Epidemiological studies indicate that a majority of the cases of colorectal cancer are etiologically related to environmental factors. Carcinogenic xenobiotics are activated by phase I biotransformation enzymes. This biotransformation mainly occurs in the liver, but also in extrahepatic tissues. Cytochrome P4501A1, 1A2 and 2E1 (CYP1A1, lA2 and 2E1) are major catalysts in the bioactivation of a number of putative colorectal cancer procarcinogens such as polycyclic aromatic hydrocarbons, heterocyclic amines and N-nitrosoamines. Thus, control of biotransformation enzymes is a potential approach to prevent tumorigenesis in the colon. Recently, we were able to demonstrate that mice deficient in the angiotensin II (Ang II) subtype 2 (AT2) receptor gene are resistant to azoxymethane (AOM)-induced colon adenocarcinoma. AOM-stimulated CYP1A1, 1A2 and 2E1 protein induction in the liver of wild type mice is more significant than in AT2: receptor-deficient (AT2-KO) mice. These preliminary studies suggest that Ang II-AT2 receptor signaling may function as a regulator of cytochrome P450 enzyme activities in the liver. Based upon our preliminary studies we hypothesize that 1) Ang II- AT2 receptor-mediated signaling is involved in the induction of carcinogen- metabolizing cytochrome P450s in the liver and/or colon epithelial cells, 2) attenuation of AT2 receptor function diminishes DNA adduct formation in the liver and colon epithelial cells, and thus 3) the Ang II-AT2 receptor-mediated signal is involved in the initiation of tumorigenesis in the colon. Accordingly, pharmacological attenuation of the AT2 receptor function prevents colon tumorigenesis. In this proposal we place our priority on the chemoprevention of AOM-induced colon cancer. Thus, we propose to determine the effect of blockade of the AT2 receptor function by the AT2 receptor- specific antagonist PD123319 in AOM-induced colon adenocarcinoma and to clarify the mechanism of low susceptibility to AOM in AT2-KO mice. These studies will clarify the role of the Ang II-AT2 receptor in colorectal tumorigenesis and will provide a totally new target for the chemoprevention of colon cancer.
