Quantitative investigation on the metabolism of 1,3-butadiene and of its oxidized metabolites in once-through perfused livers of mice and rats.
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.
Filser
Johannes G
JG
Institute of Toxicology, German Research Center for Environmental Health, Helmholtz Zentrum München, D-85764 Neuherberg, Germany. johannes.filser@helmholtz-muenchen.de
Bhowmik
Swati
S
Faller
Thomas H
TH
Hutzler
Christoph
C
Kessler
Winfried
W
Midpanon
Supatta
S
Pütz
Christian
C
Schuster
Andreas
A
Semder
Brigitte
B
Veereshwarayya
Vimal
V
Csanády
György A
GA
D000818:Animals; D002070:Butadienes / Q000493:pharmacokinetics*; D002273:Carcinogens / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests
D002070:Butadienes; D002273:Carcinogens; C031763:1,3-butadiene