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.
Highlights
Published: 28 May 2021Interferons are important signaling molecules of the innate immune system
Dulbecco’s Modified Eagle’s Medium (DMEM), Hanks’ balanced salt solution, phosphatebuffered saline (PBS), and the GenElute Mammalian Total RNA Miniprep Kit were purchased from Sigma–Aldrich (Taufkirchen, Germany)
The human colon adenocarcinoma cell line LS180 is a standard model for the investigation of the regulation of drug disposition genes, including pregnane X receptor (PXR)-mediated induction, and was shown to be superior to other models, such as HepG2 cells [24,25,26,27]
Summary
Interferons are important signaling molecules of the innate immune system. After pathogen-mediated activation of nuclear factor kappa B (NF-kB), type 1 interferons (e.g., interferon-alpha, IFN-α) and other proinflammatory cytokines (e.g., interleukin-6; tumor necrosis factor-alpha, TNF-α; etc.) are released to initiate anti-infectious responses [1]. Previous studies suggest that IFN-α activates NF-kB, leading to inhibition of PXR and subsequent downregulation of PXR target genes (e.g., CYP3A4). IFN-α 2a and IFN-α 2b have identical indications, efficacy, and safety profiles [20,21], and showed similar suppressive effects on drug-metabolizing enzymes in vitro [22,23]; these two forms can be used interchangeably. In this experimental study, IFN-α 2a was used
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