Pretranslational suppression of cytochrome P-450h (IIC11) gene expression in rat liver after administration of interferon inducers.
Administration of the interferon inducer polyriboinosinic acid.polyribocytidylic acid (poly rl.poly rC) (10 mg/kg, ip) to male rats suppressed the constitutive hepatic expression of the male-specific cytochrome P-450 [AH, reduced-flavoprotein/oxygen oxidoreductase (RH hydroxylating), EC 1.14.14.1] isozyme P450IIC11 (P-450h) to 21% of control levels within 24 hr. The mRNA for P-450h was more rapidly suppressed by the drug, being significantly suppressed to 56% of control values within 6 hr of administration. P-450h mRNA levels were further lowered to 10% of control by 24 hr. The kinetics of suppression of P-450h apoprotein and mRNA by poly rl.poly rC indicate that the primary mechanism(s) is (are) at a pretranslational level. Tilorone analog R11-877DA (TA) (50 mg/kg, ip), also an interferon inducer, produced qualitatively similar effects to those of poly rl.poly rC, although the TA produced lesser (51% and 59%) decreases in P-450h protein and mRNA, respectively, 24 hr after injection. Again, the results indicate a pretranslational mechanism of P-450h suppression. Although both interferon inducers suppressed hepatic P-450h expression, the magnitudes of these effects were not notably greater than those on total hepatic P-450, indicating that suppression of rat liver P-450 isozymes by interferon inducers is not confined to P-450h.
Morgan
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Department of Pharmacology, Emory University, Atlanta, GA 30322.
Norman
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D000818:Animals; D001059:Apoproteins / Q000378:metabolism; D015153:Blotting, Western; D002266:Carboxymethylcellulose Sodium / Q000494:pharmacology / Q000031:analogs & derivatives; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D015786:Cytochromes b5 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D066298:In Vitro Techniques; D007369:Interferon Inducers / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011107:Polylysine / Q000494:pharmacology / Q000031:analogs & derivatives; D012313:RNA / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D001059:Apoproteins; D007369:Interferon Inducers; D007527:Isoenzymes; D011107:Polylysine; D012313:RNA; C019531:poly ICLC; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C