Cancer Chemoprevention & Herbal Antioxidants 83 and current treatment approaches have met with limited success. Based on the experience with some infectious diseases and the recent progress in cardiology, prevention of diseases appears to be one of the achievable, cost effective and attractive approaches. Thus, cancer prevention serves as a promising approach to decrease cancer burden. Cancer chemoprevention can be defined as the use of natural or synthetic compounds to prevent, suppress or delay the development of invasive carcinoma. Chemoprevention offers a promising approach to primary cancer prevention for a variety of organ systems. Based on empirical experiments and clinical evaluations many compounds belonging to diverse chemical classes have been identified as potential chemopreventive agents [2]. These include vitamins, minerals, naturally occurring phytochemicals and synthetic compounds. The scientific rationale for the use of cancer chemo- prevention is based on the fundamental concept of multi-step carcinogenesis. Carcinogenesis is a long evolving process which can be broadly divided into two principal steps viz., initiation where normal cells acquire mutations via environ- mental mutagens, viruses etc. followed by promotion/ progression where the initiated/mutant cells clonally expand and further transform to give rise to neoplasia. Thus inhibition of any stage of carcinogenesis by any agent can potentially prevent cancer [3] (Fig. 1). Cellular Metabolism and Carcinogenesis Cellular metabolism plays a very critical role in the process of initiation during carcinogenesis [4]. Xenobiotics entering the cellular environment are metabolized by phase I and phase II enzymes. Phase I enzymes, predominantly Cytochrome P450s (CYP450s—a super family of heme-thiolate enzymes), are involved in the first step of metabolism where xeno- biotics are processed to more electrophilic moieties for further detoxification by phase II enzymes [5]. This step can be termed as bioactivation which renders pro-carcinogens to Fig. 1. Chemopreventive agents can prevent cancer by inhibit- ing the process of carcinogenesis either by inhibiting ini- tiation and/or promotion event. Vol. 40, No. 2, 2007 reactive intermediates and these in turn can form bio- molecular adducts e.g. DNA-adducts, protein-adducts etc. which mark the process of initiation. Thus, decreased activation of carcinogens due to modulation of the CYP 450 enzymes could be one of the plausible targets for chemoprevention to prevent the cancer initiation process. CYP1-CYP9 family of enzymes which are principally involved in xenobiotic metabolism have distinct substrate specificities and are differentially regulated by different ligands which interact with endogenous receptors like aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR). AhR is one of the well studied receptors involved in induction of CYP1A sub- family enzymes which are primarily involved in metabolizing xenobiotics like poly aromatic hydrocarbons (PAHs). AhR is a ligand dependent transcription factor and member of the basic-helix-loop-helix family. In an unliganded or inactive state the receptor is present in the cytoplasm in a complex with two molecules of molecular chaperones, hsp90, an immunophilin like protein, XAP-2 and the hsp90 interacting protein, p23. Upon ligand binding, the ligand-AhR-hsp90- XAP2-p23 complex translocates to nucleus where hsp90- XAP2-p23 dissociates from the ligand-AhR complex. This ligand-AhR complex further associates with a structurally related protein, AhR nuclear translocator (ARNT). This ligand bound AhR-ARNT complex recognizes consensus sequences termed xenobiotic response elements (XREs) to modulate the expression of downstream genes. Certain chemopreventive agents, like plant flavanoids, have shown to act as natural ligands of AhR and hence not only compete for binding with PAHs but also block subsequent nuclear translocation and DNA binding followed by transactivation of CYP genes [6]. Such agents, that can block pro-carcinogen activation, can serve as potential blockers of initiation of carcinogenesis (Fig. 2). In the next step of metabolism, detoxification by phase II enzymes decrease the burden of bio-molecular adducts by eliminating the reactive-intermediates from cellular environ- ment. Activated pro-carcinogens are conjugated with endog- enous bio-molecules like glutathione (GSH) or glucuronic acid by phase II enzymes rendering them less toxic and more water soluble, thus blocking the process of initiation [5]. Hence, any agent that can alter this cellular metabolism by inducing phase II enzymes to block the process of initiation of carcinogenesis can be employed as a potential chemo- preventive agent. Unlike phase I enzymes, phase II enzymes or more frequently referred as cyto-protective enzymes are regulated by common upstream promoter regulatory element called ARE (anti-oxidant response element) [7]. Thus, many enzymes regulated by this promoter element are referred as phase II enzymes and their inducibility can be exploited as potential chemopreventive strategy. Some of the most commonly exploited detoxifying enzymes are glutathione S- transferases (GSTs), UDP-glucuronosyltransferases, NADPH