Mense Sarah M, Chhabra Jaimeet, Bhat Hari K
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Avenue, B106, New York, NY 10032, United States.
J Steroid Biochem Mol Biol. 2008 May;110(1-2):157-62. doi: 10.1016/j.jsbmb.2008.03.029. Epub 2008 Mar 29.
Estrogen metabolism is suggested to play an important role in estrogen-induced breast carcinogenesis. Epidemiologic studies suggest that diets rich in phytoestrogens are associated with a reduced risk of breast cancer. Phytoestrogens are biologically active plant compounds that structurally mimic 17beta-estradiol (E(2)). We hypothesize that phytoestrogens, may provide protection against breast carcinogenesis by altering the expression of estrogen-metabolizing enzymes cytochrome P450 1A1 (Cyp1A1) and 1B1 (Cyp1B1). Cyp1A1 and Cyp1B1 are responsible for the metabolism of E(2) to generate 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)), respectively. Studies suggest that 2-OHE(2) and 2-methoxyestradiol may protect against breast carcinogenesis, while 4-OHE(2) is carcinogenic in rodent models. Thus, agents that increase the metabolism of E(2) by Cyp1A1 to produce 2-OHE(2) may have chemoprotective properties. The human immortalized non-neoplastic breast cell line MCF10F was treated with quercetin at 10 and 50muM concentrations for time points ranging from 3 to 48h. Total RNA and protein were isolated. Real-time PCR was used to measure the expression of Cyp1A1 and Cyp1B1 mRNA. Quercetin treatment produced differential regulation of Cyp1A1 and Cyp1B1 mRNA expression in a time- and dose-dependent manner. Treatment with 10 and 50 microM doses of quercetin produced 6- and 11-times greater inductions of Cyp1A1 mRNA over Cyp1B1 mRNA, respectively. Furthermore, quercetin dramatically increased Cyp1A1 protein levels and only slightly increased Cyp1B1 protein levels in MCF10F cells. Thus, our data suggest that phytoestrogens may provide protection against breast cancer by modulating expression of estrogen-metabolizing genes such that production of the highly carcinogenic estrogen metabolite 4-OHE(2) by Cyp1B1 is reduced and the production of the less genotoxic 2-OHE(2) by Cyp1A1 is increased.
雌激素代谢被认为在雌激素诱导的乳腺癌发生过程中起重要作用。流行病学研究表明，富含植物雌激素的饮食与降低乳腺癌风险相关。植物雌激素是一类具有生物活性的植物化合物，其结构与17β-雌二醇（E₂）相似。我们推测，植物雌激素可能通过改变雌激素代谢酶细胞色素P450 1A1（Cyp1A1）和1B1（Cyp1B1）的表达来提供对乳腺癌发生的保护作用。Cyp1A1和Cyp1B1分别负责将E₂代谢生成2-羟基雌二醇（2-OHE₂）和4-羟基雌二醇（4-OHE₂）。研究表明，2-OHE₂和2-甲氧基雌二醇可能对乳腺癌发生具有保护作用，而4-OHE₂在啮齿动物模型中具有致癌性。因此，能增加Cyp1A1介导的E₂代谢以产生2-OHE₂的物质可能具有化学保护特性。将人永生化非肿瘤性乳腺细胞系MCF10F用10和50μM浓度的槲皮素处理3至48小时的不同时间点。分离总RNA和蛋白质。使用实时PCR测量Cyp1A1和Cyp1B1 mRNA的表达。槲皮素处理以时间和剂量依赖性方式对Cyp1A1和Cyp1B1 mRNA表达产生差异调节。用10和50μM剂量的槲皮素处理分别使Cyp1A1 mRNA的诱导水平比Cyp1B1 mRNA高6倍和11倍。此外，槲皮素显著增加MCF10F细胞中Cyp1A1蛋白水平，而仅轻微增加Cyp1B1蛋白水平。因此，我们的数据表明，植物雌激素可能通过调节雌激素代谢基因的表达来提供对乳腺癌的保护作用，从而减少Cyp1B1产生高致癌性雌激素代谢物4-OHE₂，并增加Cyp1A1产生遗传毒性较小的2-OHE₂。
