Many mutagens/carcinogens need to be metabolized by cytochrome P-450 dependent monooxygenases in order to be toxic, mutagenic and/or carcinogenic. Interferon inducers have been shown to inhibit the biotransformation of some zenobiotics metabolized by the liver. We propose to examine the effects of interferon inducers and preparations on the biotransformation of procarcinogens/promutages in mouse liver and skin. These tissues are chosen because they have constitutive and inducible P-450 dependent monooxygenases, and the initation and promotional stages of chemical carcinogenesis can be experimentally separated in these two tissues. Initially, skin and liver homogenates from mice treated in vivo with interferon inducers or preparations will be tested for their abilities to activate promutagens to mutagenic metabolites that can be scored in an Ames Salmonella assay. The effects of interferon preparations on mutagenesis will also be analyzed in a cell-mediated mutagenesis assay that uses cultured keratinocytes for the metabolism of promutagens and V-79 fibroblasts as a detection system. Data from the mutation analyses will be used to design tumor studies to test if interferon inducers and preparations can inhibit the initiation stage of chemical carcinogenesis in skin and liver two-stage carcinogenesis protocols. Analyses of promutagen/procarcinogen metabolites by HPLC, components of the mixed-function oxygenase system, epoxide hydrase, detoxification-conjugation enzymes, and effects upon direct acting carcinogens will be made in cultured keratinocytes and tissue homogenates following interferon induction or treatment. Mock, heat inactivated, and immunoabsorbed interferon preparations will be tested in the cell-mediated mutagenesis assay and in two-stage skin tumor protocols in order to determine if interferon is the factor responsible for the detected effects. This proposal will provide new and important data on the effects of interferon inducers and preparations on the initiation phase of chemical carcinogenesis. In addition, these studies have clinical significance because of the dramatic changes interferon might cause in the pharmacokinetics and metabolism of drugs metabolized by P-450 dependent monooxygenases.
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