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:  Publisher    
Abstract/OtherAbstract:
In this study, we provided molecular evidences that IL-6 contributed to the decreased capacity of oxidative biotransformation in human liver by suppressing the expression of CYP3A4. After human hepatocytes were treated with IL-6, 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:
Mao Zhao; Luan Xiaofei; Cao Gang; Liu Wei; Xiong Jing; Hu Gang; Chen Ruini; Ning Rui; Shang Wei; Yang Jian; Yan Bingfang
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-6-20
Journal Detail:
Title:  Biochemical pharmacology     Volume:  -     ISSN:  1873-2968     ISO Abbreviation:  -     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-6-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Inc.
Affiliation:
Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China; Nanjing Jinling Hospital, 210002.
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