Molecular Pharmacology, Vol 15, 698-707, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Effects of Interferon Inducing Agents (Polyriboinosinic Acid · Polyribocytidylic Acid, Tilorone) on Hepatic Hemoproteins (Cytochrome P-450, Catalase, Tryptophan 2,3-Dioxygenase, Mitochondrial Cytochromes), Heme Metabolism and Cytochrome P-450-Linked Monooxygenase Systems

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

Single doses of the interferon inducing agents, poly rI·rC and tilorone, were shown to depress hepatic cytochrome P-450, cytochrome b₅, catalase and tryptophan 2,3-dioxygenase. The cytochrome P-450 level of microsomes declined progressively after a single dose of poly rI·rC for 40 hr and then recovered to within 25% of the control level by 96 hr. The ethylmorphine N-demethylase activity of the microsomes paralleled the cytochrome P-450 level except during the first 4 hr after administration of poly rI·rC when there was a greater loss of demethylase activity than could be accounted for by the loss of cytochrome P-450. Tilorone had effects similar to those of poly rI·rC on cytochrome P-450 and ethylmorphine N-demethylase activity, but its action was delayed. Temporal aspects of the loss and recovery of the catalase of liver homogenates after the administration of poly rI·rC or tilorone were similar to those of microsomal cytochrome P-450. About 60% of the total tryptophan 2,3-dioxygenase (apo + holo enzyme) activity of the 100,000 x g supernatant fraction of liver homogenate was lost within 6 hr of the administration of poly rI·rC; activity returned to the control level by 15 hr. However, there was a transient rise in the ratio of holo:total tryptophan 2,3-dioxygenase activity at 3 hr which returned to the control value by 5 hr. Tilorone had no statistically significant effect on either the total activity of this enzyme or the ratio of holo to total enzyme. The increase in the ratio of holo:total enzyme was followed by a depression of -aminolevulinic acid synthetase (ALA-S) activity at 5 hr and an induction of heme oxygenase activity at 6 to 8 hr. ALA-S activity returned to the control level within 24 hr, but the induced level of heme oxygenase activity remained for 40 hr and did not return to normal until 96 hr. Tilorone had a similar but delayed effect on ALA-S activity. Tilorone induced heme oxygenase activity to a degree equal to that produced by poly rI·rC, but a much longer time was required to reach maximal activity (2 to 3 hr versus 20 to 30 hr). These temporal aspects of the effects of interferon inducing agents on the ratio of holo:total tryptophan 2,3dioxygenase, ALA-S and heme oxygenase are thought to reflect changes in the size of an unassigned heme pool that regulates the synthesis of heme. Mitochondrial cytochromes a, b, and c were not depressed significantly after 4 daily doses of poly rI·rC; cytochrome C₁ was depressed about 20%. The cytochrome P-450 content and benzo[a]pyrene activity of intestinal mucosa and adrenal were not affected by 4 daily doses of poly rI·rC; the cytochrome P-450 content of the kidney cortex was not altered, but the benzo[a]pyrene hydroxylase activity was lowered by 40%.

Note:
ACKNOWLEDGMENT We are indebted to Ms. Viola Abbott for the determination of benzo[a]pyrene hydroxylase activities of the extrahepatic tissues.