Molecular Pharmacology, Vol 17, 395-399, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Effect of Interferon Inducing Agents (Polyriboinosinic Acid· Polyribocytidylic Acid and Tilorone) on the Heme Turnover of Hepatic Cytochrome P-450

¹ Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

The cytochrome P-450 and heme contents of microsomes are lowered markedly in livers of rats treated with the interferon inducing agents, tilorone and poly(rI·rC) (polyriboinosinic acid·polyribocytidylic acid). The turnover of cytochrome P-450 heme was studied to determine whether the loss of cytochrome P-450 and heme was due to a decreased synthesis or to an increased degradation of the hemoprotein. Two populations of cytochrome P-450 exist in hepatic microsomes, one with a relatively short and one with a long half-life. The half-lives of cytochrome P-450 heme in control animals were determined to be about 8 and 40 h. After the administration of tilorone or poly(rI·rC), the half-life of the short-lived cytochrome P-450 was lowered to about 5 h but that of the long-lived cytochrome P-450 was not changed. These interferon inducing agents produced no appreciable decrease in the incorporation of the radioactivity of administered ALA-3,5-³H or glycine-2-¹⁴C into the heme of cytochrome P-420 derived from cytochrome P-450. However, a rise in specific activity was observed 10 and 24 h after the administration of poly(rI·rC) and tilorone, respectively. This increase in specific activity is interpreted to mean that interferon inducing agents increase the rate of breakdown of preformed cytochrome P-450 heme and that some of this is replaced by newly synthesized labeled heme. It is concluded from these results that poly(rI·rC) and tilorone lower the concentration of hepatic hemoproteins by increasing their degradation rather than by depressing their synthesis.