Induction and depression of cytochrome P-450-dependent mixed-function oxidase by a cloned consensus alpha-interferon (IFN-alpha CON1) in the hamster.
A novel analogue of human alpha-interferon (IFN-alpha CON1) was tested for its ability to modify the hepatic cytochrome P-450-dependent mixed-function oxidase system in the hamster. This cloned interferon was derived by selecting the most frequently observed amino acid sequences at each position in the known human alpha-interferon subtypes. IFN-alpha CON1 had a biphasic effect on cytochrome P-450 and related drug biotransformation in the hamster causing an initial increase followed by a significant depression. IFN-alpha CON1 also had a biphasic effect on cytochrome P-450 in the lung, adrenal and spleen but only a depressant effect in the kidney. This effect was not due to morphological damage and followed the species specificity for this type of interferon. Both the increase and the decrease in cytochrome P-450 could be prevented by the administration of the protein synthesis inhibitor puromycin. Various isozymes of cytochrome P-450 induced by phenobarbital, beta-napthaflavone and clofibrate were also depressed by this interferon. The results presented in this report suggest that IFN-alpha CON1 interferon will likely depress drug biotransformation in humans because the antiviral effects and the "anti-cytochrome P-450" effect of interferons cannot be separated, and this interferon has antiviral properties in both hamster and human cells. Clinically relevant drug interactions may be common during the concomitant use of this interferon and other drugs that are metabolized by cytochrome P-450.
Moochhala
S M
SM
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Renton
K W
KW
Stebbing
N
N
D000818:Animals; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D007370:Interferon Type I / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000032:analysis*; D011691:Puromycin / Q000494:pharmacology; D011994:Recombinant Proteins
D007370:Interferon Type I; D011994:Recombinant Proteins; D011691:Puromycin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases