CHEMICAL AND MOLECULAR REGULATION OF ENZYMES THAT DETOXIFY CARCINOGENS
CHEMICAL AND MOLECULAR REGULATION OF ENZYMES THAT DETOXIFY CARCINOGENS
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DOI：
10.1073/pnas.90.7.2965
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发表时间：
1993-04-01
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;HOLTZCLAW, WD;TALALAY, P
解毒（第 2 相）酶的诱导，例如谷胱甘肽转移酶和 NAD(P)H:（醌受体）氧化还原酶，是保护动物及其细胞免受致癌物毒性和肿瘤作用的主要机制。这些诱导是转录增强的结果，由多种化学试剂引起：可氧化的二酚和苯二胺；迈克尔反应受体；有机异硫氰酸酯；其他亲电子试剂，例如烷基卤化物和芳基卤化物；金属离子，例如 HgCl2 和 CdCl2；三价砷衍生物；邻位二硫醇；有机氢过氧化物和过氧化氢；和1,2-二硫醇-3-硫酮。借助含有源自小鼠肝脏谷胱甘肽转移酶 Ya 亚基基因 5' 上游区域的 41 bp 增强子元件的构建体来分析这些诱导的分子机制，该增强子元件连接到该基因的分离启动子区域的 5' 端，并插入到含有人生长激素报告基因的质粒中。当将该构建体转染到 Hep G2 人肝癌细胞中时，使生长激素产量加倍所需的 28 种化合物（来自上述类别）的浓度，以及使 Hepa 1c1c7 细胞中醌还原酶比活性加倍所需的浓度跨越四个数量级的范围，但密切线性相关。测试的六种化合物在两个系统中均无活性。上述增强子寡核苷酸的 26 bp 亚区域（包含两个串联的“AP-1 样”位点，但缺乏前面的 ETS 蛋白结合序列）对相同诱导物的反应要小得多。我们得出的结论是，41 bp 增强子元件介导所有这些广泛不同类别的化合物的大部分（如果不是全部）2 相酶诱导剂活性。
Inductions of detoxication (phase 2) enzymes, such as glutathione transferases and NAD(P)H:(quinone-acceptor) oxidoreductase, are a major mechanism for protecting animals and their cells against the toxic and neoplastic effects of carcinogens. These inductions result from enhanced transcription, and they are evoked by diverse chemical agents: oxidizable diphenols and phenylenediamines; Michael reaction acceptors; organic isothiocyanates; other electrophiles-e.g., alkyl and aryl halides; metal ions e.g., HgCl2 and CdCl2; trivalent arsenic derivatives; vicinal dimercaptans; organic hydroperoxides and hydrogen peroxide; and 1,2-dithiole-3-thiones. The molecular mechanisms of these inductions were analyzed with the help of a construct containing a 41-bp enhancer element derived from the 5' upstream region of the mouse liver glutathione transferase Ya subunit gene ligated to the 5' end of the isolated promoter region of this gene, and inserted into a plasmid containing a human growth hormone reporter gene. When this construct was transfected into Hep G2 human hepatoma cells, the concentrations of 28 compounds (from the above classes) required to double growth hormone production, and the concentrations required to double quinone reductase specific activities in Hepa 1c1c7 cells, spanned a range of four orders of magnitude but were closely linearly correlated. Six compounds tested were inactive in both systems. A 26-bp subregion of the above enhancer oligonucleotide (containing the two tandem ''AP-1-like'' sites but lacking the preceding ETS protein binding sequence) was considerably less responsive to the same inducers. We conclude that the 41-bp enhancer element mediates most, if not all, of the phase 2 enzyme inducer activity of all of these widely different classes of compounds.