84 Fig. 2. Schematic presentations of steps where chemopreven- tive agents can inhibit phase I enzyme induction. Chemopreventive agents can block the process of initia- tion by inhibiting xenobiotic induced transcriptional up- regulation of phase I enzymes either by competing for receptor, inhibiting nuclear translocation of ligand and receptor complex or by inhibiting the binding of receptor ligand complex to specific promoter element. X = XAP2; 90 = heat shock protein 90; L = ligand (ex- ogenous/endogenous); XRE = xenobiotic response ele- ment; C = chemopreventive agent. quinone oxidoreductase I (NQO1) and certain other anti- oxidant enzymes like superoxide dismutase, catalase etc. Agents that induce phase II enzymes bring about activation of ARE by activating an obligate transcription factor Nuclear Erythroid Factor 2 – Related Factor 2 (Nrf2), member of the Cap ‘n’ Collar family of basic region leucine b-ZIP transcription factor. Nrf2 heterodimerizes with array of leucine b-zip family members like small maf proteins, jun, fos etc. to either upregulate or inhibit transcription through ARE. Nrf2 under normal uninduced cellular environment is strictly regulated by its cytosolic inhibitor Keap1 which in turn is bound to actin cytoskeleton. Upon activation Nrf2 is released from Keap1 and translocates to nucleus where it binds to ARE after heterodimerizing to other leucine zipper proteins to transciptionally activate the downstream genes. Activating signals are generally regulated by ROS modulation in cells where a number of signaling molecules might interplay in cell type specific manner [7]. Most chemopreventive agents are modulators of cellular ROS and hence activate Nrf2 pathway, which in turn induces phase II detoxifying enzymes thus blocking initiation event (Fig. 3). In addition to bioactivation of xenobiotics, oxidative damage to DNA, proteins and lipids in human body due to R. Patel, et al. Fig. 3. Model representing putative signaling cascade modulat- ed by chemopreventive agents for induction of phase II enzymes. ROS modulation brought about by chemopre- ventive agents activate signaling kinases which modify NRF2. Modified NRF2 dissociates from its inhibitor keap1 and translocates to nucleus where it heterodimer- izes with other transcription factors and binds to ARE, transactivating down stream genes. exposure to endogenous or exogenous chemical agents, chronic infections and inflammations, is also an important factor in carcinogenesis. Thus, quenching of these reactive intermediates or radicals by chemopreventive agents like plant derived anti-oxidants is another important strategy for attenuation of carcinogenesis. In addition to directly quenching reactive intermediates, chemopreventive agents also quench reactive intermediates by activating certain cellular anti-oxidant enzymes like catalase or ameliorating their chemical transformation to carcinogenic products. Furthermore, initiation event can be blocked by enhancing cellular DNA repair [8]. Cellular Proliferation and Apoptosis During carcinogenesis, initiated cells, after accumulating environmental insults and mutations, transform and clonally expand to give rise to tumor and this process is called J. Clin. Biochem. Nutr.