title: Resveratrol and its methoxy derivatives modulate the expression of estrogen metabolism enzymes in breast epithelial cells by AhR down-regulation.
abstract: Our earlier studies have shown that compared to resveratrol, its analogs with ortho-methoxy substituents exert stronger antiproliferative and proapoptotic activity. Since estrogens are considered the major risk factors of breast carcinogenesis, the aim of this study was to evaluate the effect of 3,4,2'-trimethoxy (3MS), 3,4,2',4'-tetramethoxy (4MS), and 3,4,2',4',6'-pentamethoxy (5MS) trans-stilbenes on the constitutive expression of the enzymes involved in estrogen metabolism, as well as receptors: AhR and HER2 in breast epithelial cell line MCF10A. The results showed different effect of resveratrol and its methoxy derivatives on the expression of genes encoding key enzymes of estrogen synthesis and catabolism. Resveratrol at the doses of 1 and 5 µmol/L increased the level of CYP19 transcript and protein level, while 5MS reduced mRNA transcript of both CYP19 and STS genes. Resveratrol and all its derivatives reduced also SULT1E1 mRNA transcript level. The reduced expression of AhR, CYP1A1, and 1B1 was also found as a result of treatment with these compounds. The most significant changes were found in the case of AhR. The most potent inhibitor of CYP1A1 and 1B1 genes expression was 5MS, which reduced the levels of mRNA transcript and protein of both CYPs from 31 to 89% of the initial levels. These results indicate that methoxy derivatives of resveratrol might be efficient modulators of estrogen metabolism. Moreover, the number of methoxy groups introduced to stilbene structure may play a certain role in this effect.
authors.affiliation: Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Licznerska
authors.affiliation: Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Szaefer
authors.affiliation: Department of Chemical Synthesis of Drugs, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Wierzchowski
authors.affiliation: Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Sobierajska
authors.affiliation: Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznan, Poland. baerw@ump.edu.pl.
authors.forename: Wanda
authors.initials: W
authors.lastname: Baer-Dubowska
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004967:Estrogens / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D015238:Sulfotransferases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003577:Cytochrome P-450 Enzyme System; D004967:Estrogens; D009363:Neoplasm Proteins; D018336:Receptors, Aryl Hydrocarbon; D000077185:Resveratrol; D013267:Stilbenes; D015238:Sulfotransferases; C111235:AHR protein, human; C020122:estrone sulfotransferase
keywords: AhR; Breast cancer; CYP450; Methoxy-trans-resveratrol; STS; SULT1E1