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Role of Xanthine Oxidase in the Interferon-mediated Depression of the Hepatic Cytochrome P-450 System in Mice¹

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

Interferon, interferon inducers, and a variety of other immunomodulators are known to depress the hepatic cytochrome P-450 drug-metabolizing system. Two concepts have been proposed to explain this phenomenon. (a) The steady-state of cytochrome P-450 is altered through decreased synthesis and increased degradation of cytochrome P-450 apoprotein. (b) Interferon induces xanthine oxidase; superoxide generated by interferon-induced xanthine oxidase destroys cytochrome P-450. The current study investigated the second concept. Administered polyribonucleotides [polyriboinosinic acid·polyribocytidylic acid (poly IC), polyriboinosinic acid·polycytidylic acid, polylysine and carboxymethylcellulose, mismatched poly IC], recombinant murine -interferon, and a natural murine /ß-interferon were shown to depress hepatic cytochrome P-450 and selected microsomal cytochrome P-450-dependent monooxygenase reactions and to induce hepatic xanthine oxidase activity. The feeding of tungstate in the drinking water largely depleted xanthine oxidase in mice; cytochrome P-450 levels and monooxygenase activities were not affected by tungstate treatment. Tungstate rendered the level of xanthine oxidase much below that in mice that had not received tungstate regardless of whether or not they had received poly IC or interferon; nevertheless, poly IC and interferon produced losses of cytochrome P-450 and monooxygenase activities in these tungstate-treated mice equivalent to those observed in mice that had not received tungstate. The administration of N-acetylcysteine did not prevent the loss of cytochrome P-450 induced by poly IC, as has been reported, nor did the incubation of microsomal cytochrome P-450 with buttermilk xanthine oxidase and hypoxanthine cause a loss of cytochrome P-450, which has also been reported. It is concluded from these studies that the induction of xanthine oxidase and the loss of cytochrome P-450 generated by interferon are coincidental rather than causally related phenomena.

¹ Supported by United States Public Health Service Grant GM27780. A preliminary report of part of this work was presented at the 1985 Annual Meeting of the American Society of Pharmacology and Experimental Therapeutics, Boston, MA (14).

² To whom requests for reprints should be addressed.

Received 8/25/87. Revised 12/10/87. Accepted 1/13/88.

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