Estrogen metabolism and formation of estrogen-DNA adducts in estradiol-treated MCF-10F cells The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin induction and catechol-O-methyltransferase inhibition
Estrogen metabolism and formation of estrogen-DNA adducts in estradiol-treated MCF-10F cells The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin induction and catechol-O-methyltransferase inhibition
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DOI：
10.1016/j.jsbmb.2006.12.102
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发表时间：
2007-06-01
影响因子：
4.1
通讯作者：
Rogan, Eleanor G.
中科院分区：
文献类型：
--
作者：
Lu, Fang;Zahid, Muhammad;Rogan, Eleanor G.
与DNA反应的雌激素代谢物的形成被认为是雌激素引发癌症的机制。雌激素雌酮（E-1）和雌二醇（E-2）可形成儿茶酚雌激素（CE）代谢物，儿茶酚雌激素醌[E-1（E-2）-3，4-Q]，其与DNA反应主要形成脱嘌呤加合物。这可能会导致引发癌症的突变。儿茶酚-O-甲基转移酶（COMT）催化CE的失活（保护）途径。本研究调查了抑制COMT活性对人乳腺上皮细胞中脱嘌呤4-OHE 1（E-2）-1-N3 Ade和4-OHE 1（E-2）-1-N7 Gua加合物水平的影响。MCF-10 F细胞用细胞色素P450诱导剂TCDD处理，然后用E-2和COMT抑制剂Ro 41 -0960处理。用高效液相色谱电化学检测法分析培养基中的雌激素代谢产物和脱嘌呤DNA加合物。用TCDD预处理细胞增加E2代谢为4-OHE 1（E-2）和4-OCH 3E 1（E-2）。在培养基中包含Ro 41 -0960和E-2阻断甲氧基CE的形成，并观察到脱嘌呤加合物。使用Ro 41 -0960，在暴露于1 μ M E-2的MCF-10 F细胞中检测到更多的加合物，而在没有抑制剂的情况下，在E-2 < 10 μ M时未检测到加合物的增加。我们的结论是，低COMT活性和脱嘌呤加合物的形成增加可能是导致乳腺癌发生的关键因素。(c)2007爱思唯尔有限公司保留所有权利。
Formation of estrogen metabolites that react with DNA is thought to be a mechanism of cancer initiation by estrogens. The estrogens estrone (E-1) and estradiol (E-2) can form catechol estrogen (CE) metabolites, catechol estrogen quinones [E-1(E-2)-3,4-Q], which react with DNA to form predominantly depurinating adducts. This may lead to mutations that initiate cancer. Catechol-O-methyltransferase (COMT) catalyzes an inactivation (protective) pathway for CE. This study investigated the effect of inhibiting COMT activity on the levels of depurinating 4-OHE1(E-2)-1-N3Ade and 4-OHE1(E-2)-1-N7Gua adducts in human breast epithelial cells. MCF-10F cells were treated with TCDD, a cytochrome P450 inducer, then with E-2 and Ro41-0960, a COMT inhibitor. Estrogen metabolites and depurinating DNA adducts in culture medium were analyzed by HPLC with electrochemical detection. Pre-treatment of cells with TCDD increased E2 metabolism to 4-OHE1 (E-2) and 4-OCH3E1 (E-2) Inclusion of Ro41-0960 and E-2 in the medium blocked formation of methoxy CE, and depurinating adducts were observed. With Ro41-0960, more adducts were detected in MCF-10F cells exposed to 1 mu M E-2, whereas without the inhibitor, no increases in adducts were detected with E-2 < 10 mu M. We conclude that low COMT activity and increased formation of depurinating adducts can be critical factors leading to initiation of breast cancer. (c) 2007 Elsevier Ltd. All rights reserved.