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 CYP3A4 substrates to avoid the occurrence of adverse drug interactions. Crown Copyright (C) 2011 Published by Elsevier Inc. All rights reserved.