The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin
The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin
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DOI：
10.1042/bst0280033
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发表时间：
2000-02-01
影响因子：
3.9
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
--
作者：
Hayes, JD;Chanas, SA;Yamamoto, M
综述了酚类抗氧化剂和6-乙氧基-1,2-二氢-2,2,4-三甲基喹啉（乙氧基喹啉）的癌症化学预防作用。这些药物主要通过诱导II期药物代谢酶（如谷胱甘肽s -转移酶（GST））来发挥其有益作用。讨论了合成抗氧化剂对含羰基化合物（包括醌类）的氧化代谢要求，以便它们能诱导基因表达。先前的研究表明亮氨酸拉链转录因子Nrf2参与了酚类抗氧化剂丁基羟基茴香醚（BHA）诱导GST的过程。在小鼠肝脏中，具有Nrf2基因靶向破坏的小鼠提供的证据表明，转录因子调节几种α类和Mu类GST亚基的基础表达，但不调节Pi类GST。在Nrf2敲除小鼠中，BHA和合成抗氧化剂乙氧基醌对α类和Mu类GST的肝脏诱导作用同样受损，表明这些药物通过相关机制影响基因激活。值得注意的是，抗氧化剂对GST的残留诱导在Nrf2突变小鼠中很明显，这表明存在另一种基因激活机制。
An overview is provided of the cancer chemoprevention actions of phenolic antioxidants and 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline(ethoxyquin). These agents principally appear to exert their beneficial effects through induction of phase II drug-metabolizing enzymes such as glutathione S-transferase (GST). The requirement for oxidative metabolism of the synthetic antioxidants to carbonyl-containing compounds, including quinones, in order that they can induce gene expression is discussed. Previous work has shown that the basic leucine zipper transcription factor Nrf2 is involved in induction of GST by the phenolic antioxidant butylated hydroxyanisole (BHA). Evidence is provided from a mouse possessing a targeted disruption of the Nrf2 gene that, in murine liver, the transcription factor regulates basal expression of several class Alpha and class Mu GST subunits, but not class Pi GST. In the Nrf2 knock-out mouse, hepatic induction of class Alpha and class Mu GST by BHA and the synthetic antioxidant ethoxyquin is similarly impaired, suggesting that these agents affect gene activation by a related mechanism. Significantly, residual induction of GST by antioxidants is apparent in the Nrf2 mutant mouse, indicating the existence of an alternative mechanism of gene activation.