Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, India.
Biochimie. 2013 Aug;95(8):1629-39. doi: 10.1016/j.biochi.2013.05.004. Epub 2013 May 21.
Identifying agents that activate nuclear factor erythroid-2 related factor-2 (Nrf2), a key regulator of various cytoprotective antioxidant, and detoxifying enzymes has evolved as a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary supplementation of structurally diverse phytochemicals- astaxanthin, blueberry, chlorophyllin, ellagic acid, and theaphenon-E on Nrf2 signaling, and xenobiotic-metabolizing and antioxidant enzymes in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model. We observed that these phytochemicals induce nuclear accumulation of Nrf2 while downregulating its negative regulator, Keap-1. This was associated with reduced expression of CYP1A1 and CYP1B1, the cytochrome P450 isoforms involved in the activation of DMBA, and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine coupled with upregulation of the phase II detoxification enzymes glutathione S-transferases and NAD(P)H:quinone oxidoreductase 1 and the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. In addition, these dietary phytochemicals also enhanced the DNA repair enzymes 8-oxoguanine glycosylase 1 (OGG1), xeroderma pigmentosum D (XPD), xeroderma pigmentosum G (XPG), and x-ray repair cross complementing group 1 (XRCC1). Our data provide substantial evidence that the dietary phytochemicals inhibit the development of HBP carcinomas through the activation of Nrf2/Keap-1 signaling and by upregulating cytoprotective enzymes. The extent of the chemopreventive effects of the phytochemicals was in the order: chlorophyllin > blueberry > ellagic acid > astaxanthin > theaphenon-E. Thus these dietary phytochemicals that function as potent activators of Nrf2 and its orchestrated response are novel candidates for cancer chemoprevention.
鉴定能够激活核因子红细胞 2 相关因子 2（Nrf2）的物质，作为癌症化学预防的一种有前途的策略，Nrf2 是各种细胞保护抗氧化剂和解毒酶的关键调节剂。在本研究中，我们研究了结构多样的植物化学物质——虾青素、蓝莓、叶绿素、鞣花酸和茶素 E 在 7,12-二甲基苯并[a]蒽（DMBA）诱导的颊囊（HBP）致癌模型中对 Nrf2 信号转导和异生物质代谢及抗氧化酶的影响。我们观察到，这些植物化学物质诱导 Nrf2 的核积累，同时下调其负调节剂 Keap-1。这与 CYP1A1 和 CYP1B1 的表达减少有关，CYP1A1 和 CYP1B1 是参与 DMBA 激活的细胞色素 P450 同工酶，以及氧化应激标志物 8-羟基-2'-脱氧鸟苷与 II 相解毒酶谷胱甘肽 S-转移酶和 NAD(P)H：醌氧化还原酶 1 和抗氧化酶超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶的上调有关。此外，这些膳食植物化学物质还增强了 DNA 修复酶 8-氧鸟嘌呤糖苷酶 1（OGG1）、着色性干皮病 D（XPD）、着色性干皮病 G（XPG）和 X 射线修复交叉互补组 1（XRCC1）。我们的数据提供了充分的证据表明，膳食植物化学物质通过激活 Nrf2/Keap-1 信号并上调细胞保护酶来抑制 HBP 癌的发展。植物化学物质的化学预防效果的程度依次为：叶绿素>蓝莓>鞣花酸>虾青素>茶素 E。因此，这些作为 Nrf2 及其协调反应的有效激活剂的膳食植物化学物质是癌症化学预防的新候选物。
