Document Detail


Cytochrome P450 2E1 (CYP2E1) is essential for acrylonitrile metabolism to cyanide: comparative studies using CYP2E1-null and wild-type mice.
MedLine Citation:
PMID:  12124309     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Acrylonitrile (AN) is a rodent carcinogen and suspected human carcinogen. Metabolism of AN proceeds via conjugation with glutathione or epoxidation via cytochrome P4502E1 (CYP2E1) to cyanoethylene oxide (CEO). It was hypothesized that CEO metabolism via epoxide hydrolase (EH) is the primary pathway for cyanide formation. The objective of this work is to assess the enzymatic basis of metabolism to cyanide. Male wild-type and CYP2E1-null mice received 0, 2.5, 10, 20, or 40 mg of AN/kg by gavage, and cyanide was measured in blood and tissues. CYP2E1 and EH expression were assessed using Western blot analyses. Present results demonstrated that cyanide concentrations in blood and tissues of AN-treated wild-type mice were higher at 1 versus 3 h, increased in a dose-dependent manner, and were significantly higher in AN-treated versus vehicle-treated mice. In contrast, cyanide concentrations in the blood and tissues of AN-treated CYP2E1-null mice were not statistically different from those of vehicle-treated mice. Furthermore, this work showed that EH is expressed in CYP2E1-null and wild-type mice. In conclusion, under the current experimental conditions using CYP2E1-null mice, current work demonstrated for the first time that CYP2E1-mediated oxidation is a prerequisite for AN metabolism to cyanide. Since earlier studies showed that CYP2E1 is the only enzyme responsible for AN epoxidation, it is concluded that AN metabolism to CEO is a prerequisite for cyanide formation, and this pathway is exclusively catalyzed by CYP2E1. Finally, this work confirmed that cyanide plays an essential role in the causation of the acute toxicity/mortality of AN.
Authors:
Hongbing Wang; Brian Chanas; Burhan I Ghanayem
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  30     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2002 Aug 
Date Detail:
Created Date:  2002-07-18     Completed Date:  2003-01-27     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  911-7     Citation Subset:  IM    
Affiliation:
Laboratory of Pharmacology and Chemistry, Environmental Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
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MeSH Terms
Descriptor/Qualifier:
Acrylonitrile / metabolism*,  pharmacology
Acute Toxicity Tests
Animals
Cytochrome P-450 CYP2E1 / genetics,  metabolism*
Dose-Response Relationship, Drug
Epoxide Hydrolases / metabolism
Kidney / drug effects,  enzymology
Liver / enzymology
Lung / drug effects,  enzymology
Male
Mice
Mice, Mutant Strains
Microsomes / drug effects,  enzymology
Species Specificity
Tissue Distribution
Chemical
Reg. No./Substance:
107-13-1/Acrylonitrile; EC 1.14.14.1/Cytochrome P-450 CYP2E1; EC 3.3.2.-/Epoxide Hydrolases

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


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