Document Detail


Physiological modeling of butadiene disposition in mice and rats.
MedLine Citation:
PMID:  11397397     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The earliest physiological models of 1,3-butadiene disposition reproduced uptake of the gas from closed chambers but over-predicted steady-state circulating concentrations of the mutagenic intermediates 1,2-epoxybut-3-ene and 1,2:3,4-diepoxybutane. A preliminary model based on the observation of a transient complex between cytochrome P450 and microsomal epoxide hydrolase on the endoplasmic reticulum membrane reproduced the blood epoxide concentrations as well as the chamber uptake data. This model was enhanced by the addition of equations for the production and detoxication of 3,4-epoxybutane-1,2-diol in the liver, lungs, and kidneys. The model includes flow-restricted delivery of butadiene and its metabolites to compartments for lungs, liver, fat, kidneys, gastrointestinal tract, other rapidly perfused tissues, and other slowly perfused tissues. Blood was distributed among compartments for arterial, venous, and tissue capillary spaces. Channeling of the three bound epoxides to epoxide hydrolase and their release from the endoplasmic reticulum are competing processes in this model. Parameters were estimated to fit data for chamber uptake of butadiene and epoxybutene, steady-state blood concentrations of epoxybutene and diepoxybutane, and the fractions of the inhaled dose of butadiene that appears as various excreted metabolites. The optimal values of the apparent K(m)s of membrane-bound epoxides for epoxide hydrolase were only 5% of the values for the cytosolic substrate, consistent with the observation of a transient complex between epoxide hydrolase and the cytochrome P450 that produces the epoxide. This proximity effect corresponds to the notion that epoxides produced in situ have privileged access to epoxide hydrolase. The model also predicts considerable accumulation of epoxybutanediol, in agreement with the observation that most of the DNA adducts in animals exposed to butadiene arise from this metabolite.
Authors:
M C Kohn; R L Melnick
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Chemico-biological interactions     Volume:  135-136     ISSN:  0009-2797     ISO Abbreviation:  Chem. Biol. Interact.     Publication Date:  2001 Jun 
Date Detail:
Created Date:  2001-06-08     Completed Date:  2001-12-04     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0227276     Medline TA:  Chem Biol Interact     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  285-301     Citation Subset:  IM    
Affiliation:
Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Mail Drop A3-06, Research Triangle Park, NC 27709, USA. kohn@valiant.niehs.nih.gov
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MeSH Terms
Descriptor/Qualifier:
Animals
Butadienes / chemistry,  metabolism*
Cytochrome P-450 Enzyme System / metabolism
DNA Adducts / metabolism
Epoxide Hydrolases / metabolism
Epoxy Compounds / metabolism
Kinetics
Male
Mice
Models, Biological
Oxidation-Reduction
Rats
Tissue Distribution
Chemical
Reg. No./Substance:
0/Butadienes; 0/DNA Adducts; 0/Epoxy Compounds; 106-99-0/1,3-butadiene; 9035-51-2/Cytochrome P-450 Enzyme System; 930-22-3/3,4-epoxy-1-butene; EC 3.3.2.-/Epoxide Hydrolases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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