Epoxide hydrolase-dependent metabolism of butadiene monoxide to 3-butene-1,2-diol in mouse, rat, and human liver.
Incubations of butadiene monoxide (BMO) with mouse, rat, and human liver microsomes or cDNA-expressed human microsomal epoxide hydrolase led to 3-buten-1,2-diol (BDD) detection; the BDD peak exhibited a GC/MS fragmentation pattern similar to that of reference material. Incubations with rat liver cytosol did not lead to BDD detection; however, when mouse or human liver cytosol was used, BDD was detected but at levels lower than those detected with the liver microsomes. The catalytic efficiency (V(max)/K(m) ratio) of BDD formation in rat liver microsomes was nearly 3-fold higher than the ratio obtained with mouse liver microsomes. Among two human liver microsomal samples, one sample exhibited a ratio that was nearly 3-fold higher than that of rat liver microsomes, and the second sample exhibited a ratio that was similar to that of rat liver microsomes. Although these results suggest epoxide hydrolases may play a role in BMO metabolism in vivo, rats and mice given BMO (71.3-285 micromol/kg) excreted <1% of the dose as BDD into urine within 24 hr. Thus, further studies into the role of epoxide hydrolases in BMO metabolism and disposition and the fate of BDD are warranted.
Krause
R J
RJ
Department of Comparative Biosciences and Environmental Toxicology Center, University of Wisconsin-Madison 53706, USA.
Sharer
J E
JE
Elfarra
A A
AA
D000293:Adolescent; D000328:Adult; D000818:Animals; D004851:Epoxide Hydrolases / Q000378:metabolism*; D004852:Epoxy Compounds / Q000493:pharmacokinetics*; D006018:Glycols / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004852:Epoxy Compounds; D006018:Glycols; C024370:3,4-epoxy-1-butene; D004851:Epoxide Hydrolases; C034598:3-butene-1,2-diol