Document Detail


Up-regulation of human CYP2J2 in HepG2 cells by butylated hydroxyanisole is mediated by c-Jun and Nrf2.
MedLine Citation:
PMID:  20194533     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cytochrome P450 2J2 oxidizes arachidonic acid to a series of epoxyeicosatrienoic acid (EET) isomers in human tissues. EETs regulate numerous homeostatic processes, including cytoprotective and proliferative responses against injurious stresses. There is little information currently available on the factors that regulate CYP2J2, but strategies to activate expression could use the beneficial effects of EETs in cells. The basic leucine zipper (bZIP) transcription factor c-Jun has been shown previously to maintain CYP2J2 expression in human HepG2 cells; c-Jun forms transcriptionally active dimers with the antioxidant-inducible bZIP factor Nrf2. In the present study, we tested the hypothesis that CYP2J2 expression may be activated in cells by c-Jun/Nrf2 heterodimers. Treatment of HepG2 cells with butylated hydroxyanisole elicited concentration- and time-dependent activation of CYP2J2 expression, as well as the bZIP factors Nrf2 and c-Jun; chromatin immunoprecipitation assays revealed a pronounced increase in binding of these bZIP factors to the CYP2J2 5'-flank. Transient transfection analysis using deletion constructs and gel-shift assays were consistent with a role for the -105/-88 region of CYP2J2 in c-Jun/Nrf2 responsiveness. Using a series of mutant expression plasmids, we identified c-Jun as the critical partner in CYP2J2 transactivation. Coimmunoprecipitation experiments confirmed the importance of the leucine zipper region of Nrf2 in the enhancement of c-Jun-dependent transactivation of CYP2J2. Agents that activate CYP2J2 expression may offer a new approach to using the beneficial effects of EETs in cells.
Authors:
Andy C Lee; Michael Murray
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-01
Journal Detail:
Title:  Molecular pharmacology     Volume:  77     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-18     Completed Date:  2010-06-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  987-94     Citation Subset:  IM    
Affiliation:
Pharmacogenomics and Drug Development Group, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia.
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MeSH Terms
Descriptor/Qualifier:
Antioxidants / pharmacology*
Base Sequence
Butylated Hydroxyanisole / pharmacology*
Cell Line
Chromatin Immunoprecipitation
Cytochrome P-450 Enzyme System / genetics,  metabolism*
DNA Primers
Electrophoretic Mobility Shift Assay
Humans
NF-E2-Related Factor 2 / physiology*
Polymerase Chain Reaction
Promoter Regions, Genetic
Proto-Oncogene Proteins c-jun / physiology*
Transcriptional Activation
Up-Regulation / drug effects*
Chemical
Reg. No./Substance:
0/Antioxidants; 0/DNA Primers; 0/NF-E2-Related Factor 2; 0/NFE2L2 protein, human; 0/Proto-Oncogene Proteins c-jun; 25013-16-5/Butylated Hydroxyanisole; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.14.1/arachidonate epoxygenase

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


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