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

Journal Article · Wed Jun 01 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.03.019· OSTI ID:21535310

Flaman, Anathea S; Gravel, Caroline ^[1]; Hashem, Anwar M ^[1]; Tocchi, Monika ^[1]

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1. Centre for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON (Canada)

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.

• OSTI ID: 21535310
• Journal Information: Toxicology and Applied Pharmacology, Vol. 253, 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.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

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