), has been well studied in mice, rats, and humans (as reviewed in Himmelstein et al [16], Albertini et al [17], Kirman et al [18], Filser et al [19], which indicates that the metabolic pathways for BD are qualitatively similar, but exhibit large quantitative differences across species. Internal doses of these metabolites reflect pathways accounting for their formation (e.g., oxidation) as well as their clearance (e.g., hydrolysis, conjugation) as depicted in Figure 1.…”

“…In the effluent of mouse livers perfused with BD, all three epoxides (EB, DEB, and EBD) and BD-diol were observed, while in effluents from rat livers perfused with BD, only EB and BD-diol were detected. When the mouse and rat livers were perfused with EB, Filser et al [ 19 , 26 ] found that BD-diol, EBD, and DEB were formed, with BD-diol predominating in both species. DEB formation was greater in mouse than in rat livers [ 19 ].…”

“…When the mouse and rat livers were perfused with EB, Filser et al [ 19 , 26 ] found that BD-diol, EBD, and DEB were formed, with BD-diol predominating in both species. DEB formation was greater in mouse than in rat livers [ 19 ]. Following in vivo exposures of rats and mice to BD via inhalation, differences in circulating DEB levels have been reported to be over 100-fold greater in mice than in rats [ 27 , 28 , 29 ].…”