Janus kinase-dependent regulation of drug detoxifying protein expression by interleukin-22 in human hepatic cells.

Abstract

Interleukin (IL)-22 is a cytokine up-regulated in inflammatory situations and known to exert various hepatic effects. The potential impact of IL-22 towards liver drug detoxifying proteins remains nevertheless unknown, but may be important to determine owing to the well-established alterations of liver detoxification occuring during inflammation. The present study was therefore designed to analyze the effects of IL-22 towards drug metabolizing enzyme and drug transporter expression and activity in cultured human hepatic cells. Exposure of differentiated hepatoma HepaRG cells or primary human hepatocytes to 10 ng/mL IL-22 was found to repress mRNA expression of cytochrome P-450 (CYP) 1A2, CYP3A4, CYP2B6 and CYP2C9 and of the sinusoidal sodium-taurocholate co-transporting polypeptide (NTCP); such IL-22 effects were concentration-dependent for CYP3A4 (IC50 = 1.7 ng/mL), CYP2B6 (IC50 = 0.9 ng/mL) and NTCP (IC50 = 1.8 ng/mL). Activity of CYP1A2 (phenacetin O-deethylation), CYP3A4 (midazolam hydroxylation) and CYP2B6 (bupropion hydroxylation), as well as that of NTCP (taurocholate uptake) were concomitantly decreased in IL-22-treated HepaRG cells; by contrast, activity of organic anion transporter polypeptides (OATPs) (estrone-3-sulfate uptake) and of organic cation transporter (OCT) 1 (tetra-ethylammonium uptake) remained unchanged. IL-22 was next found to activate the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) 3 pathway, whose inhibition by the JAK inhibitor ruxolitinib fully prevented the IL-22-mediated CYP3A4, CYP2B6 and NTCP repression in HepaRG cells. This JAK-dependent down-regulation of hepatic drug detoxifying proteins, notably of CYPs, by IL-22 may contribute to alteration of pharmacokinetics in patients suffering from acute and chronic inflammatory diseases and may be the source of drug-drug interactions.

• Authors: Marc Le Vée, Arnaud Bruyère, Elodie Jouan, Olivier Fardel
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 83 Pg. 106439 (Jun 2020) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 32234672 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Interleukins
• Nitriles
• Organic Anion Transporters
• Organic Anion Transporters, Sodium-Dependent
• Pyrazoles
• Pyrimidines
• STAT3 Transcription Factor
• Symporters
• sodium-bile acid cotransporter
• ruxolitinib
• Cytochrome P-450 CYP1A2
• Cytochrome P-450 CYP2B6
• Cytochrome P-450 CYP3A
• Janus Kinases

Topics

• Cytochrome P-450 CYP1A2 (genetics, metabolism)
• Cytochrome P-450 CYP2B6 (metabolism)
• Cytochrome P-450 CYP3A (metabolism)
• Gene Expression Regulation
• Hep G2 Cells
• Hepatocytes (physiology)
• Humans
• Inactivation, Metabolic
• Interleukins (genetics, metabolism)
• Janus Kinases (metabolism)
• Nitriles
• Organic Anion Transporters (genetics, metabolism)
• Organic Anion Transporters, Sodium-Dependent (genetics, metabolism)
• Pyrazoles (pharmacokinetics)
• Pyrimidines
• STAT3 Transcription Factor (metabolism)
• Signal Transduction
• Symporters (genetics, metabolism)
• Interleukin-22