Document Detail

Opposing effects of oestradiol and progesterone on intracellular pathways and activation processes in the oxidative stress induced activation of cultured rat hepatic stellate cells.
MedLine Citation:
PMID:  16284289     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Oxidative stress, including the generation of reactive oxygen species (ROS), is involved in hepatofibrogenesis. The authors' previous studies have shown that oestradiol suppresses hepatic fibrosis in animal models and attenuates the activation of cultured rat hepatic stellate cells (HSCs), which possess oestrogen receptor subtype beta and are also activated by ROS.
AIMS: To define the mechanisms by which female sex hormones play an antifibrogenic role in activated HSCs, the effects of oestradiol and progesterone on ROS generation processes and intracellular pathways, leading to the activation of HSCs undergoing oxidative stress, was examined.
METHODS: HSCs, isolated from rats, were cultured for 7 days with oestradiol or progesterone for 24 hours as pretreatment, and oxidative stress was then induced by exposure to low doses of hydrogen peroxide for another 24 hours.
RESULTS: Oestradiol inhibited ROS generation and antioxidant enzyme loss via the suppression of NADH/NADPH oxidase activity, and attenuated hydrogen peroxide induced transforming growth factor-beta1 (TGF-beta1) expression, HSC proliferation and transformation, and the activation of mitogen activated protein kinase (MAPK) pathways and transcription factors. Progesterone exerted a stimulatory effect through the progesterone receptor on the induction of ROS generation processes and intracellular pathways, resulting in TGF-beta1 expression and HSC activation, and fibrogenic effects were inhibited by oestradiol.
CONCLUSION: These findings show for the first time that oestradiol inhibits the activation of transcription factors by suppressing ROS generation processes and the MAPK pathways, and inactivates the downstream transcription processes involved in TGF-beta1 expression and HSC activation, whereas progesterone acts in opposition to the favourable effects of oestradiol and its effects are blocked by oestradiol.
T Itagaki; I Shimizu; X Cheng; Y Yuan; A Oshio; K Tamaki; H Fukuno; H Honda; Y Okamura; S Ito
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Gut     Volume:  54     ISSN:  0017-5749     ISO Abbreviation:  Gut     Publication Date:  2005 Dec 
Date Detail:
Created Date:  2005-11-14     Completed Date:  2005-12-12     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  2985108R     Medline TA:  Gut     Country:  England    
Other Details:
Languages:  eng     Pagination:  1782-9     Citation Subset:  AIM; IM    
Department of Digestive and Cardiovascular Medicine, Tokushima University Graduate School, Kuramoto-cho, Tokushima 770-8503, Japan.
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MeSH Terms
Cell Proliferation
Cells, Cultured
Enzyme-Linked Immunosorbent Assay
Estradiol / pharmacology*
Gene Expression Regulation / drug effects
Hydrogen Peroxide / pharmacology
Lipid Peroxidation / drug effects
Liver / cytology,  drug effects*,  metabolism
Mitogen-Activated Protein Kinases / metabolism
Multienzyme Complexes / metabolism
NAD / metabolism
NADH, NADPH Oxidoreductases / metabolism
Oxidative Stress / drug effects,  physiology
Progesterone / pharmacology*
Rats, Wistar
Reactive Oxygen Species / metabolism
Receptors, Progesterone / genetics,  metabolism
Reverse Transcriptase Polymerase Chain Reaction / methods
Signal Transduction / drug effects
Transforming Growth Factor beta / metabolism
Transforming Growth Factor beta1
Reg. No./Substance:
0/Multienzyme Complexes; 0/Reactive Oxygen Species; 0/Receptors, Progesterone; 0/Tgfb1 protein, rat; 0/Transforming Growth Factor beta; 0/Transforming Growth Factor beta1; 50-28-2/Estradiol; 53-84-9/NAD; 57-83-0/Progesterone; 7722-84-1/Hydrogen Peroxide; EC 1.6.-/NADH oxidase; EC 1.6.-/NADH, NADPH Oxidoreductases; EC Protein Kinases
Erratum In:
Gut. 2008 Nov;57(11):1634

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

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