TY - JOUR
T1 - Metabolism of 1,3-butadiene to toxicologically relevant metabolites in single-exposed mice and rats
AU - Filser, Johannes Georg
AU - Hutzler, Christoph
AU - Meischner, Veronika
AU - Veereshwarayya, Vimal
AU - Csanády, György András
N1 - Funding Information:
The authors thank Mr. Christian Pütz for his excellent technical assistance and Dr. Judith Baldwin for the quality assurance reviews. Financial support of the American Chemistry Council is gratefully acknowledged.
PY - 2007/3/20
Y1 - 2007/3/20
N2 - 1,3-Butadiene (BD) was carcinogenic in rodents. This effect is related to reactive metabolites such as 1,2-epoxy-3-butene (EB) and especially 1,2:3,4-diepoxybutane (DEB). A third mutagenic epoxide, 3,4-epoxy-1,2-butanediol (EBD), can be formed from DEB and from 3-butene-1,2-diol (B-diol), the hydrolysis product of EB. In BD exposed rodents, only blood concentrations of EB and DEB have been published. Direct determinations of EBD and B-diol in blood are missing. In order to investigate the BD-dependent blood burden by all of these metabolites, we exposed male B6C3F1 mice and male Sprague-Dawley rats in closed chambers over 6-8 h to constant atmospheric BD concentrations. BD and exhaled EB were measured in chamber atmospheres during the BD exposures. EB blood concentrations were obtained as the product of the atmospheric EB concentration at steady state with the EB blood-to-air partition coefficient. B-diol, EBD, and DEB were determined in blood collected immediately at the end of BD exposures up to 1200 ppm (B-diol, EBD) and 1280 ppm (DEB). Analysis of BD was done by GC/FID, of EB, DEB, and B-diol by GC/MS, and of EBD by LC/MS/MS. EB blood concentrations increased with BD concentrations amounting to 2.6 μmol/l (rat) and 23.5 μmol/l (mouse) at 2000 ppm BD and to 4.6 μmol/l in rats exposed to 10000 ppm BD. DEB (detection limit 0.01 μmol/l) was found only in blood of mice rising to 3.2 μmol/l at 1280 ppm BD. B-diol and EBD were quantitatively predominant in both species. B-diol increased in both species with the BD exposure concentration reaching 60 μmol/l at 1200 ppm BD. EBD reached maximum concentrations of 9.5 μmol/l at 150 ppm BD (rat) and of 42 μmol/l at 300 ppm BD (mouse). At higher BD concentrations EBD blood concentrations decreased again. This picture probably results from a competitive inhibition of the EBD producing CYP450 by BD, which occurs in both species.
AB - 1,3-Butadiene (BD) was carcinogenic in rodents. This effect is related to reactive metabolites such as 1,2-epoxy-3-butene (EB) and especially 1,2:3,4-diepoxybutane (DEB). A third mutagenic epoxide, 3,4-epoxy-1,2-butanediol (EBD), can be formed from DEB and from 3-butene-1,2-diol (B-diol), the hydrolysis product of EB. In BD exposed rodents, only blood concentrations of EB and DEB have been published. Direct determinations of EBD and B-diol in blood are missing. In order to investigate the BD-dependent blood burden by all of these metabolites, we exposed male B6C3F1 mice and male Sprague-Dawley rats in closed chambers over 6-8 h to constant atmospheric BD concentrations. BD and exhaled EB were measured in chamber atmospheres during the BD exposures. EB blood concentrations were obtained as the product of the atmospheric EB concentration at steady state with the EB blood-to-air partition coefficient. B-diol, EBD, and DEB were determined in blood collected immediately at the end of BD exposures up to 1200 ppm (B-diol, EBD) and 1280 ppm (DEB). Analysis of BD was done by GC/FID, of EB, DEB, and B-diol by GC/MS, and of EBD by LC/MS/MS. EB blood concentrations increased with BD concentrations amounting to 2.6 μmol/l (rat) and 23.5 μmol/l (mouse) at 2000 ppm BD and to 4.6 μmol/l in rats exposed to 10000 ppm BD. DEB (detection limit 0.01 μmol/l) was found only in blood of mice rising to 3.2 μmol/l at 1280 ppm BD. B-diol and EBD were quantitatively predominant in both species. B-diol increased in both species with the BD exposure concentration reaching 60 μmol/l at 1200 ppm BD. EBD reached maximum concentrations of 9.5 μmol/l at 150 ppm BD (rat) and of 42 μmol/l at 300 ppm BD (mouse). At higher BD concentrations EBD blood concentrations decreased again. This picture probably results from a competitive inhibition of the EBD producing CYP450 by BD, which occurs in both species.
KW - 1,2-Epoxy-3-butene
KW - 1,2:3,4-Diepoxybutane
KW - 1,3-Butadiene
KW - 3,4-Epoxy-1,2-butanediol
KW - 3-Butene-1,2-diol
KW - Inhalation
KW - Mouse
KW - Rat
UR - http://www.scopus.com/inward/record.url?scp=33947105963&partnerID=8YFLogxK
U2 - 10.1016/j.cbi.2006.03.002
DO - 10.1016/j.cbi.2006.03.002
M3 - Article
C2 - 16616907
AN - SCOPUS:33947105963
SN - 0009-2797
VL - 166
SP - 93
EP - 103
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
IS - 1-3
ER -