Document Detail


Estradiol induces cytochrome P450 2B6 expression at high concentrations: implication in estrogen-mediated gene regulation in pregnancy.
MedLine Citation:
PMID:  22484313     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pregnancy alters the rate and extent of drug metabolism, but little is known about the underlying molecular mechanism. We have found that 17β-estradiol (E2) upregulates expression of the major drug-metabolizing enzyme CYP2B6 in primary human hepatocytes. Results from promoter reporter assays in HepG2 cells revealed that E2 activates constitutive androstane receptor (CAR) and enhances promoter activity of CYP2B6, for which high concentrations of E2 reached during pregnancy were required. E2 triggered nuclear translocation of CAR in primary rat hepatocytes that were transiently transfected with human CAR as well as in primary human hepatocytes, further confirming transactivation of CAR by E2. E2-activated estrogen receptor (ER) also enhanced CYP2B6 promoter activity. The DNA-binding domain of ER was not required for the induction of CYP2B6 promoter activity by E2, suggesting involvement of a non-classical mechanism of ER action. Results from deletion and mutation assays as well as electrophorectic mobility shift and supershift assays revealed that two AP-1 binding sites (-1782/-1776 and -1664/-1658 of CYP2B6) are critical for ER-mediated activation of the CYP2B6 promoter by E2. Concurrent activation of both ER and CAR by E2 enhanced CYP2B6 expression in a synergistic manner. Our data demonstrate that at high concentrations reached during pregnancy, E2 activates both CAR and ER that synergistically induce CYP2B6 expression. These results illustrate pharmacological activity of E2 that would likely become prominent during pregnancy.
Authors:
Kwi Hye Koh; Steve Jurkovic; Kyunghee Yang; Su-Young Choi; Jin Woo Jung; Kwang Pyo Kim; Wei Zhang; Hyunyoung Jeong
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-03-30
Journal Detail:
Title:  Biochemical pharmacology     Volume:  84     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-05-07     Completed Date:  2012-07-09     Revised Date:  2014-01-07    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  93-103     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aryl Hydrocarbon Hydroxylases / genetics*,  metabolism
Binding Sites
Cell Nucleus / metabolism
Chromatin Immunoprecipitation
Chromatography, High Pressure Liquid
Dose-Response Relationship, Drug
Electrophoretic Mobility Shift Assay
Estradiol / blood,  pharmacology*
Estrogens / blood,  pharmacology*
Female
Gene Expression Profiling
Gene Expression Regulation, Enzymologic / drug effects*
Genes, Reporter
Hep G2 Cells
Hepatocytes / drug effects*,  enzymology
Humans
Luciferases / genetics
Middle Aged
Nuclear Proteins / metabolism
Oligonucleotide Array Sequence Analysis
Oxidoreductases, N-Demethylating / genetics*,  metabolism
Pregnancy / blood,  genetics*
Promoter Regions, Genetic
Real-Time Polymerase Chain Reaction
Receptors, Cytoplasmic and Nuclear / genetics,  metabolism
Receptors, Estrogen / genetics,  metabolism
Tandem Mass Spectrometry
Transcription Factor AP-1 / genetics,  metabolism
Transcriptional Activation
Grant Support
ID/Acronym/Agency:
HD065532/HD/NICHD NIH HHS; HHSN267200700004C/LM/NLM NIH HHS; K12 HD055892/HD/NICHD NIH HHS; K12 HD055892-05/HD/NICHD NIH HHS; K12HK055892/HK/PHITPO CDC HHS; N01-DK-7-0004/DK/NIDDK NIH HHS; R01 HD065532/HD/NICHD NIH HHS; R01 HD065532-01A1/HD/NICHD NIH HHS; R01 HD065532-02/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Estrogens; 0/Nuclear Proteins; 0/Receptors, Cytoplasmic and Nuclear; 0/Receptors, Estrogen; 0/Transcription Factor AP-1; 0/constitutive androstane receptor; 4TI98Z838E/Estradiol; EC 1.13.12.-/Luciferases; EC 1.14.13.-/cytochrome P-450 CYP2B6; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.5.-/Oxidoreductases, N-Demethylating
Comments/Corrections

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