IDENTIFICATION OF A COMMON CHEMICAL SIGNAL REGULATING THE INDUCTION OF ENZYMES THAT PROTECT AGAINST CHEMICAL CARCINOGENESIS
IDENTIFICATION OF A COMMON CHEMICAL SIGNAL REGULATING THE INDUCTION OF ENZYMES THAT PROTECT AGAINST CHEMICAL CARCINOGENESIS
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DOI：
10.1073/pnas.85.21.8261
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发表时间：
1988-11-01
影响因子：
11.1
通讯作者：
PROCHASKA, HJ
中科院分区：
文献类型：
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作者：
TALALAY, P;DELONG, MJ;PROCHASKA, HJ
致癌作用被属于许多不同类别的各种各样的试剂阻断-例如，酚类抗氧化剂、偶氮染料、多环芳族化合物、类黄酮、香豆素、肉桂酸酯、吲哚、异硫氰酸酯、1，2-二硫醇-3-硫酮和硫代氨基甲酸酯。这些抗癌剂唯一已知的共同特性是，它们能够提高动物细胞中酶的活性，从而抑制活性亲电形式的致癌物。对醌还原酶[NAD（P）H：（醌受体）氧化还原酶，EC 1.6.099.2]和谷胱甘肽S-转移酶诱导作用的结构-活性研究表明，许多抗癌酶诱导剂含有一种独特的、迄今尚未认识的化学特征（或在代谢后获得这种特征），可调节这些保护酶的合成。诱导剂是迈克尔反应受体，其特征在于通过与吸电子取代基缀合而呈现亲电性（带正电荷）的烯属（或炔属）键。诱导剂的效力与其在Michael反应中的效率平行。许多诱导剂也是谷胱甘肽S-转移酶的底物，这进一步证明了它们的亲电性。这些概括不仅提供了机制的洞察力，这些看似无关的抗癌剂如何诱导化学保护酶的复杂问题，但也导致了潜在的化学保护活性的诱导剂的结构的预测。
Carcinogenesis is blocked by an extraordinary variety of agents belonging to many different classes-e.g., phenolic antioxidants, azo dyes, polycyclic aromatic, flavonoids, coumarins, cinnamates, indoles, isothiocyanates, 1,2-dithiol-3-thiones, and thiocarbamates. The only known common property of these anticarcinogens is their ability to elevate in animal cells the activities of enzymes that inactivate the reactive electrophilic forms of carcinogens. Structure-activity studies on the induction of quinone reductase [NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.099.2] and glutathione S-transferases have revealed that many anticarcinogenic enzyme inducers contain a distinctive and hitherto unrecognized chemical feature (or acquire this feature after metabolism) that regulates the synthesis of these protective enzymes. The inducers are Michael reaction acceptors characterized by olefinic (or acetylenic) bonds that are rendered electrophillic (positively charged) by conjugation with electron-withdrawing substituents. The potency of inducer parallels their efficiency in Michael reaction. Many inducers are also substrates for glutathione S-transferases, which is further evidence for their electrophilicity. These generalizations have not only provided mechanistic insight into the perplexing question of how such seemingly unrelated anticarcinogens induce chemoprotective enzymes, but also have led to the prediction of the structures of inducers with potential chemoprotective activity.