skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: The effect of interferon-{alpha} on the expression of cytochrome P450 3A4 in human hepatoma cells

Abstract

Interferon {alpha} (IFN{alpha}) is used to treat malignancies and chronic viral infections. It has been found to decrease the rate of drug metabolism by acting on cytochrome P450 enzymes, but no studies have investigated the consequences of IFN{alpha} treatment on the CYP3A4 isoform, responsible for the metabolism of a majority of drugs. In this study, we have examined the effect of IFN{alpha} on CYP3A4 catalytic activity and expression in human hepatoma cells. We found that IFN{alpha} inhibits CYP3A4 activity and rapidly down-regulates the expression of CYP3A4, independent of de novo protein synthesis. Pharmacologic inhibitors and a dominant-negative mutant expression plasmid were used to dissect the molecular pathway required for CYP3A4 suppression, revealing roles for Jak1 and Stat1 and eliminating the involvement of the p38 mitogen-activated and extracellular regulated kinases. Treatment of hepatoma cells with IFN{alpha} did not affect the nuclear localization or relative abundance of Sp1 and Sp3 transcription factors, suggesting that the suppression of CYP3A4 by IFN{alpha} does not result from inhibitory Sp3 out-competing Sp1. To our knowledge, this is the first report that IFN{alpha} down-regulates CYP3A4 expression largely through the JAK-STAT pathway. Since IFN{alpha} suppresses CYP3A4 expression, caution is warranted when IFN{alpha} is administered in combination with CYP3A4more » substrates to avoid the occurrence of adverse drug interactions.« less

Authors:
;  [1];  [1];  [1]
  1. Centre for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON (Canada)
Publication Date:
OSTI Identifier:
21535310
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 253; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2011.03.019; PII: S0041-008X(11)00113-X; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; DRUGS; ELECTROPHORESIS; HEPATOMAS; HUMAN POPULATIONS; INHIBITION; INTERACTIONS; INTERFERON; LUCIFERASE; METABOLISM; MUTANTS; ORGANIC FLUORINE COMPOUNDS; PHOSPHATES; PHOSPHOTRANSFERASES; POLYMERASE CHAIN REACTION; POLYVINYLS; SULFATES; SYNTHESIS; TRANSCRIPTION FACTORS; CARCINOMAS; DISEASES; ENZYMES; GENE AMPLIFICATION; GROWTH FACTORS; LYMPHOKINES; MITOGENS; NEOPLASMS; ORGANIC COMPOUNDS; ORGANIC HALOGEN COMPOUNDS; ORGANIC POLYMERS; OXIDASES; OXIDOREDUCTASES; OXYGEN COMPOUNDS; PHOSPHORUS COMPOUNDS; PHOSPHORUS-GROUP TRANSFERASES; POLYMERS; POPULATIONS; PROTEINS; SULFUR COMPOUNDS; TRANSFERASES

Citation Formats

Flaman, Anathea S, Gravel, Caroline, Hashem, Anwar M, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Tocchi, Monika, Li Xuguang, E-mail: Sean.Li@hc-sc.gc.ca, and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON. The effect of interferon-{alpha} on the expression of cytochrome P450 3A4 in human hepatoma cells. United States: N. p., 2011. Web. doi:10.1016/j.taap.2011.03.019.
Flaman, Anathea S, Gravel, Caroline, Hashem, Anwar M, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Tocchi, Monika, Li Xuguang, E-mail: Sean.Li@hc-sc.gc.ca, & Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON. The effect of interferon-{alpha} on the expression of cytochrome P450 3A4 in human hepatoma cells. United States. https://doi.org/10.1016/j.taap.2011.03.019
Flaman, Anathea S, Gravel, Caroline, Hashem, Anwar M, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Tocchi, Monika, Li Xuguang, E-mail: Sean.Li@hc-sc.gc.ca, and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON. 2011. "The effect of interferon-{alpha} on the expression of cytochrome P450 3A4 in human hepatoma cells". United States. https://doi.org/10.1016/j.taap.2011.03.019.
@article{osti_21535310,
title = {The effect of interferon-{alpha} on the expression of cytochrome P450 3A4 in human hepatoma cells},
author = {Flaman, Anathea S and Gravel, Caroline and Hashem, Anwar M and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON and Tocchi, Monika and Li Xuguang, E-mail: Sean.Li@hc-sc.gc.ca and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON},
abstractNote = {Interferon {alpha} (IFN{alpha}) is used to treat malignancies and chronic viral infections. It has been found to decrease the rate of drug metabolism by acting on cytochrome P450 enzymes, but no studies have investigated the consequences of IFN{alpha} treatment on the CYP3A4 isoform, responsible for the metabolism of a majority of drugs. In this study, we have examined the effect of IFN{alpha} on CYP3A4 catalytic activity and expression in human hepatoma cells. We found that IFN{alpha} inhibits CYP3A4 activity and rapidly down-regulates the expression of CYP3A4, independent of de novo protein synthesis. Pharmacologic inhibitors and a dominant-negative mutant expression plasmid were used to dissect the molecular pathway required for CYP3A4 suppression, revealing roles for Jak1 and Stat1 and eliminating the involvement of the p38 mitogen-activated and extracellular regulated kinases. Treatment of hepatoma cells with IFN{alpha} did not affect the nuclear localization or relative abundance of Sp1 and Sp3 transcription factors, suggesting that the suppression of CYP3A4 by IFN{alpha} does not result from inhibitory Sp3 out-competing Sp1. To our knowledge, this is the first report that IFN{alpha} down-regulates CYP3A4 expression largely through the JAK-STAT pathway. Since IFN{alpha} suppresses CYP3A4 expression, caution is warranted when IFN{alpha} is administered in combination with CYP3A4 substrates to avoid the occurrence of adverse drug interactions.},
doi = {10.1016/j.taap.2011.03.019},
url = {https://www.osti.gov/biblio/21535310}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 253,
place = {United States},
year = {2011},
month = {6}
}