Prevention of estrogen-DNA adduct formation in MCF-10F cells by resveratrol.
Resveratrol (Resv), a natural occurring phytolexin present in grapes and other foods, possesses chemopreventive effects revealed by its striking modulation of diverse cellular events associated with tumor initiation, promotion, and progression. Catechol estrogens generated in the metabolism of estrogens are oxidized to catechol quinones that react with DNA to form predominantly depurinating estrogen-DNA adducts. This event can generate the mutations responsible for cancer initiation. In this regard, Resv acts as both an antioxidant and an inducer of the phase II enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1). In this report, we present the effects of Resv on the metabolism of estrogens in normal breast epithelial cells (MCF-10F) treated with 4-hydroxyestradiol (4-OHE(2)) or estradiol-3,4-quinone (E(2)-3,4-Q). Resv induced NQO1 in a dose- and time-dependent manner, but did not affect the expression of catechol-O-methyltransferase. Ultraperformance liquid chromatography/tandem mass spectrometry was used to determine the effects of Resv on estrogen metabolism. Preincubation of the cells with Resv for 48 h decreased the formation of depurinating estrogen-DNA adducts from 4-OHE(2) or E(2)-3,4-Q and increased formation of methoxycatechol estrogens. When Resv was also present with the 4-OHE(2) or E(2)-3,4-Q, even greater increases in methoxycatechol estrogens were observed, and the DNA adducts were undetectable. We conclude that Resv can protect breast cells from carcinogenic estrogen metabolites, suggesting that it could be used in breast cancer prevention.
Zahid
Muhammad
M
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA.
Gaikwad
Nilesh W
NW
Ali
Mohamed F
MF
Lu
Fang
F
Saeed
Muhammad
M
Yang
Li
L
Rogan
Eleanor G
EG
Cavalieri
Ercole L
EL
D000975:Antioxidants / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000517:prevention & control*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D018736:DNA Adducts / Q000187:drug effects*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000187:drug effects; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
D000975:Antioxidants; D018736:DNA Adducts; D004967:Estrogens; D013267:Stilbenes; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D000077185:Resveratrol