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Effects of interferon on drug metabolism
Abstract:
The induction and passive transfer of interferons have been shown to depress the level of cytochrome P-450 drug metabolism system of liver microsomes. Inducers of alpha or beta (Type I) interferons, such as Tilorone-HCl, statalon, mengovirus and others, suppressed the cytochrome P-450 system of rats or mice after administration. Induction of gamma (Type II) interferon also resulted in depression of the cytochrome P-450 system of mice. The gamma interferon was induced by sensitization of mice with Mycobacterium bovis strain BCG followed by challenge with tuberculin. The degree of depression of the cytochrome P-450 system correlated with the levels of interferon induced. In addition, passive transfer of exogenous gamma interferon also resulted in depression of the murine cytochrome-450 system. The metabolism of diphenylhydantoin, a drug metabolized by cytochrome-450, was examined in mice in which gamma interferon was induced. The metabolism of diphenylhydanoin was severely inhibited in mice which interferon was induced, and the level of inhibition correlated with the titer of gamma interferon induced. Passive transfer of gamma interferon also depressed the metabolism of diphenylhydantoin by murine cytochrome P-450.
Insights
Interferon induction and transfer suppress liver cytochrome P-450 drug metabolism. This impacts how the body processes drugs like diphenylhydantoin, with effects correlating to interferon levels.
Area of Science:
- Biochemistry
- Pharmacology
- Immunology
Background:
- Interferons are key immune signaling molecules.
- Cytochrome P-450 enzymes are crucial for drug metabolism in the liver.
- Previous studies suggest interferons can affect drug metabolism.
Purpose of the Study:
- To investigate the impact of interferon induction and passive transfer on cytochrome P-450 activity.
- To determine the relationship between interferon levels and the suppression of drug metabolism.
- To examine the effect of gamma interferon on the metabolism of diphenylhydantoin.
Main Methods:
- Administering Type I interferon inducers (Tilorone-HCl, statalon, mengovirus) to rats or mice.
- Inducing gamma (Type II) interferon in mice via BCG sensitization and tuberculin challenge.
- Assessing cytochrome P-450 levels and activity in liver microsomes.
- Measuring diphenylhydantoin metabolism in mice with induced interferon.
- Performing passive transfer of exogenous gamma interferon.
Main Results:
- Both Type I and Type II interferon induction suppressed cytochrome P-450 activity in rodents.
- The degree of cytochrome P-450 depression correlated with induced interferon levels.
- Gamma interferon induction and passive transfer significantly inhibited diphenylhydantoin metabolism.
- Inhibition of diphenylhydantoin metabolism was dose-dependent on induced gamma interferon levels.
Conclusions:
- Interferon induction and administration negatively impact hepatic cytochrome P-450 drug metabolism.
- Gamma interferon plays a significant role in suppressing drug metabolism, affecting drugs like diphenylhydantoin.
- These findings highlight potential drug-drug interactions and altered pharmacokinetics in conditions involving interferon activity.