ELECTROPHILE AND ANTIOXIDANT REGULATION OF ENZYMES THAT DETOXIFY CARCINOGENS
ELECTROPHILE AND ANTIOXIDANT REGULATION OF ENZYMES THAT DETOXIFY CARCINOGENS
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DOI：
10.1073/pnas.92.19.8965
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发表时间：
1995-09-12
影响因子：
11.1
通讯作者：
TALALAY, P
中科院分区：
文献类型：
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作者：
PRESTERA, T;TALALAY, P
解毒(2相)；酶，如谷胱甘肽S转移酶(GSTs)，NAD(P)H：(苯醌受体)氧化还原酶(QR)和UDP-葡萄糖醛酸基转移酶，暴露于各种亲电化合物和酚类抗氧化剂的动物细胞中。诱导可以抵抗致癌物的毒性和肿瘤效应，并通过激活上游electrophile-responsive/antioxidant-responsive元件(EPRE/ARE)来调节这些增强子的激活机制，通过瞬时基因表达生长激素报告构建体(GSTYa基因5‘-上游区含有EPRE/ARE元件)和该元件被一个或两个共识佛波醇12-十四酸13-乙酸酯(TPA)反应元件(TRES)取代的生长激素报告构建体的瞬时基因表达来分析这些增强子的激活机制。在Hep G2(人)和HEPA 1c1c7(小鼠)肝癌细胞中比较这三种结构，野生型序列被不同的诱导剂高度激活，包括叔丁基对苯二酚、Michael反应受体、1，2-二硫-3-硫酮、萝卜硫醚、2，3-二硫-1-丙醇、HgCl2、亚砷酸钠和苯砷氧化物，相反，具有一致tre位点的结构没有被显著诱导，TPA和这些化合物联合导致EpRE/are结构的相加或协同诱导，但对tre结构的诱导与TPA单独诱导相似，将EpRE/are报告结构转入F9细胞，缺乏内源性TrE结合蛋白，在相同的化合物诱导下产生大量的诱导，这也诱导了这些细胞中的QR活性，我们得出结论，亲电和抗氧化诱导剂激活EpRE/ARE是由EPRE/ARE特异性蛋白介导的。
Detoxication (phase 2); enzymes, such as glutathione S-transferases (GSTs), NAD(P)H: (quinone-acceptor) oxidoreductase (QR), and UDP-glucuronosyltransferase, are induced in animal cells exposed to a variety of electrophilic compounds and phenolic antioxidants. Induction protects against the toxic and neoplastic effects of carcinogens and is mediated by activation of upstream electrophile-responsive/antioxidant-responsive elements (EpRE/ARE), The mechanism of activation of these enhancers was analyzed by transient gene expression of growth hormone reporter constructs containing a 41-bp region derived from the-mouse GST Ya gene 5'-upstream region that contains the EpRE/ARE element and of constructs in which this element was replaced with either one or two consensus phorbol 12-tetradecanoate 13-acetate (TPA)-responsive elements (TREs). When these three constructs were compared in Hep G2 (human) and Hepa 1c1c7 (murine) hepatoma cells, the wild-type sequence nas highly activated by diverse inducers, including tert-butylhydroquinone, Michael reaction acceptors,1,2-dithiole-3-thione, sulforaphane, 2,3-dimercapto-1-propanol, HgCl2, sodium arsenite, and phenylarsine oxide, In contrast, constructs with consensus TRE sites were not induced significantly, TPA in combination with these compounds led to additive or synergistic inductions of the EpRE/ARE construct, but induction of the TRE construct was similar to that induced by TPA alone, Transfection of the EpRE/ARE reporter construct into F9 cells, which lack endogenous TRE binding proteins, produced large inductions by the same compounds, which also induced QR activity in these cells, We conclude that activation of the EpRE/ARE by electrophile and antioxidant inducers is mediated by EpRE/ARE-specific proteins.