Document Detail


DEC1 binding to the proximal promoter of CYP3A4 ascribes to the downregulation of CYP3A4 expression by IL-6 in primary human hepatocytes.
MedLine Citation:
PMID:  22728071     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this study, we provided molecular evidences that interleukin-6 (IL-6) contributed to the decreased capacity of oxidative biotransformation in human liver by suppressing the expression of cytochrome P450 3A4 (CYP3A4). After human hepatocytes were treated with IL-6, differentially expressed in chondrocytes 1 (DEC1) expression rapidly increased, and subsequently, the CYP3A4 expression decreased continuously. Furthermore, the repression of CYP3A4 by IL-6 occurred after the increase of DEC1 in primary human hepatocytes. In HepG2 cells, knockdown of DEC1 increased the CYP3A4 expression and its enzymatic activity. In addition, it partially abolished the decreased CYP3A4 expression as well as its enzymatic activity induced by IL-6. Consistent with this, overexpression of DEC1 markedly reduced the CYP3A4 promoter activity and the CYP3A4 expression as well as its enzymatic activity. Using sequential truncation and site directed mutagenesis of CYP3A4 proximal promoter with DEC1 construct, we showed that DEC1 specifically bound to CCCTGC sequence in the proximal promoter of CYP3A4, which was validated by EMSA and ChIP assay. These findings suggest that the repression of CYP3A4 by IL-6 is achieved through increasing the DEC1 expression in human hepatocytes, the increased DEC1 binds to the CCCTGC sequence in the promoter of CYP3A4 to form CCCTGC-DEC1 complex, and the complex downregulates the CYP3A4 expression and its enzymatic activity.
Authors:
Zhao Mao; Xiaofei Luan; Gang Cao; Wei Liu; Jing Xiong; Gang Hu; Ruini Chen; Rui Ning; Wei Shang; Jian Yang; Bingfang Yan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-21
Journal Detail:
Title:  Biochemical pharmacology     Volume:  84     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-07-30     Completed Date:  2012-10-15     Revised Date:  2014-08-10    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  701-11     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Base Sequence
Binding Sites
Cell Line
Cytochrome P-450 CYP3A / metabolism*
DNA Primers
Down-Regulation / physiology*
Electrophoretic Mobility Shift Assay
Hepatocytes / drug effects*,  metabolism
Interleukin-6 / physiology*
Mutagenesis, Site-Directed
Promoter Regions, Genetic*
Protein Binding
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Proteins / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
F05AT003019/AT/NCCAM NIH HHS; R01 ES007965/ES/NIEHS NIH HHS; R01 GM061988/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/DEC1 protein, human; 0/DNA Primers; 0/Interleukin-6; 0/Tumor Suppressor Proteins; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A
Comments/Corrections

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


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