Although the ability of inorganic selenium to inhibit chemical carcinogenesis in animal models is well recognized, the very narrow boundary between an effective dose and a dose that is toxic is a severe limitation to its use as a chemopreventive agent under realistic conditions. In contrast, the finding that certain organic compounds containing selenium are active in cancer chemoprevention offers the possibility that the structures of these compounds can be modified for maximum efficacy and minimum toxicity. To rationally design more effective organoselenium chemopreventive compounds, it is necessary that their biological effects and their mechanisms of action be well characterized. Since the chemopreventive potency as well as the toxicity of these compounds depend strongly on their disposition, a major aim of Lab Program 3 is to examine organoselenium compounds in terms of absorption, distribution and excretion alter acute and prolonged administration to male and female rats. Since previous studies indicated that the inhibition of azoxymethane (AOM)-induced colon carcinogenesis in rats by benzyl selenocyanate (BSC), a versatile chemopreventive agent developed in Lab Program 1, depends on its ability to induce cytochrome P45OIIE1, the second major aim is to further characterize BSC and other organoselenium compounds as modifiers of phase I and phase II enzymes involved in the metabolism of xenobiotics in rat liver and in other rat organs. This will be carried out using substrate-specific assays and immunological methods. A closely related aim is to examine effects of organoselenium compounds found to be active in producing aberrant crypt foci by Lab Program 2 specifically on the modification of AOM metabolism in rat liver and colon. Since several organoselenium compounds described in the literature possess glutathione peroxidase like activity and inhibit radiation damage and lipid peroxidation, another major aim will be to assay organoselenium compounds developed in Lab Program 1 for ability to suppress oxidative damage to lipids and nucleic acids in rat organs. Based on the observation that BSC inhibits the formation of 8-oxoguanine and other modified bases produced in rat liver DNA and RNA by the hepatocarcinogen 2-nitropropane, the prediction that BSC (or other organoselenium compounds) will inhibit the carcinogenicity of 2-nitropropane and ferric nitrilotriacetate for rat liver and kidney, respectively, will be tested. Further characterization of newly developed organoselenIum compounds with respect to pharmacokinetics, enzyme induction, influence on AOM metabolism and ability to inhibit oxidative damage, as proposed in this Lab Program, is expected to provide increased understanding of their mechanisms of action, thus indicating directions for the synthesis of even more effective chemopreventive agents.
