Time-resolved effect of interferon-alpha 2a on activities of nuclear factor kappa B, pregnane X receptor and on drug disposition genes

• Verfasst von: Theile, Dirk [VerfasserIn]
• Verfasst von: Wagner, Lelia [VerfasserIn]
• Verfasst von: Bay, Cindy [VerfasserIn]
• Verfasst von: Haefeli, Walter E. [VerfasserIn]
• Verfasst von: Weiß, Johanna [VerfasserIn]
• Titel: Time-resolved effect of interferon-alpha 2a on activities of nuclear factor kappa B, pregnane X receptor and on drug disposition genes
• Verf.angabe: Dirk Theile, Lelia Wagner, Cindy Bay, Walter Emil Haefeli and Johanna Weiss
• E-Jahr: 2021
• Jahr: 28 May 2021
• Umfang: 11 S.
• Teil: volume:13
• Teil: year:2021
• Teil: number:6
• Teil: elocationid:808
• Teil: pages:1-11
• Teil: extent:11
• Fussnoten: Gesehen am 14.07.2021
• Titel Quelle: Enthalten in: Pharmaceutics
• Ort Quelle: Basel : MDPI, 2009
• Jahr Quelle: 2021
• Band/Heft Quelle: 13(2021), 6, Artikel-ID 808, Seite 1-11
• ISSN Quelle: 1999-4923
• DOI: doi:10.3390/pharmaceutics13060808
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: cytochrome P-450 3A4
• Sach-SW: interferon-alpha
• Sach-SW: nuclear factor kappa B
• Sach-SW: pharmacokinetic drug-drug interactions
• Sach-SW: pregnane X receptor
• K10plus-PPN: 1762885336

Abstract

Interferon-alpha (IFN-α) is suggested to cause pharmacokinetic drug interactions by lowering expression of drug disposition genes through affecting the activities of nuclear factor kappa B (NF-ĸB) and pregnane X receptor (PXR). The time-resolved impact of IFN-α 2a (1000 U/mL; 5000 U/mL; 2 h to 30 h) on the activities of NF-ĸB and PXR and mRNA expression (5000 U/mL; 24 h, 48 h) of selected drug disposition genes and on cytochrome P450 (CYP3A4) activity in LS180 cells (5000 U/mL; 24 h, 48 h) was evaluated using luciferase-based reporter gene assays, reverse transcription polymerase chain reaction, and luminescence-based CYP3A4 activity assays. The cross-talk between NF-ĸB activation and PXR suppression was evaluated by NF-ĸB blockage (10 µM parthenolide). IFN-α 2a initially (2 h, 6 h) enhanced NF-ĸB activity 2-fold and suppressed PXR activity by 30%. mRNA of CYP3A4 was halved, whereas UGT1A1 was increased (1.35-fold) after 24 h. After 48 h, ABCB1 expression was increased (1.76-fold). CYP3A4 activity remained unchanged after 24 h, but was enhanced after 48 h (1.35-fold). IFN-α 2a demonstrated short-term suppressive effects on PXR activity and CYP3A4 mRNA expression, likely mediated by activated NF-ĸB. Longer exposure enhanced CYP3A4 activity. Clinical trials should evaluate the relevance by investigating the temporal effects of IFN-α on CYP3A4 using a sensitive marker substrate.