Department of Nutrition, China Medical University, Taichung, Taiwan.
Food Funct. 2015 Jun;6(6):1936-43. doi: 10.1039/c4fo01131g.
Induction of phase II enzymes is important in cancer chemoprevention. We compared the effect of rosemary diterpenes on the expression of the pi class of glutathione S-transferase (GSTP) in rat liver Clone 9 cells and the signaling pathways involved. Culturing cells with 1, 5, 10, or 20 μM carnosic acid (CA) or carnosol (CS) for 24 h in a dose-dependent manner increased the GSTP expression. CA was more potent than CS. The RNA level and the enzyme activity of GSTP were also enhanced by CA treatment. Treatment with 10 μM CA highly induced the reporter activity of the enhancer element GPEI. Furthermore, CA markedly increased the translocation of nuclear factor erythroid-2 related factor 2 (Nrf2) from the cytosol to the nucleus after 30 to 60 min. CA the stimulated the protein induction of p38, nuclear Nrf2, and GSTP was diminished in the presence of SB203580 (a p38 inhibitor). In addition, SB203580 pretreatment or silencing of Nrf2 by siRNA suppressed the CA-induced GPEI-DNA binding activity and GSTP protein expression. Knockdown of p38 or Nrf2 by siRNA abolished the activation of p38 and Nrf2 as well as the protein induction and enzyme activity of GSTP by CA. These results suggest that CA up-regulates the expression and enzyme activity of GSTP via the p38/Nrf2/GPEI pathway.
诱导 II 相酶在癌症化学预防中很重要。我们比较了迷迭香二萜对大鼠肝克隆 9 细胞中 pi 类谷胱甘肽 S-转移酶 (GSTP)表达的影响及其涉及的信号通路。用 1、5、10 或 20 μM 迷迭香酸 (CA) 或迷迭香醇 (CS) 培养细胞 24 小时，呈剂量依赖性增加 GSTP 表达。CA 比 CS 更有效。CA 处理还增强了 GSTP 的 RNA 水平和酶活性。用 10 μM CA 处理可高度诱导增强子元件 GPEI 的报告基因活性。此外，CA 在 30 至 60 分钟后可明显将核因子红细胞 2 相关因子 2 (Nrf2) 从细胞质转位到细胞核。CA 刺激 p38、核 Nrf2 和 GSTP 的蛋白诱导，而在存在 SB203580(一种 p38 抑制剂)的情况下则减弱。此外，SB203580 预处理或 siRNA 沉默 Nrf2 可抑制 CA 诱导的 GPEI-DNA 结合活性和 GSTP 蛋白表达。siRNA 敲低 p38 或 Nrf2 可消除 CA 激活的 p38 和 Nrf2 以及 CA 诱导的 GSTP 的蛋白诱导和酶活性。这些结果表明 CA 通过 p38/Nrf2/GPEI 通路上调 GSTP 的表达和酶活性。
