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Modulation of constitutive and inducible hepatic cytochrome(s) P-450 by interferon beta in mice
M Carelli1, M C Porras, M Rizzardini
1Istituto de Ricerche Farmacologiche Mario Negri, Milan, Italy.
Aims/Methods:
Interferon beta is used as a therapeutic agent, but its effects on the hepatic cytochrome P-450-dependent drug metabolizing system have not yet been characterized. We investigated the effect of interferon beta on cytochrome P-450 in mice.
Results:
Interferon beta (2 x 10(5) units/mouse) significantly reduced total hepatic cytochrome P-450 (20%) and the activity of NADPH cytochrome C reductase (12%) 24 h after administration; lower doses had no such effect. Various monooxygenase activities were slightly reduced, the one most affected being 7-ethoxycoumarin O-deethylase (29%). In phenobarbital-treated mice, interferon beta reduced the induction of total cytochrome P-450 (22%), the activities of pentoxyresorufin O-dealkylase (38%), benzyloxyresorufin O-dealkylase (30%), erythromycin N-demethylase (30%), 7-ethoxycoumarin O-deethylase (16%) and cytochrome P-450 2B1 (33%) and 3A (45%) proteins. In beta-naphthoflavone-treated mice, interferon beta lowered the induction of total cytochrome P-450 (18%), the activities of ethoxyresorufin O-deethylase (31%) and of 7-ethoxycoumarin O-deethylase (25%) and of cytochrome P-450 1A1 protein (31%).
Conclusions:
Thus it appears that induced cytochrome(s) P-450 were susceptible to interferon beta, this effect not being influenced by the type of inducer. Since various members of the same cytochrome P-450 subfamilies catalyze oxidation of drugs in humans, our findings have potential significance as regards the fate of drugs or exogenous compounds given to patients receiving interferon beta.
Insights
Interferon beta significantly reduced cytochrome P-450 levels and activity in mice. This suggests potential interactions with drug metabolism in patients receiving interferon therapy.
Area of Science:
- Pharmacology
- Hepatology
- Drug Metabolism
Background:
- Interferon beta is a therapeutic agent with incompletely understood effects on drug metabolism.
- The hepatic cytochrome P-450 system is crucial for metabolizing drugs and xenobiotics.
Purpose of the Study:
- To investigate the impact of interferon beta on the mouse hepatic cytochrome P-450 system.
- To characterize the effects of interferon beta on drug-metabolizing enzyme activities.
Main Methods:
- Administration of interferon beta to mice at a dose of 2 x 10(5) units/mouse.
- Measurement of total hepatic cytochrome P-450 and NADPH cytochrome C reductase activity.
- Assay of various monooxygenase activities and specific cytochrome P-450 isoforms (CYP1A1, CYP2B1, CYP3A).
- Evaluation in both untreated and induced (phenobarbital, beta-naphthoflavone) mice.
Main Results:
- A single dose of interferon beta significantly reduced total hepatic cytochrome P-450 (20%) and NADPH cytochrome C reductase (12%) activity.
- Specific monooxygenase activities, such as 7-ethoxycoumarin O-deethylase, were also reduced.
- Interferon beta diminished the induction of cytochrome P-450 by phenobarbital and beta-naphthoflavone, affecting specific isoforms like CYP1A1, CYP2B1, and CYP3A.
- Lower doses of interferon beta did not produce significant effects.
Conclusions:
- Induced cytochrome P-450 enzymes are susceptible to interferon beta, irrespective of the inducer used.
- These findings highlight the potential for interferon beta to alter the metabolism of drugs and exogenous compounds in patients.
- Understanding these interactions is crucial for managing drug therapy in patients receiving interferon beta.