Effect of interferon inducing agents (polyriboinosinic acid-polyribocytidylic acid and tilorone) on the heme turnover of hepatic cytochrome P-450

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 hr. After the administration of tilorone or poly(rI-rC), the half-life of the short-lived cytochrome P-450 was lowered to about 5 hr 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 hr 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.