The suppression of hepatic cytochrome P4504A mRNA mediated by the interferon inducer polyinosinic acid.polycytidylic acid.
Interferon and interferon inducers are well known to depress the cytochrome P450-dependent hepatic mixed-function oxidase system and cause a decrease in the capacity of the liver to metabolize drugs and xenobiotics. In this study we have shown that the interferon-mediated changes in an induced form of hepatic cytochrome P450 (CYP4A) are mediated via a depression in the levels of mRNA as assessed by Northern blot and slot blot analyses using a 20-base synthetic oligodeoxyribonucleotide hybridization probe. Rats were pretreated with clofibrate to maximize CYP4A mRNA levels prior to the administration of polyinosinic acid.polycytidylic acid (poly IC), an alpha/beta interferon inducer. Hepatic CYP4A mRNA levels were decreased by 49 and 30% at 6 and 24 hr, respectively, following poly IC administration. In hepatic microsomes cytochrome P450 and functional CYP4A as measured by lauric acid hydroxylation, were not affected at 6 hr, but were depressed by 39 and 27%, respectively, 24 hr following poly IC administration. These results suggest that interferon depresses induced levels of hepatic drug metabolism by lowering the level of cytochrome P450 mRNAs and subsequent synthesis of cytochrome P450 apoproteins.
Knickle
L C
LC
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Spencer
D F
DF
Renton
K W
KW
D000818:Animals; D001483:Base Sequence; D002994:Clofibrate; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis* / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007372:Interferons / Q000096:biosynthesis; D007850:Lauric Acids / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008969:Molecular Sequence Data; D011070:Poly I-C / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D011919:Rats, Inbred Strains
D007850:Lauric Acids; D012333:RNA, Messenger; C030358:lauric acid; D007372:Interferons; D003577:Cytochrome P-450 Enzyme System; D002994:Clofibrate; D011070:Poly I-C