Associations between Cytokine Levels and CYP3A4 Phenotype in Patients with Rheumatoid Arthritis

Abstract

Systemic inflammation has been linked to suppressed CYP3A4 activity. The aim of this study was to examine associations between levels of a broad selection of cytokines and CYP3A4 phenotype in patients with rheumatoid arthritis (RA). The study included 31 RA patients treated with tumor necrosis factor (TNF)- inhibitors. CYP3A4 phenotype was measured as serum concentration of 4-hydroxycholesterol (4OHC) by ultra-performance liquid chromatography-tandem mass spectrometry in samples collected prior to and 3 months after initiation of treatment with TNF- inhibitors. Serum levels of the following 21 cytokines were determined in the same samples using a bead-based multiplex immunoassay (Luminex technology): CCL2, CCL3, CXCL8, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon , interleukin (IL)-1, IL-1 receptor antagonist (ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-18, IL-23, and TNF- Correlations between levels of cytokines and 4OHC were assessed by Spearman's rank correlation tests. Among the investigated cytokines, three were negatively correlated with CYP3A4 phenotype during treatment with TNF- inhibitors: i.e., IL-1ra ( = -0.408, = 0.023), IL-6 ( = -0.410, = 0.022) and CXCL8 ( = -0.403, = 0.025) ( ≥ 0.3 for all other cytokines). None of the analyzed cytokines were correlated with CYP3A4 phenotype prior to TNF- inhibitor treatment ( > 0.1 for all cytokines). These findings suggest that immune responses associated with increased levels of IL-1ra, IL-6, and CXCL8 may suppress CYP3A4 metabolism. Further studies are required to evaluate these preliminary findings in different patient populations and also examine the possible molecular mechanisms behind our observations.

Correlation of Body Weight and Composition With Hepatic Activities of Cytochrome P450 Enzymes

“…23e27 Furthermore, IL-6 was recently found to be negatively correlated with 4-bhydroxycholesterol, an endogenous marker of CYP3A activity in vivo, in patients with rheumatoid arthritis. 28 Although possibly confounded by the existing positive correlation between IL-6 and body weight, the present study supports the speculation that inflammatory status, e.g. increased IL-6 levels, may partly mediate the obesity-induced hepatic CYP3A suppression.…”

Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment

“…In addition, rheumatoid arthritis patients exhibit higher plasma concentrations of simvastatin, another CYP450 substrate ( Schmitt, Kuhn, Zhang, Kivitz, & Grange, 2011 ) and lower plasma concentrations of 4-ßhydroxycholesterol, an endogenous CYP3A4 metabolite ( Wollmann et al, 2017 ). CYP3A4 activity has been shown to correlate with proinflammatory cytokine levels, especially those of IL-1ra, IL-6, and CXCL8 ( Wollmann et al, 2018 ). In addition, the central role of IL-6 in the inhibition of CYP clearance in rheumatoid arthritis has been shown in clinical trials evaluating monoclonal antibodies targeting IL-6 ( Lee, Tripathi, & Morgan, 2017 ; Schmitt et al, 2011 ; Zhuang et al, 2015 ).…”

The regulation of drug-metabolizing enzymes and membrane transporters by inflammation: Evidences in inflammatory diseases and age-related disorders

“…Inhibition of cytokines production by non-steroidal anti-inflammatory drugs (NSAIDs) or treatment with antibodies against specific cytokines can reverse the reduction of CYP enzymes and the changes in the clearance of propranolol in RA animal models [ 76 , 77 ], confirming that cytokines have an important role in the regulation of CYP enzymes in RA. In humans, it was recently reported that the levels of inflammatory cytokines are negatively associated with CYP3A4 phenotype in RA patients [ 78 ]. On the other hand, in terms of membrane transporters, the mRNA levels of numerous ABC and SLC transporters (e.g., Oatps , Mdr1a , Mrp2 ) are decreased in adjuvant- or collagen-induced arthritis rats [ 75 , 79 ].…”