The JAK1/2 Inhibitor Ruxolitinib Reverses Interleukin-6-Mediated Suppression of Drug-Detoxifying Proteins in Cultured Human Hepatocytes.

Abstract

The inflammatory cytokine interleukin (IL)-6, which basically activates the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) signaling pathway, is well known to repress expression of hepatic cytochromes P-450 (P450s) and transporters. Therapeutic proteins, like monoclonal antibodies targeting IL-6 or its receptor, have consequently been demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract the repressing effects of IL-6 toward hepatic detoxifying systems. Ruxolitinib was found to fully inhibit IL-6-mediated repression of P450 (CYP1A2, CYP2B6, and CYP3A4) and transporter (NTCP, OATP1B1, and OCT1) mRNA levels in primary human hepatocytes and differentiated hepatoma HepaRG cells. Such effects were dose-dependent, with ruxolitinib EC50 values around 1.0-1.2 μM and thus close to ruxolitinib plasma levels that can be reached in patients. Moreover, they were associated with concomitant restoration of P450 and drug transporter activities in IL-6-exposed HepaRG cells. By contrast, ruxolitinib failed to suppress the repression of drug-detoxifying protein mRNA levels caused by IL-1β The JAK inhibitor and anti-rheumatoid arthritis compound tofacitinib was additionally found to reverse IL-6-mediated suppression of P450 and transporter mRNA expressions. Taken together, our results demonstrated that small drugs acting as JAK inhibitors, like ruxolitinib, counteract IL-6-mediated repression of drug-metabolizing enzymes and drug transporters in cultured human hepatocytes. These JAK inhibitors may consequently be hypothesized to restore hepatic detoxification capacity for patients suffering from inflammatory diseases, which may in turn cause idDDIs.

• Authors: Marie Febvre-James, Arnaud Bruyère, Marc Le Vée, Olivier Fardel
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 46 Issue 2 Pg. 131-140 (02 2018) ISSN: 1521-009X [Electronic] United States
• PMID: 29162613 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• IL6 protein, human
• Interleukin-6
• Nitriles
• Pyrazoles
• Pyrimidines
• ruxolitinib
• Cytochrome P-450 Enzyme System
• JAK1 protein, human
• JAK2 protein, human
• Janus Kinase 1
• Janus Kinase 2

Topics

• Biological Transport (drug effects)
• Cell Line, Tumor
• Cells, Cultured
• Cytochrome P-450 Enzyme System (metabolism)
• Drug Interactions (physiology)
• Hepatocytes (drug effects, metabolism)
• Humans
• Inactivation, Metabolic (drug effects)
• Interleukin-6 (metabolism)
• Janus Kinase 1 (antagonists & inhibitors)
• Janus Kinase 2 (antagonists & inhibitors)
• Nitriles
• Pyrazoles (pharmacology)
• Pyrimidines
• Signal Transduction (drug effects)