Abstract:
:In previous attempts to model disposition of 1,3-butadiene in mice and rats, parameter values for 1,2-epoxybut-3-ene metabolism were optimized to reproduce elimination of this gas from closed chambers. However, each of these models predicted much higher concentrations of circulating epoxybutene than were subsequently measured in animals exposed to butadiene. To account for this discrepancy, a previous physiologically based pharmacokinetic model of butadiene disposition was modified to describe a transient complex between cytochrome P450 and epoxide hydrolase on the endoplasmic reticulum membrane. In this model the epoxide products are directly transferred from the P450 to the epoxide hydrolase in competition with release of products into the cytosol. The model includes flow-restricted delivery of butadiene and epoxides to gastrointestinal tract, liver, lung, kidney, fat, other rapidly perfused tissues, and other slowly perfused tissues. Blood was distributed among compartments for arterial, venous, and capillary spaces. Oxidation of butadiene and epoxybutene and hydrolysis and glutathione conjugation of epoxides were included in liver, lung, and kidney. The model reproduces observed uptake of butadiene and epoxybutene from closed chambers by mice and rats and steady-state concentrations of butadiene, epoxybutene, and 1,2;3,4-diepoxybutane concentrations in blood of mice and rats exposed by nose only. Successful replication of these observations indicates that the proposed privileged access of epoxides formed in situ to epoxide hydrolase is a plausible mechanistic representation for the metabolic clearance of epoxide-forming chemicals.
journal_name
Environ Health Perspectjournal_title
Environmental health perspectivesauthors
Kohn MC,Melnick RLdoi
10.1289/ehp.00108s5911subject
Has Abstractpub_date
2000-10-01 00:00:00pages
911-7eissn
0091-6765issn
1552-9924pii
sc271_5_1835journal_volume
108 Suppl 5pub_type
杂志文章abstract::Organochlorines are persistent lipophilic compounds that accumulate in Inuit people living in circumpolar countries. Organochlorines accumulate as a result of the Inuits' large consumption of sea mammal fat; however, available data are limited to blood lipids, milk fat, and adipose tissue. We report results of organoc...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.99107823
更新日期:1999-10-01 00:00:00
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journal_title:Environmental health perspectives
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doi:10.1289/ehp.1104327
更新日期:2012-08-01 00:00:00
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journal_title:Environmental health perspectives
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doi:10.1289/ehp.9086239
更新日期:1990-06-01 00:00:00
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journal_title:Environmental health perspectives
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更新日期:1997-09-01 00:00:00
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更新日期:2010-11-01 00:00:00
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doi:10.1289/ehp.0901531
更新日期:2010-06-01 00:00:00
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journal_title:Environmental health perspectives
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更新日期:2012-02-01 00:00:00
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更新日期:2003-10-01 00:00:00
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更新日期:2009-10-01 00:00:00
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pub_type: 杂志文章
doi:10.1289/ehp.7786
更新日期:2005-06-01 00:00:00
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doi:10.1289/ehp.0900871
更新日期:2009-12-01 00:00:00
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更新日期:1984-04-01 00:00:00
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更新日期:1997-09-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章
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更新日期:2009-04-01 00:00:00
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更新日期:2016-12-01 00:00:00
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更新日期:1998-04-01 00:00:00
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更新日期:1983-02-01 00:00:00
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更新日期:2007-07-01 00:00:00
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pub_type: 杂志文章
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更新日期:1999-07-01 00:00:00
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更新日期:1998-04-01 00:00:00
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更新日期:2013-06-01 00:00:00
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pub_type: 杂志文章
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更新日期:2008-11-01 00:00:00