Inhibition of catechol-0-methyltransferase increases estrogen-DNA adduct formation
Inhibition of catechol-0-methyltransferase increases estrogen-DNA adduct formation
复制标题
DOI：
10.1016/j.freeradbiomed.2007.08.005
复制
发表时间：
2007-12-01
影响因子：
7.4
通讯作者：
Cavalieri, Ercole
中科院分区：
文献类型：
--
作者：
Zahid, Muhammad;Saeed, Muhammad;Cavalieri, Ercole
乳腺癌的发展与长期接触雌激素之间的关联表明，这种激素在该疾病的病因学中具有重要的病因学意义。对雌激素代谢、DNA 加合物形成、致癌性、细胞转化和致突变性的研究得出这样的假设：某些雌激素代谢物（主要是儿茶酚雌激素-3,4-醌）与 DNA 反应形成脱嘌呤加合物 [4-OHE1(E-2)-1-N3Ade 和 4-OHE1(E-2)-1-N7Gua]。这些加合物会引起突变，导致乳腺癌的发生。儿茶酚-O-甲基转移酶 (COMT) 被认为是一种重要的酶，可通过阻止儿茶酚雌激素转化为醌来保护细胞免受儿茶酚雌激素的遗传毒性和细胞毒性。本研究的目的是研究 COMT 抑制对脱嘌呤雌激素-DNA 加合物形成的影响。永生化人乳腺上皮MCF-10F细胞在铺板后120、168、216和264小时用4-OHE2（0.2或0.5μM）处理24小时，或在存在或不存在COMT抑制剂（Ro41-0960）的情况下用1-30μM 4-OHE2处理一次。在每个点收集培养基，通过固相萃取进行提取，并通过与多通道电化学检测器连接的HPLC进行分析。结果表明，MCF-10F 细胞将 4-OHE2 氧化为 E-1(E-2)-3,4-Q，E-1(E-2)-3,4-Q 与 DNA 反应形成脱嘌呤 N3Ade 和 N7Gua 加合物。 COMT 抑制剂 Ro41-0960 阻断儿茶酚雌激素的甲氧基化，同时脱嘌呤加合物的水平增加 3 至 4 倍。因此，COMT 的低活性会导致脱嘌呤雌激素-DNA 加合物水平升高，从而诱导突变并引发癌症。 (C) 2007 Elsevier Inc. 保留所有权利。
The association found between breast cancer development and prolonged exposure to estrogens suggests that this hormone is of etiologic importance in the causation of the disease. Studies on estrogen metabolism, formation of DNA adducts, carcinogenicity, cell transformation, and mutagenicity, have led to the hypothesis that reaction of certain estrogen metabolites, predominantly catechol estrogen-3,4-quinones, with DNA forms depurinating adducts [4-OHE1(E-2)-1-N3Ade and 4-OHE1(E-2)-1-N7Gua]. These adducts, cause mutations leading to the initiation of breast cancer. Catechol-O-methyltransferase (COMT) is considered an important enzyme that protects cells from the genotoxicity and cytotoxicity of catechol estrogens, by preventing their conversion to quinones. The goal of the present study was to investigate the effect of COMT inhibition on the formation of depurinating estrogen-DNA adducts. Immortalized human breast epithelial MCF-10F cells were treated with 4-OHE2(0.2 or 0.5 mu M) for 24 h at 120, 168, 216, and 264 h postplating or one time at 1-30 mu M 4-OHE2 with or without the presence of COMT inhibitor (Ro41-0960). The culture media were collected at each point, extracted by solid-phase extraction, and analyzed by HPLC connected with a multichannel electrochemical detector. The results demonstrate that MCF-10F cells oxidize 4-OHE2 to E-1(E-2)-3,4-Q, which react with DNA to form the depurinating N3Ade and N7Gua adducts. The COMT inhibitor Ro41-0960 blocked the methoxylation of catechol estrogens, with concomitant 3- to 4-fold increases in the levels of the depurinating adducts. Thus, low activity of COMT leads to higher levels of depurinating estrogen-DNA adducts that can induce mutations and initiate cancer. (C) 2007 Elsevier Inc. All rights reserved.