Effect of Phytochemicals on Biochemical Mechanisms Relevant to Carcinogenesis

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Numerous lines of evidence have shown that diets rich in fruits and vegetables prevent or slow various types of cancers, including breast, prostate, and kidney cancers. However, the plant constituents (phytochemicals) responsible for this, and their mechanisms of action, remain to be elucidated. In this, the major project of our Section, we have examined the effect of a number of phytochemicals on various biochemical mechanisms relevant to carcinogenesis. The phytochemicals studied include the flavonoids, which are present in all fruits and vegetables. These include diosmin, from citrus fruit, quercetin, the most abundant flavonoid which is present in all dietary plants, and galangin and kaempferol, metabolites of quercetin. Other phytochemicals include the b-diketones curcumin and dibenzoylmethane, and resveratrol, a phytoalexin present in grape skins and therefore in grape juice and wine. All of these compounds have been shown to be chemopreventive in animal models of cancer, and epidemiologic studies have shown that food items containing large amounts of these compounds are associated with a reduced risk of cancer.There are many biochemical and molecular events associated with the development of cancer. One of the most important pathways is mediated by the aryl hydrocarbon receptor (AhR). The AhR is a cytoplasmic transcription factor which, upon ligand binding, translocates to the nucleus, where, with its protein partner ARNT, it interacts with the xenobiotic responsive element (XRE) present in the promoter region of a number of genes. The best characterized molecular response to ligands of the AhR is the induction of expression of cytochrome P450 1A1 (CYP1A1). CYP1A1 is a Phase 1 metabolic enzyme that activates environmental procarcinogens to their ultimate genotoxic forms. In addition to CYP1A1, the AhR controls a number of other genes, termed the "AhR battery", which affect both the activation and detoxification of carcinogens. We have concentrated on the Phase 1, or activating, enzymes, including CYP1A1, CYP1B1, and CYP1A2. We have also examined the effect phytochemicals on quinone reductase, a Phase 2, or detoxifying, enzyme, that is part of the AhR battery. In carrying out this research, we have done both in vitro experimentation in a variety of cell lines, as well as in vivo experimentation in rodents. We have examined how certain phytochemicals affect the activity of the AhR, including its ability to bind carcinogenic ligands and to interact with the XRE. We have examined the transcriptional activation of CYP1A1 and determined the effect of chemopreventive compounds on the expression and enzymatic activity of CYP1A1, CYP1B1, and CYP1A2. We have studied a number of environmental carcinogens that bind to the AhR, such as benzo[a]pyrene (BP), a polycyclic aromatic hydrocarbon (PAH) that is a potent environmental carcinogen present in cooked meat, cigarettes, and as by-products of industrial waste. We have also examined 2,3,5,7-tetrachlorodibenzo-p-dioxin(TCDD), a member of the dioxin family of potent carcinogens and the prototypical AhR ligand. We have found that many dietary phytochemicals modulate the cellular response to environmental carcinogens by affecting the AhR. For example, we demonstrated that resveratrol inhibits both the activity and expression of CYP1A1 that is normally induced by carcinogens such as TCDD or BP. It does this by blocking the binding of the ligand-activated AhR with the XRE of the CYP1A1 promoter, preventing the upregulation of transcription. In addition, it directly inhibits enzymatic activity by a competitive mechanism. Thus, this dual mechanism of inhibiting the major carcinogen-activating enzyme in most tissues provides a biochemical mechanism for its proven chemopreventive effect. We have also found that AhR activity is modulated by curcumin, dibenzoylmethane, quercetin, diosmin, and a number of other phytochemicals. We are currently investigating the effect of these compounds on other mechanisms involved in carcinogenesis, including the modulation of expression of g-glutamyltranspeptidase and telomerase. In order to identify further molecular targets of phytochemicals, we are also utilizing microarray technology. We have also examined the effects of other chemopreventive compounds that are not phytochemicals, on the AhR. These include the steroid hormone dehydroepiandrosterone and the nonsteroidal anti-inflammatant drug, sulindac.