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

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Time-Resolved Effect of Interferon-Alpha 2A on Activities of Nuclear Factor Kappa B, Pregnane X Receptor and on Drug Disposition Genes pharmaceutics Article Time-Resolved Effect of Interferon-Alpha 2a on Activities of Nuclear Factor Kappa B, Pregnane X Receptor and on Drug Disposition Genes Dirk Theile , Lelia Wagner , Cindy Bay, Walter Emil Haefeli and Johanna Weiss * Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; [email protected] (D.T.); [email protected] (L.W.); [email protected] (C.B.); [email protected] (W.E.H.) * Correspondence: [email protected]; Tel.: +49-6221-5639402 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-kB) 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-kB 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-kB activation and PXR suppression was evaluated by NF-kB blockage (10 µM parthenolide). IFN-α 2a initially (2 h, 6 h) enhanced NF-kB activity 2-fold and suppressed PXR Citation: Theile, D.; Wagner, L.; activity by 30%. mRNA of CYP3A4 was halved, whereas UGT1A1 was increased (1.35-fold) after Bay, C.; Haefeli, W.E.; Weiss, J. Time- 24 h. After 48 h, ABCB1 expression was increased (1.76-fold). CYP3A4 activity remained unchanged Resolved Effect of Interferon-Alpha after 24 h, but was enhanced after 48 h (1.35-fold). IFN-α 2a demonstrated short-term suppressive 2a on Activities of Nuclear Factor effects on PXR activity and CYP3A4 mRNA expression, likely mediated by activated NF-kB. Longer Kappa B, Pregnane X Receptor exposure enhanced CYP3A4 activity. Clinical trials should evaluate the relevance by investigating and on Drug Disposition Genes. Pharmaceutics 2021, 13, 808. the temporal effects of IFN-α on CYP3A4 using a sensitive marker substrate. https://doi.org/10.3390/ pharmaceutics13060808 Keywords: interferon-alpha; pregnane X receptor; nuclear factor kappa B; cytochrome P-450 3A4; pharmacokinetic drug–drug interactions Academic Editor: Im-Sook Song Received: 23 April 2021 Accepted: 27 May 2021 1. Introduction Published: 28 May 2021 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., Publisher’s Note: MDPI stays neutral interferon-alpha, IFN-α) and other proinflammatory cytokines (e.g., interleukin-6; tumor with regard to jurisdictional claims in necrosis factor-alpha, TNF-α; etc.) are released to initiate anti-infectious responses [1]. published maps and institutional affil- Given the additional antiproliferative (antineoplastic) and immune response-regulating iations. effects of IFN-α, this compound attracted scientific and clinical attention for more than five decades, and was developed as a therapeutic drug [1] against several cancers (e.g., cuta- neous T-cell lymphoma, chronic myeloid leukemia, melanoma, and renal cell carcinoma) and virus hepatitis B and C [2,3]. IFN-α administration can induce an inflammatory pheno- Copyright: © 2021 by the authors. type (causing fever, myalgia, and headache) [4,5], which was associated with diminished Licensee MDPI, Basel, Switzerland. clearance of small molecule drugs [6,7]. In humans, IFN-α administration was shown to This article is an open access article lower drug clearance [8,9], raising the possibility of pharmacokinetic drug–drug interac- distributed under the terms and tions with coadministered compounds. However, the actual evidence for this assumption conditions of the Creative Commons remains uncertain. While the impact of long-term IFN-α administration on cytochrome Attribution (CC BY) license (https:// P450 isozyme 1A2 (CYP1A2) expression or pharmacokinetics of its prototypical substrate creativecommons.org/licenses/by/ 4.0/). theophylline was convincingly shown in vitro [10], in healthy volunteers [11], and also in Pharmaceutics 2021, 13, 808. https://doi.org/10.3390/pharmaceutics13060808 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, 808 2 of 11 patients with viral hepatitis [12,13], the effect on the most prominent drug-metabolizing enzyme CYP3A4 is contradicting. Some clinical trials suggested that IFN-α suppresses CYP3A4 activity [14,15], whereas others found no change [16] or even enhanced CYP3A4 activity [17]. The interpretation is further complicated by the fact that these studies were made after different durations of IFN-α exposure (short-term: [12,16]; long-term: [11,13,16]). CYP3A4 expression and activity is tightly regulated by the nuclear pregnane X receptor (PXR) [18], so investigation of the time-resolved influence of IFN-α on this transcription factor should provide insight into the regulation of CYP3A4 and other drug disposition genes. To date, a previous experimental study suggested that cytokines (e.g., interleukin-6) can indeed antagonize PXR activity and subsequently