A methoxyflavonoid, chrysoeriol, selectively inhibits the formation of a carcinogenic estrogen metabolite in MCF-7 breast cancer cells
A methoxyflavonoid, chrysoeriol, selectively inhibits the formation of a carcinogenic estrogen metabolite in MCF-7 breast cancer cells
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DOI：
10.1016/j.jsbmb.2009.10.002
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发表时间：
2010-01
期刊：
影响因子：
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通讯作者：
H. Takemura;H. Uchiyama;T. Ohura;H. Sakakibara;R. Kuruto;T. Amagai;K. Shimoi
中科院分区：
文献类型：
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作者：
H. Takemura;H. Uchiyama;T. Ohura;H. Sakakibara;R. Kuruto;T. Amagai;K. Shimoi
17β-雌二醇（E2）分别通过细胞色素P450（CYP）1A 1和1B 1水解为2-羟基-E2（2-OHE 2）和4-羟基-E2（4-OHE 2）。在包括乳腺、卵巢和子宫在内的雌激素靶组织中，CYP 1B 1高度表达，而4-OHE 2主要在癌组织中形成。本研究采用体外和细胞培养技术研究了天然甲氧基黄酮类化合物chrysoeriol（luceremin-3′-methoxy ether）对CYP 1A 1和1B 1的抑制作用。Chrysoeriol选择性抑制人重组CYP 1B 1介导的7-乙氧基试卤灵-O-脱乙基（EROD）活性，其抑制程度是竞争性抑制CYP 1A 1介导活性的5倍。此外，chrysoeriol抑制E2羟基化是由CYP 1B 1催化的，而不是由CYP 1A 1。4-OHE 2的甲基化被认为是一个解毒过程，但不受黄菊醇的影响。在人乳腺癌MCF-7细胞中，chrysoeriol不影响CYP 1A 1和1B 1的基因表达，但显著抑制4-甲氧基E2的生成，对2-甲氧基E2的生成无影响。总之，我们提出的第一份报告表明，chrysoeriol是一种化学预防性的天然成分，可以选择性地抑制CYP 1B 1的活性，并防止致癌的4-OHE 2从E2的形成。
A 17β-estradiol (E2) is hydrolyzed to 2-hydroxy-E2(2-OHE2) and 4-hydroxy-E2(4-OHE2) via cytochrome P450 (CYP) 1A1 and 1B1, respectively. In estrogen target tissues including the mammary gland, ovaries, and uterus, CYP1B1 is highly expressed, and 4-OHE2is predominantly formed in cancerous tissues. In this study, we investigated the inhibitory effects of chrysoeriol (luteorin-3′-methoxy ether), which is a natural methoxyflavonoid, against activity of CYP1A1 and 1B1 using in vitro and cultured cell techniques. Chrysoeriol selectively inhibited human recombinant CYP1B1-mediated 7-ethoxyresorufin-O-deethylation (EROD) activity 5-fold more than that of CYP1A1-mediated activity in a competitive manner. Additionally, chrysoeriol inhibited E2hydroxylation was catalyzed by CYP1B1, but not by CYP1A1. Methylation of 4-OHE2, which is thought to be a detoxification process, was not affected by the presence of chrysoeriol. In human breast cancer MCF-7 cells, chrysoeriol did not affect the gene expression of CYP1A1 and 1B1, but significantly inhibited the formation of 4-methoxy E2without any effects on the formation of 2-methoxy E2. In conclusion, we present the first report to show that chrysoeriol is a chemopreventive natural ingredient that can selectively inhibit CYP1B1 activity and prevent the formation of carcinogenic 4-OHE2from E2.