ON THE MECHANISMS OF INDUCTION OF CANCER-PROTECTIVE ENZYMES - A UNIFYING PROPOSAL
ON THE MECHANISMS OF INDUCTION OF CANCER-PROTECTIVE ENZYMES - A UNIFYING PROPOSAL
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DOI：
10.1073/pnas.82.23.8232
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发表时间：
1985-01-01
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：
PROCHASKA, HJ;DELONG, MJ;TALALAY, P
解毒酶的诱导是多种化学试剂保护啮齿动物免受肿瘤、诱变和致癌物的其他毒性的主要机制。酶NAD（P）H：（醌受体）氧化还原酶（EC 1.6.99.2）可以保护免受醌的毒性，并且是保护性酶诱导的有用标记。醌还原酶可以诱导小鼠Hepa 1c 1c 7肝癌细胞和3 T3胚胎成纤维细胞的化合物，在体内的化学感受器，包括一些酚类抗氧化剂，偶氮染料，芳香族二胺，和氨基酚。结构上不同的儿茶酚（1，2-二酚）和氢醌（1，4-二酚）在这些系统中诱导醌还原酶，但间苯二酚（1，3-二酚）及其取代的类似物是无活性的。此外，只有芳香族1，2-和1，4-二胺和氨基苯酚是诱导剂，而1，3-二胺是完全无活性的。这些研究结果表明，功能能力，形成醌或醌二亚胺，而不是精确的结构，是必不可少的诱导活性和酶诱导信号的产生取决于氧化还原不稳定性。观察到一些化学保护化合物（例如，偶氮染料，β-萘酮）诱导细胞色素P-450和醌还原酶，而其它（例如，叔丁基氢醌）仅诱导醌还原酶的事实可以通过第一类型的诱导剂被P-450酶代谢以形成功能上类似于第二类型的化合物的产物的事实来调和。
Induction of detoxification enzymes is a major mechanism whereby a wide variety of chemical agents protect rodents against neoplastic, mutagenic, and other toxicities of carcinogens. The enzyme NAD(P)H:(quinone acceptor) oxidoreductase (EC 1.6.99.2) can protect against the toxicities of quinones and is a useful marker for protective enzyme induction. Quinone reductase can be induced in murine Hepa 1c1c7 hepatoma cells and 3T3 embryo fibroblasts by compounds that are chemoreceptors in vivo, including some phenolic antioxidants, azo dyes, aromatic diamines, and aminophenols. Structurally dissimilar catechols (1,2-diphenols) and hydroquinones (1,4-diphenols) induce quinone reductase in these systems, but resorcinol (1,3-diphenol) and its substituted analogues are inactive. Furthermore, only aromatic 1,2- and 1,4-diamines and aminophenols are inducers, whereas the 1,3-diamines are completely inactive. These findings suggest that the functional capacity to form quinones or quinone-diimines, rather than the precise structure, is essential for inductive activity and that the generation of the signal for enzyme induction depends upon oxidation-reduction lability. The observations that some chemoprotective compounds (e.g., azo dyes, .beta.-naphthoflavone) induce both cytochromes P-450 and quinone reductase, whereas others (e.g., tert-butylhydroquinone) induce only quinone reductase, can be reconciled by the fact that inducers of the first type are metabolized by P-450 enzymes to form products that are functionally similar to compounds of the second type.