A role for xanthine oxidase in the loss of cytochrome P-450 evoked by interferon.
It has been suggested that the loss of cytochrome P-450, which is mediated by interferon and its inducers, can result from the generation of free radical species by the enzyme xanthine oxidase. Cytochrome P-450, aminopyrine N-demethylase, and ethoxyresorufin deethylase were depressed by 35, 36, 38%, respectively, in the livers of hamsters 24 h following the administration of a synthetic interferon (IFN-alpha-Con1) which contains the most frequent amino acid sequences of the human subtypes. Interferon increased the activities of the D and O forms of xanthine oxidase by 65 and 74%, respectively, in the same animals. The induction of the D form of xanthine oxidase, which is the precursor of the O form, preceded the loss in cytochrome P-450. The protein synthesis inhibitor, actinomycin D, prevented the interferon-induced loss of drug biotransformation and the increase in xanthine oxidase. The free radical scavenger, alpha-tocopherol, and the xanthine oxidase inhibitor, allopurinol, also prevented the loss of cytochrome P-450 mediated by the interferon inducer poly rI.rC. In chickens in which xanthine oxidase cannot be formed, poly rI.rC had no effect on cytochrome P-450 levels. These results suggest that xanthine oxidase induction may play some role in the interferon-mediated loss of cytochrome P-450.
Moochhala
S M
SM
Department of Pharmacology, Dalhousie University, Halifax, Canada.
Renton
K W
KW
D000493:Allopurinol / Q000494:pharmacology; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D003208:Concanavalin A; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D007042:Hypoxanthines / Q000494:pharmacology; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011994:Recombinant Proteins; D014810:Vitamin E / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
D007042:Hypoxanthines; D007370:Interferon Type I; D011994:Recombinant Proteins; D003208:Concanavalin A; D014810:Vitamin E; D003609:Dactinomycin; D000493:Allopurinol; D007372:Interferons; D003577:Cytochrome P-450 Enzyme System; D014969:Xanthine Oxidase; D000633:Aminopyrine N-Demethylase; D011070:Poly I-C