Time-Resolved Effect of Interferon-Alpha 2a on Activities of Nuclear Factor Kappa B, Pregnane X Receptor and on Drug Disposition Genes

Interferon-alpha (IFN-alpha) is suggested to cause pharmacokinetic drug interactions by lowering expression of drug disposition genes through affecting the activities of nuclear factor kappa B (NF-kappa B) and pregnane X receptor (PXR). The time-resolved impact of IFN-alpha 2a (1000 U/mL; 5000 U/mL; 2 h to 30 h) on the activities of NF-kappa B 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-kappa B activation and PXR suppression was evaluated by NF-kappa B blockage (10 mu M parthenolide). IFN-alpha 2a initially (2 h, 6 h) enhanced NF-kappa B 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-alpha 2a demonstrated short-term suppressive effects on PXR activity and CYP3A4 mRNA expression, likely mediated by activated NF-kappa B. Longer exposure enhanced CYP3A4 activity. Clinical trials should evaluate the relevance by investigating the temporal effects of IFN-alpha on CYP3A4 using a sensitive marker substrate.

Automated summary

IFN-alpha has been shown to have time-dependent effects on NF-kappa B and PXR activities, as well as on the mRNA expression of drug disposition genes and CYP3A4 activity. Short-term exposure results in suppressed PXR activity and CYP3A4 mRNA expression, while longer exposure enhances CYP3A4 activity.