Resveratrol inhibits TCDD-induced expression of CYP1A1 and CYP1B1 and catechol estrogen-mediated oxidative DNA damage in cultured human mammary epithelial cells.
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 17beta-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 17beta-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.
Chen
Zhi-Hua
ZH
College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Hurh
Yeon-Jin
YJ
Na
Hye-Kyung
HK
Kim
Jung-Hwan
JH
Chun
Young-Jin
YJ
Kim
Dong-Hyun
DH
Kang
Kyung-Sun
KS
Cho
Myung-Haing
MH
Surh
Young-Joon
YJ
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D015152:Blotting, Northern; D001940:Breast / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology; D004958:Estradiol / Q000378:metabolism; D002393:Estrogens, Catechol / Q000378:metabolism*; D005260:Female; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D002393:Estrogens, Catechol; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013267:Stilbenes; D004958:Estradiol; D004247:DNA; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D000077185:Resveratrol