Dissociation of xanthine oxidase induction and cytochrome P450 depression during interferon induction in the rat.
Interferon (IFN) and IFN inducers down-regulate hepatic cytochrome P450 (P450) through a pretranslational mechanism involving depression of P450 mRNA levels and a subsequent decrease in P450 synthesis. Current evidence suggests that interferon induces the synthesis of a protein which subsequently mediates the down-regulation of P450. Xanthine oxidase (XO) activity is induced by interferons in rodents, and the XO inhibitor allopurinol (AP) inhibits the down-regulation of P450 by interferons in the mouse and hamster so it has been proposed as the putative intermediate protein. In studies undertaken in rats to further characterize the molecular basis of the protective effect of AP, we observed that AP (20 and 50 mg/kg) did not protect against down-regulation of P450 by the interferon inducer polyinosinic-polycytidylic acid (10 mg/kg). In fact, at 50 mg/kg AP had an additive effect on the depression of CYP2E1. Total XO induction in the rat was only 30-50% compared with 100-500% in mice and hamsters, and this induction was inhibited completely by AP. Therefore, XO does not mediate the down-regulation of hepatic cytochrome P450 by interferons in the rat.
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Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Renton
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KW
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D015536:Down-Regulation; D007369:Interferon Inducers / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007372:Interferons / Q000096:biosynthesis* / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011070:Poly I-C / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D007369:Interferon Inducers; D011994:Recombinant Proteins; D000493:Allopurinol; D007372:Interferons; D003577:Cytochrome P-450 Enzyme System; D014969:Xanthine Oxidase; D011070:Poly I-C