diminish PXR target gene expression by activating NF-kB [19]. Whether this mechanism also applies to IFN-α is yet unclear. In summary, previous studies suggest that IFN-α activates NF-kB, leading to inhibition of PXR and subsequent downregulation of PXR target genes (e.g., CYP3A4). However, a functional confirmation of the NF-kB:PXR cross-talk and a precise time-resolved analysis of the IFN-α effect on NF-kB, PXR, target gene expression or activity, and the respective temporal relations were not yet described. We therefore investigated the dual effect of IFN- α on the activities of both NF-kB and PXR and examined the temporal effect of changes on genes from different classes of drug disposition: the drug-metabolizing enzymes CYP3A4 and CYP1A1, the drug-conjugating enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) and two members of the ATP-binding cassette transporter family called ABCB1 (encoding P-glycoprotein) and ABCC2 (encoding multidrug resistance-associated protein 2). 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]; thus, these two forms can be used interchangeably. In this experimental study, IFN-α 2a was used. 2. Materials and Methods 2.1. Material Dulbecco’s Modified Eagle’s Medium (DMEM), Hanks’ balanced salt solution, phosphate- buffered saline (PBS), and the GenElute Mammalian Total RNA Miniprep Kit were pur- chased from Sigma–Aldrich (Taufkirchen, Germany). Fetal calf serum (FCS) was obtained from Biochrom (Berlin, Germany). Glutamine and nonessential amino acids were from Life Technologies (Paisley, UK). Rifampicin, dimethyl sulfoxide (DMSO), and Triton® X-100 were from AppliChem (Darmstadt, Germany). IFN-α 2a was purchased from Life Tech- nologies (Thermo Fisher Scientific (Waltham, MA, USA)), while parthenolide was obtained from Abcam (Berlin, Germany), and poly I:C from Invivogen (Toulouse, France). The cytotoxicity detection kit (LDH) was obtained from Roche Applied Sciences (Mannheim, Germany). The QuantiTect® Primer Assay for UGT1A1 was obtained from Qiagen (Hilden, Germany), the RevertAid H Minus First Strand cDNA Synthesis Kit from Thermo Fisher Scientific (Waltham, MA, USA). The Absolute QPCR SYBR Green Mix was purchased from ABgene (Hamburg, Germany). Primers were synthesized by Eurofins MWG Operon (Ebersberg, Gemany). The P450-Glo CYP Screening Systems and the Dual-Glo Luciferase Assay System, the pGL4.21 vector, the pGL4.74 [hRluc/TK] renilla vector, the pNL3.2.NF- κB-RE [NlucP/NF-κB-RE/Hygro] vector, and FuGENE® HD Transfection Reagent were obtained from Promega Corporation (Madison, WI, USA). The NR1I2 (NM_003889) Human cDNATrueClone® (pCMV6-XL4 vector containing the cDNA of the PXR gene NR1I2) was obtained from OriGene (Rockville, MD, USA). 2.2. Stock Solutions DMSO was used to prepare the stock solutions of parthenolide (100 mM) and ri- fampicin (100 mM). The stock solution of poly I:C (1 mg/mL) was prepared in 0.9% sodium chloride solution, while IFN-α 2a (5 × 107 U/mL) was kept in the original stock solution provided by the manufacturer. The stock solutions were aliquoted into 500 µL reaction tubes and frozen at −20 ◦C. Pharmaceutics 2021, 13, 808 3 of 11 2.3. Cell Line The human colon adenocarcinoma cell line LS180 is a standard model for the investi- gation of the regulation of drug disposition genes, including PXR-mediated induction, and was shown to be superior to other models, such as HepG2 cells [24–27]. It is available at ATCC (Manassas, VA, USA) and was cultured under standard cell culture conditions with DMEM supplemented with 10% FCS, 2 mM glutamine, 100 U/mL penicillin, 100 µg/mL streptomycin sulphate, and 0.1 mM nonessential amino acids. 2.4. Cytotoxicity and Proliferation Assays To rule out cytotoxic off-target effects (short-term incubation) or antiproliferative effects (long-term incubation), all compounds were initially tested in quadruplets for cyto- toxicity with the Cytotoxicity Detection Kit according to the manufacturer’s instructions. In addition, growth inhibition assays were used to determine the maximum concentrations of IFN-α 2a, rifampicin, or poly I:C that had no antiproliferative effects in LS180 cells after 48-h exposure. Proliferation of LS180 cells was quantified by crystal violet staining, as de- scribed previously [28]. Antiproliferative properties were evaluated in three independent experiments with n = 4 wells for each concentration (500–50,000 U/mL). IFN-α 2a had no antiproliferative effects and reporter gene assays or gene induction assays were per- formed with 1000 U/mL to 5000 U/mL, which are concentrations in the range of previous experiments [10,23]. Accordingly, noncytotoxic or non-antiproliferative concentrations of rifampicin (20 µM) and poly I:C (1 µg/mL) were used.
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