Strong evidence supports the idea that specific metabolites of estrogens, mainly catechol estrogen-3,4-quinones, can react with DNA to become endogenous initiators of breast, prostate, and other human cancers. Oxidation of the catechol estrogen metabolites 4-hydroxyestradiol (4-OHE 2 ) and 2-OHE 2 leads to the quinones, estradiol-3,4-quinone (E 2 -3,4-Q) and estradiol-2,3-quinone (E 2 -2,3-Q), respectively. The reaction of E 2 -3,4-Q with DNA affords predominantly the depurinating adducts 4-OHE 2 -1-N3Ade and 4-OHE 2 -1-N7Gua, whereas the reaction of E 2 -2,3-Q with DNA yields the newly synthesized depurinating adduct 2-OHE 2 -6-N3Ade. The N3Ade adducts are lost from DNA by rapid depurination, while the N7Gua adduct is lost from DNA with a half-life of ∼3 h at 37°C. To compare the relative reactivity of E 2 -3,4-Q and E 2 -2,3-Q, the compounds were reacted individually with DNA for 0.5-20 h at 37°C, as well as in mixtures (3:1, 1:1, 1:3, and 5:95) for 10 h at 37°C. Depurinating and stable adducts were analyzed. In similar experiments, the relative reactivity of 4-OHE 2 and 2-OHE 2 with DNA was determined after activation by lactoperoxidase, tyrosinase, prostaglandin H synthase (PHS), or 3-methylcholanthreneinduced rat liver microsomes. Starting with the quinones, the levels of depurinating adducts formed from E 2 -3,4-Q were much higher than that of the depurinating adduct from E 2 -2,3-Q. Similar results were obtained with lactoperoxidase or tyrosinase-catalyzed oxidation of 4-OHE 2 and 2-OHE 2 , whereas with activation by PHS or microsomes, a relatively higher amount of the depurinating adduct from E 2 -2,3-Q was detected. These results demonstrate that the E 2 -3,4-Q is much more reactive with DNA than E 2 -2,3-Q. The relative reactivities of E 2 -3,4-Q and E 2 -2,3-Q to form depurinating adducts correlate with the carcinogenicity, mutagenicity, and cell-transforming activity of their precursors, the catechol estrogens 4-OHE 2 and 2-OHE 2 . This is essential information for understanding the cancer risk posed by oxidation of the two catechol estrogens.

Exposure to estrogens is a risk factor for breast cancer. Specific estrogen metabolites may initiate breast cancer and other cancers. Genotoxicity may be caused by cytochrome P450 (CYP)–mediated oxidation of catechol estrogens to quinones that react with DNA to form depurinating estrogen-DNA adducts. CYP1B1 favors quinone formation by catalyzing estrogen 4-hydroxylation, whereas NAD(P)H quinone oxidoreductase 1 (NQO1) catalyzes the protective reduction of quinones to catechols. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1B1 expression through the aryl hydrocarbon receptor (AhR). Resveratrol has anticancer effects in diverse in vitro and in vivo systems and is an AhR antagonist that decreases CYP expression but induces NQO1 expression. The chemopreventive effect of resveratrol on breast cancer initiation was investigated in MCF-10F cells. Its effects on estrogen metabolism and formation of estrogen-DNA adducts were analyzed in culture medium by high-performance liquid chromatography, where as its effects on CYP1B1 and NQO1 were determined by immunoblotting and immunostaining. The antitransformation effects of resveratrol were also examined. TCDD induced expression of CYP1B1 and its redistribution in the nucleus and cytoplasm. Concomitant treatment with resveratrol dose-dependently suppressed TCDD-induced expression of CYP1B1, mainly in the cytoplasm. Resveratrol dose- and time-dependently induced expression of NQO1. NQO1 is mainly in the perinuclear membrane of control cells, but resveratrol induced NQO1 and its intracellular redistribution, which involves nuclear translocation of nuclear factor erythroid 2–related factor 2. Resveratrol decreased estrogen metabolism and blocked formation of DNA adducts in cells treated with TCDD and/or estradiol. Resveratrol also suppressed TCDD and/or estradiol-induced cell transformation. Thus, resveratrol can prevent breast cancer initiation by blocking multiple sites in the estrogen genotoxicity pathway.

The ethyl acetate, chloroform extracts, and the two ‰avonoids kaempferol 1 and kaempferol-3-O-glucoside 2 isolated from whole plants of Thesium chinense Turcz were investigated for their antiin‰ammatory and analgesic activities. For the antiin‰ammatory activity, carrageenan-induced hind paw edema and xylene-induced mouse ear edema models, and for the analgesic activity, the acetic acid-induced abdominal constriction test was used. The ethyl acetate extract and two ‰avonoids showed signiˆcant (p＜0.05 and p＜0.01) and dose-dependent antiin‰ammatory and analgesic activity. The chloroform extract was inactive in the assay.

No abstract