Differential effects of recombinant interferon alpha on constitutive and inducible cytochrome P450 isozymes in mouse liver.
The hepatic cytochrome P450 (P450)-dependent monooxygenase system is subject to regulation by a variety of xenobiotics and endogenous factors. During infection and inflammation the P450 system is usually suppressed, but the factors responsible for this phenomenon and the P450 isozymes involved have not been identified conclusively. We have studied the effects of a specific inflammatory mediator, recombinant interferon alpha, on the constitutive and inducible expression of P450 isozymes (from the CYP1A, CYP2B, and CYP2C) gene families using isozyme preferred substrates and Western blot analysis. Both increases and decreases in P450 levels occurred in response to interferon alpha. Suppression of constitutive P450 isozyme expression occurred and was shown to involve a decrease in steady-state protein expression. The induction of 7-ethoxyresorufin O-deethylase activity by 3-MC was potentiated whereas induction of 7-pentoxyresorufin- and 7-benzyloxyresorufin O-dealkylases by PB was suppressed by interferon alpha. These data demonstrate that the effects of interferon alpha on the P450-dependent monooxygenase system are complex, involving differential regulation of several isozymes. Both direct and indirect mechanisms may participate in these phenomena.
Stanley
L A
LA
Imperial Cancer Research Fund, Molecular Pharmacology Group, Edinburgh, U.K.
Adams
D J
DJ
Balkwill
F R
FR
Griffin
D
D
Wolf
C R
CR
D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D007370:Interferon Type I / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D008862:Microsomes, Liver / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011994:Recombinant Proteins
D007370:Interferon Type I; D007527:Isoenzymes; D011994:Recombinant Proteins; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D010105:Oxygenases; D019363:Cytochrome P-450 CYP1A1; D010634:Phenobarbital