Antioxidants and oxidants regulated signal transduction pathways.
Many drugs and xenobiotics induce signal transduction events leading to gene expression of either pharmacologically beneficial effects, or unwanted side effects such as cytotoxicity which can compromise drug therapy. Using dietary chemopreventive compounds (isothiocyanates and green tea polyphenols), which are effective against various chemically-induced carcinogenesis models in animals studies, we studied the signal transduction events and gene expression profiles. These compounds have typically generated cellular "oxidative stress" and modulated gene expression including phase II detoxifying enzymes GST and QR as well as cellular defensive enzymes, heme oxygenase 1 (HO-1) and GST via the antioxidant/electrophile response element (ARE/EpRE). Members of the bZIP transcription factor, Nrf2 which heterodimerizes with Maf G/K, were found to bind to ARE, and transcriptionally activate ARE. Additionally the mitogen-activated protein kinases (MAPK; ERK, JNK and p38) were differentially activated by these compounds, and involved in the transcriptional activation of ARE-mediated reporter gene. Transfection studies with various cDNA encoding for wild-type of MAPK and Nrf2 showed synergistic response during co-transfection and to these agents. However, by increasing the concentrations of these xenobiotics, caspase activities and apoptosis were observed which were preceded by mitochondria damage and cytochrome c mitochondria release. Further, increased concentrations led to rapid cell necrosis. [corrected] Thus, we have proposed a model, that at low concentrations, these compounds activate MAPK pathway leading to activation of Nrf2 and ARE with subsequent induction of phase II and other defensive genes which protect cells against toxic insults thereby enhancing cell survival, a beneficial homeostatic response. At higher concentrations, these agents activate the caspase pathways, leading to apoptosis, a potential cytotoxic effect if it occurred in normal cells. The studies of these signaling pathways may yield important insights into the pharmacodynamic and toxicodynamic effects of drugs and xenobiotics during pharmaceutical drug discovery and development.
Owuor
Edward D
ED
Department of Pharmaceutics, Ernest Mario School of Pharmacy, and the Environmental and Occupational Health Sciences Institute (EOHSI), Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Kong
Ah-Ng Tony
AN
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis; D018890:Chemoprevention; D004268:DNA-Binding Proteins / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051267:NF-E2-Related Factor 2; D009369:Neoplasms / Q000517:prevention & control; D016877:Oxidants / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology
D000975:Antioxidants; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016877:Oxidants; D015534:Trans-Activators; D020928:Mitogen-Activated Protein Kinases