Glucagon-like peptide 2 prevents down-regulation of intestinal multidrug resistance-associated protein 2 and P-glycoprotein in endotoxemic rats

Arana, Maite Rocío; Tocchetti, Guillermo Nicolás; Zecchinati, Felipe; Londero, Ana Sofía; Domínguez, Camila Juliana; Perdomo, Virginia; Rigalli, Juan Pablo; Villanueva, Silvina Stella Maris; Mottino, Aldo D.

doi:10.1016/j.tox.2017.08.007

Cited by 10 publications

(10 citation statements)

References 42 publications

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“…In addition, the in vitro P -gp upregulations are not consistent with in vivo preclinical studies on treated rodents that have shown a systematic downregulation of intestinal P -gp expression. − This downregulation of P -gp was fully supported by the analysis of human intestinal biopsies from patients with Crohn’s disease that showed a decrease in mRNA levels of ABCB1 compared to the healthy biopsies . Thereby, the TNF-α-induced upregulation of ABCB1 gene observed in this study suggests that P -gp could be regulated differently in vitro, mainly depending on the inflammatory stimuli.…”

Section: Discussioncontrasting

confidence: 53%

TNF-α and IL-1β Exposure Modulates the Expression and Functionality of P-Glycoprotein in Intestinal and Renal Barriers

et al. 2022

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Inflammation is characterized by an increased secretion of proinflammatory cytokines known to alter the expression and functionality of drug transporters. Since P-glycoprotein (P-gp) plays a key role in the pharmacokinetics of several drugs, these modulations could further affect drug exposure. In this context, this study aims to investigate the impact of in vitro cytokine exposure on the expression and activity of P-gp using the intestinal model Caco-2 and the human renal cells RPTEC/TERT1. Cells were exposed to various concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1β for 24 or 72 h. Gene expression was then assessed by RT-qPCR followed by absolute quantification of P-gp using liquid chromatography coupled with mass spectrometry. Then, the activity of P-gp was assessed by the intracellular accumulation of rhodamine 123. TNF-α increased both the gene expression and P-gp activity by 15−40% in each model. Minor modulations were observed at the protein level with increases of up to 8% for RPTEC/TERT1 cells and 24% for Caco-2 cells. Conversely, IL-1β led to a downregulation of gene, protein, and functionality by 48 and 25% in intestinal and renal cells, respectively. Taken together, these data highlighted that gene expression levels and functional activity of P-gp are altered by the pro-inflammatory cytokines in intestinal and renal cells. Such pronounced changes in human P-gp could result in altered exposure to drug substrates. Further in vivo studies are needed to confirm the impact of inflammation on drug pharmacokinetics.

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Section: Discussioncontrasting

confidence: 53%

TNF-α and IL-1β Exposure Modulates the Expression and Functionality of P-Glycoprotein in Intestinal and Renal Barriers

et al. 2022

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“…LPS administration in rats induced a decrease of both P-gp and MRP2 mRNA in the ileum and jejunum 8 h after treatment using the RT-PCR technique. This regulation was associated with an increase of Il-6 and IL-1β mRNA in the same gut areas supporting the role of cytokines in drug transporter modulation [ 75 , 76 , 77 ]. Kalitsky-Szirtes et al (2004) also showed a 50% reduced P-gp-efflux (basal to apical transport) of an antiarrhythmic drug, amiodarone, from treated rat cells.…”

Section: Inflammation-mediated Changes On Drug Transportersmentioning

confidence: 62%

Inflammation Induces Changes in the Functional Expression of P-gp, BCRP, and MRP2: An Overview of Different Models and Consequences for Drug Disposition

Saib

Delavenne

2021

Pharmaceutics

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The ATP-binding cassette (ABC) transporters play a key role in drug pharmacokinetics. These membrane transporters expressed within physiological barriers can be a source of pharmacokinetic variability. Changes in ABC transporter expression and functionality may consequently affect the disposition of substrate drugs, resulting in different drug exposure. Inflammation, present in several acute and chronic diseases, has been identified as a source of modulation in drug transporter expression leading to variability in drug response. Its regulation may be particularly dangerous for drugs with a narrow therapeutic index. In this context, numerous in vitro and in vivo models have shown up- or downregulation in the expression and functionality of ABC transporters under inflammatory conditions. Nevertheless, the existence of contradictory data and the lack of standardization for the models used have led to a less conclusive interpretation of these data.

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“…in 0.4 mL of saline), adenosine (10 mg/kg b.w. in 0.4 mL of saline) or saline alone were administered 29,57,58 . After 20 minutes, MRP2 activity studies were performed.…”

Section: Methodsmentioning

confidence: 99%

Intraluminal nutrients acutely strengthen rat intestinal MRP2 barrier function by a glucagon‐like peptide‐2‐mediated mechanism

et al. 2020

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Aim MRP2 is an intestinal ABC transporter that prevents the absorption of dietary xenobiotics. The aims of this work were: (1) to evaluate whether a short‐term regulation of intestinal MRP2 barrier function takes place in vivo after luminal incorporation of nutrients and (2) to explore the underlying mechanism. Methods MRP2 activity and localization were assessed in an in vivo rat model with preserved irrigation and innervation. Nutrients were administered into distal jejunum. After 30‐minutes treatments, MRP2 activity was assessed in proximal jejunum by quantifying the transport of the model substrate 2,4‐dinitrophenyl‐S‐glutathione. MRP2 localization was determined by quantitative confocal microscopy. Participation of extracellular mediators was evaluated using selective inhibitors and by immunoneutralization. Intracellular pathways were explored in differentiated Caco‐2 cells. Results Oleic acid, administered intraluminally at dietary levels, acutely stimulated MRP2 insertion into brush border membrane. This was associated with increased efflux activity and, consequently, enhanced barrier function. Immunoneutralization of the gut hormone glucagon‐like peptide‐2 (GLP‐2) prevented oleic acid effect on MRP2, demonstrating the participation of this trophic factor as a main mediator. Further experiments using selective inhibitors demonstrated that extracellular adenosine synthesis and its subsequent binding to enterocytic A2B adenosine receptor (A2BAR) take place downstream GLP‐2. Finally, studies in intestinal Caco‐2 cells revealed the participation of A2BAR/cAMP/PKA intracellular pathway, ultimately leading to increased MRP2 localization in apical domains. Conclusion These findings reveal an on‐demand, acute regulation of MRP2‐associated barrier function, constituting a novel physiological mechanism of protection against the absorption of dietary xenobiotics in response to food intake.

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Glucagon-like peptide 2 prevents down-regulation of intestinal multidrug resistance-associated protein 2 and P-glycoprotein in endotoxemic rats

Cited by 10 publications

References 42 publications

TNF-α and IL-1β Exposure Modulates the Expression and Functionality of P-Glycoprotein in Intestinal and Renal Barriers

TNF-α and IL-1β Exposure Modulates the Expression and Functionality of P-Glycoprotein in Intestinal and Renal Barriers

Inflammation Induces Changes in the Functional Expression of P-gp, BCRP, and MRP2: An Overview of Different Models and Consequences for Drug Disposition

Intraluminal nutrients acutely strengthen rat intestinal MRP2 barrier function by a glucagon‐like peptide‐2‐mediated mechanism

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