Williams S N, Shih H, Guenette D K, Brackney W, Denison M S, Pickwell G V, Quattrochi L C
Section of Medical Toxicology, Department of Medicine, University of Colorado Health Sciences Center, B146, 4200 East 9th Avenue, 80262, Denver, CO, USA.
Chem Biol Interact. 2000 Nov 1;128(3):211-29. doi: 10.1016/s0009-2797(00)00204-0.
Green tea possesses significant anticancer activity in numerous experimental animal models, including demonstrated protection against aryl hydrocarbon induced cancers. The aryl hydrocarbon receptor (AhR) mediates the transcriptional activation of CYP1A1 and CYP1A2. In the present study, we investigated the effects of commercially available green tea extracts (GTEs) and individual tea catechins on the function of the AhR and on CYP1A gene expression in human hepatoma HepG2 cells and primary cultures of human hepatocytes. GTEs inhibited the transcription of a human CYP1A1 promoter-driven reporter gene induced by the AhR ligand 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in a concentration-dependent manner and inhibited the induced accumulation of both CYP1A1 and CYP1A2 mRNAs. GTEs blocked TCDD-induced binding of the AhR to DNA in HepG2 cells and in vitro in isolated hepatic cytosol. To determine if the observed effects were due to a single green tea component, we examined the four major catechins present in GTEs. Only (-)-epigallocatechin gallate (EGCG), the most abundant catechin in green tea, was able to inhibit TCDD-induced binding of the AhR to DNA and subsequent CYP1A transcription, however EGCG alone was less effective than GTEs. We next examined GTEs and catechins for AhR agonist activity. GTEs caused a concentration-dependent increase in CYP1A1-promoter driven reporter gene activity and caused accumulation of CYP1A1 mRNA and protein, but we found that individual catechins were unable to induce the expression of CYP1A1. Our results demonstrate that GTEs as a whole exert mixed agonist/antagonist activity on the AhR, while EGCG functions as a strict AhR antagonist. Therefore, modulation of human CYP1A expression by green tea extracts can not be attributed to the action of a single tea catechin, but rather is due to the effects of a complex mixture. These findings may be useful in future studies concerning green tea as a cancer preventive agent.
绿茶在众多实验动物模型中具有显著的抗癌活性，包括对芳烃诱导的癌症有明显的保护作用。芳烃受体（AhR）介导CYP1A1和CYP1A2的转录激活。在本研究中，我们调查了市售绿茶提取物（GTEs）和单个儿茶素对人肝癌HepG2细胞和原代人肝细胞中AhR功能以及CYP1A基因表达的影响。GTEs以浓度依赖性方式抑制由AhR配体2,3,7,8-四氯二苯并对二恶英（TCDD）诱导的人CYP1A1启动子驱动的报告基因的转录，并抑制CYP1A1和CYP1A2 mRNA的诱导积累。GTEs在HepG2细胞和体外分离的肝细胞溶胶中阻断TCDD诱导的AhR与DNA的结合。为了确定观察到的效应是否归因于单一绿茶成分，我们检测了GTEs中存在的四种主要儿茶素。只有（-）-表没食子儿茶素没食子酸酯（EGCG），绿茶中含量最丰富的儿茶素，能够抑制TCDD诱导的AhR与DNA的结合以及随后的CYP1A转录，然而单独的EGCG比GTEs效果差。接下来我们检测GTEs和儿茶素的AhR激动剂活性。GTEs导致CYP1A1启动子驱动的报告基因活性呈浓度依赖性增加，并导致CYP1A1 mRNA和蛋白质的积累，但我们发现单个儿茶素无法诱导CYP1A1的表达。我们的结果表明，GTEs整体上对AhR发挥混合激动剂/拮抗剂活性，而EGCG作为严格的AhR拮抗剂发挥作用。因此，绿茶提取物对人CYP1A表达的调节不能归因于单一茶儿茶素的作用，而是由于复杂混合物的效应。这些发现可能对未来关于绿茶作为癌症预防剂的研究有用。
