Activation of mitogen-activated protein kinases by green tea polyphenols: potential signaling pathways in the regulation of antioxidant-responsive element-mediated phase II enzyme gene expression

Abstract

Green tea polyphenols, major constituents of green tea, are potent chemopreventive agents in a number of experimental models of cancer in animals. The mechanisms of cancer protection by these agents are not clear, but may involve modulation of the enzyme systems responsible for the detoxification of chemical carcinogens. The present studies show that a green tea polyphenol extract (GTP) induces chloramphenicol acetyltransferase (CAT) activity in human heptoma HepG2 cells transfected with a plasmid construct which contains an antioxidant-responsive element (ARE) and a minimal glutathione S-transferase Ya promoter linked to the CAT reporter gene. This indicates that GTP stimulates the transcription of Phase II detoxifying enzymes through the ARE. To explore the upstream signaling pathways leading to gene expression, we studied the involvement of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 2 (ERK2) and c-Jun N-terminal kinase 1 (JNK1). Potent activation of ERK2 was seen following treatment of HepG2 cells with different concentrations of GTP. Similar to ERK2, JNK1 was also strongly activated by treatment with GTP, although to a lesser extent and in a different dose-dependent fashion. Kinetic studies revealed that GTP activation of JNK1 was delayed and sustained, whereas ERK2 activation was rapid and transient. Furthermore, GTP treatment also increased mRNA levels of the immediate-early genes c-jun and c-fos, as determined by reverse transcriptase-coupled polymerase chain reaction. Taken together, these studies provide insights into the action of GTP and suggest that the stimulation MAPKs may be the potential signaling pathways utilized by GTP to activate ARE-dependent genes.

Green Tea Polyphenol Protection Against 4-Nitroquinoline 1-Oxide-Induced Bone Marrow Lipid Peroxidation and Genotoxicity in Wistar Rats

“…GTP transcriptionally activates phase II genes, thereby increasing the synthesis of antioxidant enzymes (Yu et al, 1997). So, elevation in the activity of GST enhances the detoxification of 4-NQO, thus the level of tissue damage was found to be decreased in rats simultaneously treated with GTP and 4-NQO.…”

Bioactive substances of plant origin in food - impact on genomics

“…Dietary flavonoids are ligands of the AhR and affect cyp1a1 expression, with quercetin being a very potent activator whereas kaempferol and green tea polyphenols (GTP) -catechins; especially (-)-epigallocatechin gallate (EGCG) inhibit cyp1a1 transcription induced by TCDD [19,104]. Alternatively, flavonoids are reported to act through the transcriptional regulation of genes by directly affecting the antioxidant/oxidant response element (ARE/ORE) in the promoter regions of some of the genes (gsta1, cyp1a1, cyp1a2) of the XME [108]. It should be noted that ARE/ORE is the electrophile response element, so flavonoids may act directly on ARE/ORE as phenolic radicals or indirectly by the effects on oxidative stress.…”

“…Certain polyphenols may directly or indirectly induce phase II enzymes such as glutathione transferases (GSTs), NAD(P)H:quinone reductases, epoxide hydrolases, and UDPglucuronosyltransferases that will enhance the excretion of oxidising species [29,108]. Concomitantly, flavonoids significantly decrease the activity of antioxidant enzymes glutathione reductase (GR), catalase (CAT) and glutathione peroxidase (GPx) in the red blood cells of rats [11].…”

“…They either activate NF-kB (measured by the electrophoretic mobility shift assay) with the formation of H 2 O 2 [82], or phenoxyl radicals and/or their derivatives [51] or inhibit NF-kB DNA binding [10]. Phenolics trigger c-Jun N-terminal kinase (JNK1) and/or extracellular signal regulated protein kinase (ERK2) in a dose-dependent fashion [108]. In contrast to Yu et al [108] who observed activation, Chung et al [18] found the inhibition of ERK2, JNK1, and AP-1 activity.…”

“…Phenolics trigger c-Jun N-terminal kinase (JNK1) and/or extracellular signal regulated protein kinase (ERK2) in a dose-dependent fashion [108]. In contrast to Yu et al [108] who observed activation, Chung et al [18] found the inhibition of ERK2, JNK1, and AP-1 activity. Since JNKs are strongly and preferentially activated by stress stimuli, this signaling pathway as one of the stress responses and is functionally involved in cellular survival and/or apoptosis [47].…”