Activation of dioxin response element (DRE)-associated genes by benzo(a)pyrene 3,6-quinone and benzo(a)pyrene 1,6-uinone in MCF-10A human mammary epithelial cells
Activation of dioxin response element (DRE)-associated genes by benzo(a)pyrene 3,6-quinone and benzo(a)pyrene 1,6-uinone in MCF-10A human mammary epithelial cells
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DOI：
10.1016/j.taap.2007.02.020
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发表时间：
2007-06-01
影响因子：
3.8
通讯作者：
Oprea, Tudor I.
中科院分区：
文献类型：
--
作者：
Burchiel, Scott W.;Thompson, Todd A.;Oprea, Tudor I.
苯并(a)芘（BaP）是一种已知的人类致癌物，也是一种可疑的乳腺癌完全致癌物。BaP通过几种代谢途径代谢，其中一些具有生物活性，另一些具有解毒特性。bap -醌（BPQs）通过细胞色素P450和过氧化物酶依赖途径形成。本实验室前期研究表明，BPQs对体外检测的人MCF-10A乳腺上皮细胞具有显著的促生长和抗凋亡活性。先前的研究结果表明BPQs通过氧化还原循环和氧化应激起作用。然而，由于两种特异性bpq （1,6- bpq和3,6- bpq）产生活性氧（ROS）的能力不同，但都具有很强的增殖和EGF受体激活活性，因此我们利用mRNA表达阵列和qRT-PCR来确定基因激活的潜在途径和机制。本研究结果表明，1,6- bpq和3,6- bpq可激活二氧化英响应元件（DRE，也称为异种响应元件，XRE）和抗氧化响应元件（ARE，也称为亲电响应元件，EpRE）。3,6- bpq的DRE活性高于1,6- bpq，而ARE的活性则相反。3,6- bpq和1,6- bpq诱导氧化应激相关基因（HMOX1、GCLC、GCLM和SLC7A11）、2期酶基因（NQO1、NQO2、ALDH3A1）、PAH代谢基因（CYP1B1、EPHX1、AKR1C1）和某些EGF受体相关基因（EGFR、IER3、ING1、SQSTM1和TRIM16）。这些研究结果表明，BPQs激活了人类乳腺上皮细胞中与细胞生长和存活增加相关的许多途径，这些途径可能在turner促进中发挥重要作用。(C) 2007爱思唯尔公司版权所有。
Benzo(a)pyrene (BaP) is a known human carcinogen and a suspected breast cancer complete carcinogen. BaP is metabolized by several metabolic pathways, some having bioactivation and others detoxification properties. BaP-quinones (BPQs) are formed via cytochrome P450 and peroxidase dependent pathways. Previous studies by our laboratory have shown that BPQs have significant growth promoting and anti-apoptotic activities in human MCF-10A mammary epithelial cells examined in vitro. Previous results suggest that BPQs act via redox-cycling and oxidative stress. However, because two specific BPQs (1,6-BPQ and 3,6-BPQ) differed in their ability to produce reactive oxygen species (ROS) and yet both had strong proliferative and EGF receptor activating activity, we utilized mRNA expression arrays and qRT-PCR to determine potential pathways and mechanisms of gene activation. The results of the present studies demonstrated that 1,6-BPQ and 3,6-BPQ activate dioxin response elements (DRE, also known as xenobiotic response elements, XRE) and anti-oxidant response elements (ARE, also known as electrophile response elements, EpRE). 3,6-BPQ had greater DRE activity than 1,6-BPQ, whereas the opposite was true for the activation of ARE. Both 3,6-BPQ and 1,6-BPQ induced oxidative stress-associated genes (HMOX1, GCLC, GCLM, and SLC7A11), phase 2 enzyme genes (NQO1, NQO2, ALDH3A1), PAH metabolizing genes (CYP1B1, EPHX1, AKR1C1), and certain EGF receptor-associated genes (EGFR, IER3, ING1, SQSTM1 and TRIM16). The results of these studies demonstrate that BPQs activate numerous pathways in human mammary epithelial cells associated with increased cell growth and survival that may play important roles in turner promotion. (C) 2007 Elsevier Inc. All rights reserved.