dinoprost and alpha-naphthoflavone

The mechanisms underlying the pathogenesis of estrogen-induced breast carcinogenesis remain unclear. The present study investigated the roles of estrogen metabolism and oxidative stress in estrogen-mediated mammary carcinogenesis in vivo. Female August Copenhagen Irish (ACI) rats were treated with 17beta-estradiol (E(2)), the antioxidant vitamin C, the estrogen metabolic inhibitor alpha-naphthoflavone (ANF), or cotreated with E(2) + vitamin C or E(2) + ANF for up to 8 months. E(2) (3 mg) was administered as an subcutaneous implant, ANF was given via diet (0.2%) and vitamin C (1%) was added to drinking water. At necropsy, breast tumor incidence in the E(2), E(2) + vitamin C and E(2) + ANF groups was 82, 29 and 0%, respectively. Vitamin C and ANF attenuated E(2)-induced alterations in oxidative stress markers in breast tissue, including 8-iso-prostane F(2alpha) formation and changes in the activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase. Quantification of 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)) formation in breast tissue confirmed that ANF inhibited 4-hydroxylation of E(2) and decreased formation of the highly carcinogenic 4-OHE(2). These results demonstrate that antioxidant vitamin C reduces the incidence of estrogen-induced mammary tumors, increases tumor latency and decreases oxidative stress in vivo. Further, our data indicate that ANF completely abrogates breast cancer development in ACI rats. The present study is the first to demonstrate the inhibition of breast carcinogenesis by antioxidant vitamin C or the estrogen metabolic inhibitor ANF in an animal model of estrogen-induced mammary carcinogenesis. Taken together, these results suggest that E(2) metabolism and oxidant stress are critically involved in estrogen-induced breast carcinogenesis.

Topics: Animals; Antioxidants; Ascorbic Acid; Benzoflavones; Cell Transformation, Neoplastic; Dinoprost; Estradiol; Estrogens, Catechol; Female; Mammary Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Oxidative Stress; Rats; Rats, Inbred ACI

Different estrogens vary in their carcinogenic potential despite having similar hormonal potencies; however, mechanisms of estrogen-induced carcinogenesis remain to be fully elucidated. It has been hypothesized that generation of reactive estrogen-quinones and oxidative stress, both of which result from metabolic activation of estrogens, play an essential role in estrogen-induced carcinogenesis. This hypothesis was tested using the estrogen-receptor (ER)-alpha-positive hamster kidney tumor (H301) and the human breast cancer (MCF-7) cell lines. Estrogens with differing carcinogenic potentials were compared in terms of their capacities to induce 8-iso-prostaglandin F(2alpha) (8- iso-PGF(2alpha)), a marker of oxidative stress. Tumor cells were treated with either 17beta-estradiol (E2), a carcinogenic estrogen or 17-alpha-ethinylestradiol (EE), a weakly-carcinogenic estrogen. Tumor cells were also treated with alpha-naphthoflavone, a cytochrome P450 inhibitor, or a combination of alpha-naphthoflavone and E2 to study the effect of metabolic activation of E2 on E2-induced oxidative stress. H301 cells treated with E2 displayed time- and dose-dependent increases in 8-iso-PGF(2alpha), compared to controls; treatment with 10 nM E2 resulted in a maximal 4-fold induction following 48 h of treatment. In contrast, H301 cells treated with EE did not display an increase in 8-iso-PGF(2alpha) compared with controls. In H301 cells cotreated with alpha-naphthoflavone and E2, alpha-naphthoflavone inhibited the E2-induced increase in 8-iso-PGF(2alpha). These data indicate that a carcinogenic estrogen shows strong oxidant potential, whereas a weakly-carcinogenic estrogen shows poor oxidant potential. Furthermore, inhibiting metabolic activation of a carcinogenic estrogen blocks its oxidant potential. Our data support the hypothesis that metabolic activation and subsequent generation of oxidative stress may play critical roles in estrogen-induced carcinogenesis.

Topics: Animals; Benzoflavones; Biotransformation; Carcinogens; Cell Line, Tumor; Cricetinae; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dinoprost; Estradiol; Estrogens; Humans; Oxidants; Oxidative Stress

Human amnion, trophoblast and umbilical vein endothelial cells synthesise an arachidonic acid metabolite which is neither a lipoxygenase nor a cyclo-oxygenase product. It is sensitive to stimulants and inhibitors of the cytochrome-P450-dependent epoxygenase system and co-migrates on HPLC with 14,15-epoxyeicosatrienoic acid (14,15-EET), which is an epoxygenase product. The function of 14,15-EET in these reproductive tissues is unknown, but it may be involved in the maintenance of vascular function.

Topics: 6-Ketoprostaglandin F1 alpha; 8,11,14-Eicosatrienoic Acid; Arachidonic Acids; Benzoflavones; Dinoprost; Endothelium; Fatty Acids, Unsaturated; Female; Humans; Hydroxyeicosatetraenoic Acids; Lipoxygenase; Placenta; Pregnancy; Prostaglandin-Endoperoxide Synthases; Trophoblasts; Umbilical Veins