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Role of Reactive Oxygen Intermediates in the Interferon-mediated Depression of Hepatic Drug Metabolism and Protective Effect of N-Acetylcysteine in Mice¹

Laboratory for Enzyme Research, Istituto di Ricerche Farmacologiche "Mario Negri," 20157 Milan [P. G., M. B., L. G., M. S.], and Istituto di Microbiologia, Università degli Studi di Torino, 10126 Torino [S. L.], Italy

Interferon (IFN) and IFN inducers are known to depress hepatic microsomal cytochrome P-450 levels, and the liver toxicity of IFN was reported to be lethal in newborn mice.

We have observed that administration to mice of IFN and IFN inducers caused a marked increase in liver xanthine oxidase activity. Because this enzyme is well known to produce reactive oxygen intermediates and cytochrome P-450 was reported to be sensitive to the oxidative damage, we have tested the hypothesis that a free radical mechanism could mediate the depression of cytochrome P-450 levels by IFN.

Administration to mice of the IFN inducer polyinosinic-polycytidylic acid (2 mg/kg i.p.) caused a 29 to 52% decrease in liver cytochrome P-450. Concomitant p.o. administration of the free radical scavenger, N-acetylcysteine (as a 2.5% solution in drinking water), or the xanthine oxidase inhibitor, allopurinol (100 mg/kg), protected against the IFN-mediated depression of P-450 levels. The results suggest that an increased endogenous generation of free radicals, possibly due to the induction of xanthine oxidase, is implicated in the IFN-mediated depression of liver drug metabolism.

The relevance of these data also extends to cases in which this side effect is observed in pathological situations (e.g., viral diseases and administration of vaccines) associated with an induction of IFN.

¹ Partially supported by Zambon S.p.A.

The generous contribution of the Italian Association for Cancer Research, Milan, Italy, is gratefully acknowledged. A preliminary account of this work was presented as the 75th Annual Meeting of the American Association for Cancer Research, Toronto, May 1984 (12).

² Training fellow of C.N.R. (National Research Council). To whom requests for reprints should be addressed.

Received 7/30/84. Revised 12/11/84. Accepted 3/25/85.

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