Interferon (IF) was first recognized as an antiviral agent formed in a variety of cells in response to viral infections. It is now known to affect a wide variety of biological systems: IF is multiple in nature, with individual species exhibiting different patterns of activities. IFs are becoming recognized as natural regulators of cellular processes; in many cases they function by inhibiting the synthesis of macromolecules. In 1976 we made the observation that IF inducing agents (e.g., poly IC and tilorone) markedly depress hepatic cytochrome P-450-linked drug metabolizing systems. These systems largely determine the intensity and duration of drug action because they metabolize most drugs to less toxic and more readily excreted products. Since patients who receive IF will often be treated simultaneously with other drugs, it will be important to know to what extent IF will depress drug metabolism in man. More recently, it has been shown that pure recombinent IF depresses these systems. Studies in our laboratory have led us to the working hypothesis that the more rapidly turning over species of P-450 are the P-450s most depressed by IF. This P-450s are more depressed while they are being induced. Now that it is known that IF depresses the synthesis of a wide variety of proteins, the hypothesis is extended to include enzymes other than the P-450s, particularly those induced during prenatal, early neonatal and suckling phases of development, all of which are under hormonal control. The following major projects are proposed: 1) the effects of IF and IF-inducing agents on a variety of enzymes with widely different half-lives will be studied both in vivo and in cultured primary mouse hepatocytes; 2) the effects of IF on the developmental marker enzymes of mice through prenatal, early neonatal and suckling periods will be compared with effects on constitutive enzymes; 3) the effects of pure reaconstituted human IFs on drug metabolism will be studied in the rhesus monkey; 4) studies already in progress on the effect of impure human leukocyte IF on theophylline metabolism in cancer patients will be continued; these studies may be extended to include studies with pure recombinant human IFs. The research described in this project should contribute to the understanding of the regulatory functions of IF, particularly as applied to the P-450-linked drug metabolizing systems and developmental processes.
| Gooderham, N J; Mannering, G J (1990) In vitro translational activity of messenger-RNA isolated from mice treated with the interferon inducer, polyriboinosinic acid.polyribocytidylic acid. Biochem Pharmacol 39:865-71 |
| Gooderham, N J; Mannering, G J (1986) Depression of cytochrome P-450 and alterations of protein metabolism in mice treated with the interferon inducer polyriboinosinic acid X polyribocytidylic acid. Arch Biochem Biophys 250:418-25 |
| Deloria, L; Abbott, V; Gooderham, N et al. (1985) Induction of xanthine oxidase and depression of cytochrome P-450 by interferon inducers: genetic difference in the responses of mice. Biochem Biophys Res Commun 131:109-14 |
