title: The effect of interferon-α on the expression of cytochrome P450 3A4 in human hepatoma cells.
abstract: Interferon α (IFNα) 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 IFNα treatment on the CYP3A4 isoform, responsible for the metabolism of a majority of drugs. In this study, we have examined the effect of IFNα on CYP3A4 catalytic activity and expression in human hepatoma cells. We found that IFNα 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 IFNα did not affect the nuclear localization or relative abundance of Sp1 and Sp3 transcription factors, suggesting that the suppression of CYP3A4 by IFNα does not result from inhibitory Sp3 out-competing Sp1. To our knowledge, this is the first report that IFNα down-regulates CYP3A4 expression largely through the JAK-STAT pathway. Since IFNα suppresses CYP3A4 expression, caution is warranted when IFNα is administered in combination with CYP3A4 substrates to avoid the occurrence of adverse drug interactions.
authors.affiliation: Centre for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada.
authors.forename: Anathea S
authors.initials: AS
authors.lastname: Flaman
authors.forename: Caroline
authors.initials: C
authors.lastname: Gravel
authors.forename: Anwar M
authors.initials: AM
authors.lastname: Hashem
authors.forename: Monika
authors.initials: M
authors.lastname: Tocchi
authors.forename: Xuguang
authors.initials: X
authors.lastname: Li
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000502:physiology; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D050794:STAT1 Transcription Factor / Q000502:physiology
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D016898:Interferon-alpha; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D048049:Extracellular Signal-Regulated MAP Kinases