Resveratrol inhibits TCDD-induced expression of CYP1A1 and CYP1B1 and catechol estrogen-mediated oxidative DNA damage in cultured human mammary epithelial cells

• Published in: Carcinogenesis (New York) 2004-10, Vol.25 (10), p.2005-2013
• Main Authors: Chen, Zhi-Hua, Hurh, Yeon-Jin, Na, Hye-Kyung, Kim, Jung-Hwan, Chun, Young-Jin, Kim, Dong-Hyun, Kang, Kyung-Sun, Cho, Myung-Haing, Surh, Young-Joon
• Format: Article
• Language: English
• Subjects: 17β-estradiol; 2-hydroxyestradiol; 2-OHE2; 2′-deoxyguanosine; 4-hydroxyestradiol; 4-OHE2; 7-ethoxyresorufin O-deethylation; 8-dihydro-2′-deoxyguanosine; 8-oxo-7; 8-oxo-dGuo; 8-tetrachlorodibenzo-p-dioxin; AhR; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; aryl hydrocarbon receptor; Biological and medical sciences; Blotting, Northern; Breast - cytology; Carcinogenesis, carcinogens and anticarcinogens; Cell Division - drug effects; Cells, Cultured; CYP; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1B1; cytochrome P450; DCF-DA; dGuo; dichlorofluorescein diacetate; dithiothreitol; DNA - metabolism; DNA Damage - drug effects; DTT; Electrophoretic Mobility Shift Assay; Epithelial Cells - drug effects; Epithelial Cells - enzymology; EROD; Estradiol - metabolism; Estrogens, Catechol - metabolism; Female; Humans; Medical sciences; Oxidative Stress - drug effects; Polychlorinated Dibenzodioxins - antagonists & inhibitors; Polychlorinated Dibenzodioxins - pharmacology; reactive oxygen species; Reactive Oxygen Species - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; ROS; Stilbenes - pharmacology; TCDD; Tumors
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgh183

Resveratrol (3,5,4′-trihydroxystilbene), a naturally occurring phytoalexin present in grapes and other foods, has been reported to possess chemopreventive effects as revealed by its striking inhibition of diverse cellular events associated with tumor initiation, promotion and progression. In our present study, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), when treated with the cultured human mammary epithelial (MCF-10A) cells, induced the expression of cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) that are responsible for the oxidation of 17β-estradiol to produce catechol estrogens. Resveratrol strongly inhibited the TCDD-induced aryl hydrocarbon receptor (AhR) DNA binding activity, the expression of CYP1A1 and CYP1B1 and their catalytic activities in MCF-10A cells. It also reduced the formation of 2-hydroxyestradiol and 4-hydroxyestradiol from 17β-estradiol by recombinant human CYP1A1 and CYP1B1, respectively. Furthermore, resveratrol significantly attenuated the intracellular reactive oxygen species (ROS) formation and oxidative DNA damage as well as the cytotoxicity induced by the catechol estrogens. Our data suggest that CYP1A1- and CYP1B1-catalyzed catechol estrogen formation might play a key role in TCDD-induced oxidative damage, and resveratrol can act as a potential chemopreventive against dioxin-induced human mammary carcinogenesis by blocking the metabolic formation of the catechol estrogens and scavenging the ROS generated during their redox cycling.