Effects of monocyte chemoattractant protein‐1, macrophage inflammatory protein‐1α, and interferon‐α2a on P450 enzymes in human hepatocytes in vitro

Abstract

Some immunomodulatory agents stimulate the release of cytokines capable of suppressing P450 enzymes and potentially affecting pharmacokinetics of coadministered medications. Cytokines released in response to an immunomodulator in the blood ex vivo can be used to screen for the potential for drug‐drug interactions. Tilsotolimod, an investigational agonist of Toll‐like receptor 9, stimulated the release of macrophage chemoattractant protein‐1 (MCP‐1), macrophage inflammatory protein‐1α (MIP‐1α), and interferon‐α2a (INF‐α2a) in blood obtained from healthy donors. Although tilsotolimod did not directly affect CYP1A2, CYP2B6, or CYP3A4 expression or activity, the cytokines stimulated by the drug reduced CYP1A2 and CYP2B6 enzyme activities in cultured human hepatocytes. This study sought to identify which cytokines were responsible for tilsotolimod's indirect effects on P450 enzymes in vitro. A 72‐h treatment with recombinant human chemokines MCP‐1 and MIP‐1α did not alter CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP3A4, or signal transducer and activator of transcription 1 (STAT1) mRNA expression or CYP1A2, CYP2B6, or CYP3A4/5 enzyme activity in cocultures of human hepatocytes and Kupffer cells. INF‐α2a, at 2.5 ng/mL but not at the lower concentrations applied to the cells, increased CYP1A2 and STAT1 mRNA by 2.4‐ and 5.2‐fold, respectively, and reduced CYP2B6 enzyme activity to 46% of control. This study established that INF‐α2a, but not MCP‐1 or MIP‐1α, mediated tilsotolimod effects on CYP1A2 and CYP2B6 expression in human hepatocytes.

Clinical and Molecular Perspectives on Inflammation‐Mediated Regulation of Drug Metabolism and Transport

“…The in vitro effect of IL‐6 on the mRNA expression of CYP enzymes in primary human hepatocytes have been reported in multiple studies 25‐43 . IL‐6 substantially downregulates the mRNA expression of CYP3A4 up to 100‐fold at 10 ng/mL, 26–28,30–32,34–43 whereas other CYP enzymes are downregulated 1.5‐ to 8‐fold by 10 ng/mL IL‐6 26–28,31,34,35,37–43 .…”

“…The in vitro effect of IL-6 on the mRNA expression of CYP enzymes in primary human hepatocytes have been reported in multiple studies. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] IL-6 substantially downregulates the mRNA expression of CYP3A4 up to 100-fold at 10 ng/mL, [26][27][28][30][31][32][34][35][36][37][38][39][40][41][42][43] whereas other CYP enzymes are downregulated 1.5-to 8-fold by 10 ng/mL IL-6. [26][27][28]31,34,35,[37][38][39][40][41][42][43] A study reported a 2-fold upregulation of CYP2D6 mRNA by IL-6, 34 howe...…”

“…[25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] IL-6 substantially downregulates the mRNA expression of CYP3A4 up to 100-fold at 10 ng/mL, [26][27][28][30][31][32][34][35][36][37][38][39][40][41][42][43] whereas other CYP enzymes are downregulated 1.5-to 8-fold by 10 ng/mL IL-6. [26][27][28]31,34,35,[37][38][39][40][41][42][43] A study reported a 2-fold upregulation of CYP2D6 mRNA by IL-6, 34 however, two other studies reported a maximum of 2to 3-fold downregulation of CYP2D6 mRNA at the same IL-6 concentration.…”

“…The in vitro effect of IL‐6 on the mRNA expression of CYP enzymes in primary human hepatocytes have been reported in multiple studies 25‐43 . IL‐6 substantially downregulates the mRNA expression of CYP3A4 up to 100‐fold at 10 ng/mL, 26–28,30–32,34–43 whereas other CYP enzymes are downregulated 1.5‐ to 8‐fold by 10 ng/mL IL‐6 26–28,31,34,35,37–43 . A study reported a 2‐fold upregulation of CYP2D6 mRNA by IL‐6, 34 however, two other studies reported a maximum of 2‐ to 3‐fold downregulation of CYP2D6 mRNA at the same IL‐6 concentration 33,37 .…”

Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes

“…However, tilsotolimod increased CYP1A2 and CYP2B6 mRNA levels by 2- and 5-fold, respectively, at concentrations over 2.5 ng/ml, and reduced CYP2B6 enzyme activity by 46%. That study established that while INF-2α is inactivated in human liver cells, it mediates the effects of tilsotolimod on CYP1A2 and CYP2B6 expression ( Czerwiński et al, 2019 ).…”