A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway
A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway
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DOI：
10.1074/jbc.m110244200
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发表时间：
2002-02-01
影响因子：
4.8
通讯作者：
Uchida, K
中科院分区：
文献类型：
--
作者：
Morimitsu, Y;Nakagawa, Y;Uchida, K
将细胞暴露于各种化学保护化合物可赋予细胞对一系列致癌物的抗性。对于化学保护性化合物的子集，通过增加保护性II期解毒酶（例如谷胱甘肽S-转移酶（GST））的丰度来产生保护。我们最近开发了一种细胞培养系统，使用大鼠肝上皮RL 34细胞，其有效地响应酚类抗氧化剂，导致GST活性的诱导（Kawamoto，Y.，中村，Y.，Naito，Y.，Torii，Y.，Kumagai，T.，Osawa，T.，Ohigashi，H.，萨托，K.，Imagawa，M.，和Uchida，K.（2000）J.Biol.Chem.275，11291-11299）。在本研究中，我们研究了异硫氰酸酯化合物在体外和体内的II期诱导效力，并研究了可能的诱导机制。基于对蔬菜提取物在RL 34细胞中GST诱导剂活性的广泛筛选，我们发现日本辣根、山葵（Wasabia japonica，syn. Eutrema wasabi）作为最丰富的来源，并鉴定了6-甲基亚磺酰基己基异硫氰酸酯（6-HITC）（从西兰花中分离的萝卜硫素（4-甲基亚磺酰基丁基异硫氰酸酯）的类似物）作为山葵中的主要GST诱导剂。6-HITC在RL 34细胞中有效地诱导α类GSTA 1和pi类GSTP 1同工酶。在动物实验中，我们发现6-MSHI被迅速吸收到体内，并且比萝卜硫素更有效地诱导肝脏第11相解毒酶。观察到W 6-HITC激活抗氧化反应元件（ARE），（ii）6-HITC诱导的核定位的转录因子Nrf 2结合ARE，和（iii）的诱导阶段11酶基因被完全废除的nrf 2缺陷小鼠，表明6-HITC是一个潜在的激活剂Nrf 2/ARE依赖性解毒途径。
Exposure of cells to a wide variety of chemoprotective compounds confers resistance to a broad set of carcinogens. For a subset of the chemoprotective compounds, protection is generated by an increase in the abundance of the protective phase II detoxification enzymes, such as glutathione S-transferase (GST). We have recently developed a cell culture system, using rat liver epithelial RL 34 cells, that potently responds to the phenolic antioxidants resulting in the induction of GST activity (Kawamoto, Y., Nakamura, Y., Naito, Y., Torii, Y., Kumagai, T., Osawa, T., Ohigashi, H., Satoh, K., Imagawa, M., and Uchida, K. (2000) J. Biol. Chem. 275, 11291-11299.) In the present study, we investigated the phase II-inducing potency of an isothiocyanate compound in vitro and in vivo and examined a possible induction mechanism. Based on an extensive screening of vegetable extracts for GST inducer activity in RL34 cells, we found Japanese horseradish, wasabi (Wasabia japonica, syn. Eutrema wasabi), as the richest source and identified 6-methylsulfinylhexyl isothiocyanate (6-HITC), an analogue of sulforaphane (4-methylsulfinylbutyl isothiocyanate) isolated from broccoli, as the major GST inducer in wasabi. 6-HITC potently induced both class alpha GSTA1 and class pi GSTP1 isozymes in RL34 cells. In animal experiments, we found that 6-MSHI was rapidly absorbed into the body and induced hepatic phase 11 detoxification enzymes more potently than sulforaphane. The observations that W 6-HITC activated the antioxidant response element (ARE), (ii) 6-HITC induced nuclear localization of the transcription factor Nrf2 that binds to ARE, and (iii) the induction of phase 11 enzyme genes by 6-HITC was completely abrogated in the nrf2-deficient mice, suggest that 6-HITC is a potential activator of the Nrf2/ARE-dependent detoxification pathway.