| Selective estrogen receptor modulator BC-1 activates antioxidant signaling pathway in vitro via formation of reactive metabolites. | |
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MedLine Citation:
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PMID: 23334240 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 E(2) (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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Authors:
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Bo-Lan Yu; Zi-Xin Mai; Xu-Xiang Liu; Zhao-Feng Huang |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-21 |
Journal Detail:
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Title: Acta pharmacologica Sinica Volume: - ISSN: 1745-7254 ISO Abbreviation: Acta Pharmacol. Sin. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-21 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100956087 Medline TA: Acta Pharmacol Sin Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institute, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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