Document Detail

Selective estrogen receptor modulator BC-1 activates antioxidant signaling pathway in vitro via formation of reactive metabolites.
MedLine Citation:
PMID:  23334240     Owner:  NLM     Status:  MEDLINE    
AIM: Benzothiophene compounds are selective estrogen receptor modulators (SERMs), which are recently found to activate antioxidant signaling. In this study the molecular mechanisms of antioxidant signaling activation by benzothiophene compound BC-1 were investigated.
METHODS: HepG2 cells were stably transfected with antioxidant response element (ARE)-luciferase reporter (HepG2-ARE cells). The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in HepG2-ARE cells was suppressed using siRNA. The metabolites of BC-1 in rat liver microsome incubation were analyzed using LC-UV and LC-MS.
RESULTS: Addition of BC-1 (5 μmol/L) in HepG2-ARE cells resulted in a 17-fold increase of ARE-luciferase activity. Pretreatment with the estrogen receptor agonist E2 (5 μmol/L) or antagonist ICI 182,780 (5 μmol/L) did not affect BC-1-induced ARE-luciferase activity. However, transfection of the cells with anti-Nrf2 siRNA suppressed this effect by 79%. Addition of BC-1 in rat microsome incubation resulted in formation of di-quinone methides and o-quinones, followed by formation of GSH conjugates. BC-1 analogues with hydrogen (BC-2) or fluorine (BC-3) at the 4' position did not form the di-quinone methides. Both BC-2 and BC-3 showed comparable estrogenic activity with BC-1, but did not induce ARE-luciferase activity in HepG2-ARE cells.
CONCLUSION: Benzothiophene compound BC-1 activates ARE signaling via reactive metabolite formation that is independent of estrogen receptors.
Bo-lan Yu; Zi-xin Mai; Xu-xiang Liu; Zhao-feng Huang
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-21
Journal Detail:
Title:  Acta pharmacologica Sinica     Volume:  34     ISSN:  1745-7254     ISO Abbreviation:  Acta Pharmacol. Sin.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-05     Completed Date:  2013-12-27     Revised Date:  2014-07-31    
Medline Journal Info:
Nlm Unique ID:  100956087     Medline TA:  Acta Pharmacol Sin     Country:  United States    
Other Details:
Languages:  eng     Pagination:  373-9     Citation Subset:  IM    
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MeSH Terms
Antioxidant Response Elements / drug effects*,  genetics
Antioxidants / metabolism*
Hep G2 Cells
Microsomes, Liver / drug effects,  metabolism
Molecular Structure
NF-E2-Related Factor 2 / antagonists & inhibitors,  genetics
Phenols / chemistry,  pharmacology*
RNA, Small Interfering / genetics,  pharmacology
Receptors, Estrogen / agonists,  antagonists & inhibitors
Selective Estrogen Receptor Modulators / chemistry,  pharmacology*
Signal Transduction / drug effects*
Thiophenes / chemistry,  pharmacology*
Reg. No./Substance:
0/Antioxidants; 0/BC-1 benzothiophene compound; 0/NF-E2-Related Factor 2; 0/NFE2L2 protein, human; 0/Phenols; 0/RNA, Small Interfering; 0/Receptors, Estrogen; 0/Selective Estrogen Receptor Modulators; 0/Thiophenes

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