Selective estrogen receptor modulator BC-1 activates antioxidant signaling pathway in vitro via formation of reactive metabolites.
Acta Pharmacol Sin
; 34(3): 373-9, 2013 Mar.
Article
em En
| MEDLINE
| ID: mdl-23334240
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Fenóis
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Tiofenos
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Transdução de Sinais
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Moduladores Seletivos de Receptor Estrogênico
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Elementos de Resposta Antioxidante
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Antioxidantes
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article