Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice:: mechanism of its anti-initiating action
Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice:: mechanism of its anti-initiating action
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DOI：
10.1093/carcin/bgn064
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发表时间：
2008-05-01
期刊：
影响因子：
4.7
通讯作者：
Maru, Girish B.
中科院分区：
文献类型：
--
作者：
Garg, Rachana;Gupta, Sanjay;Maru, Girish B.
姜黄素在实验体系中显示出具有抗引发和抗促进活性。然而，其作用机制在体内并没有完全阐明。本研究以苯并[a]芘（B[a] P）为模型致癌物，研究姜黄素介导的抗启动机制。用化学预防剂量的姜黄素对小鼠进行饮食预处理，结果显示，在肝和肺中，B[a] P诱导的酶活性、细胞色素P450 1A 1/1A 2的蛋白质和信使RNA（mRNA）水平显著抑制。虽然单独的姜黄素没有改变芳烃受体（AhR）的基础水平，但它显著降低了B[a] P诱导的AhR蛋白水平、其磷酸化、核转位和随后与DNA的结合，从而降低了CYP 1A的反式激活。与对照组相比，膳食姜黄素导致小鼠肝和肺中NF-E2相关因子-2（Nrf 2）蛋白水平增加，并增强其核转位。此外，增加结合Nrf 2的抗氧化反应元件发生在核提取物从肝脏和肺的小鼠用饮食姜黄素预处理。在小鼠中，通过饮食姜黄素诱导谷胱甘肽S-转移酶、其亚型和NAD（P）H：醌氧化还原酶-1的活性、蛋白质和mRNA水平抑制了姜黄素介导的Nrf 2活化，导致B[a] P的解毒增加。与观察到的姜黄素介导的B[a] P诱导的I相酶减少和伴随的II相酶诱导一致，饮食姜黄素预处理导致B[a] P诱导的DNA加合物、氧化损伤和炎症显著减少。总之，姜黄素通过调节小鼠I相和II相酶的转录调节因子而表现出抗启动作用。
Curcumin has been shown to possess anti-initiating and anti-promoting activity in experimental systems. However, the mechanisms of its actions are not fully elucidated in vivo. In the present study, mechanisms of curcumin-mediated anti-initiation were investigated in mice employing benzo[a] pyrene (B[a] P) as a model carcinogen. Dietary pretreatment of mice with chemopreventive doses of curcumin showed significant inhibition of B[a] P-induced enzyme activity, protein and messenger RNA (mRNA) levels of cytochrome P450 1A1/1A2 in liver and lungs. Although curcumin alone did not alter the basal levels of aryl hydrocarbon receptor (AhR), it significantly decreased the B[a] P-induced AhR protein levels, its phosphorylation, nuclear translocation and subsequent binding to DNA, thereby decreasing the transactivation of CYP1A. Dietary curcumin led to increase in NF-E2-related factor-2 (Nrf2) protein levels and enhanced its nuclear translocation in liver and lungs of mice as compared with controls. Additionally, increased binding of Nrf2 to antioxidant response element occurred in nuclear extracts from liver and lungs of mice pretreated with dietary curcumin. Induction of activity, protein and mRNA levels of glutathione S-transferase, its isoforms and NAD(P) H:quinone oxidoreductase-1 by dietary curcumin in mice paralleled the curcumin-mediated activation of Nrf2, leading to increased detoxification of B[a] P. In agreement with the observed curcumin-mediated decrease in B[a] P-induced phase I enzyme and concomitant induction of phase II enzymes, pretreatment with dietary curcumin resulted in significant reduction of B[a] P-induced DNA adduct, oxidative damage and inflammation. To conclude, curcumin exhibits anti-initiating effects via modulating the transcriptional regulators of phase I and phase II enzymes in mice.