Physiological and pathophysiological factors affecting the expression and activity of the drug transporter MRP2 in intestine. Impact on its function as membrane barrier

Arana, Maite Rocío; Tocchetti, Guillermo Nicolás; Rigalli, Juan Pablo; Mottino, Aldo D.; Villanueva, Silvina Stella Maris

doi:10.1016/j.phrs.2016.04.014

Cited by 22 publications

(10 citation statements)

References 150 publications

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“…The mechanism responsible for the observed increase in small intestinal Mrp2 protein expression can only be speculated at this stage. While many diseases are associated with reduced MRP2 expression such as hepatic failure and diabetes 31 , intestinal MRP2 expression and function have been reported to be increased by the inflammatory cascade associated with intestinal infections 32 . APP/PS1 mice exhibit increased pro-inflammatory markers in their small intestinal lumen 33 .…”

Section: Discussionmentioning

confidence: 99%

Altered Expression of Small Intestinal Drug Transporters and Hepatic Metabolic Enzymes in a Mouse Model of Familial Alzheimer’s Disease

et al. 2018

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Drug transporter expression and function at the blood-brain barrier is altered in Alzheimer's disease (AD). However, the impact of AD on the expression of transporters and metabolizing enzymes in peripheral tissues has received little attention. The current study evaluated the expression of drug transporters and metabolizing enzymes in the small intestine and liver from 8- to 9-month-old female wild-type (WT) and APPswe/PSEN 1dE9 (APP/PS1) transgenic mice, a widely used AD model, using a quantitative targeted absolute proteomics (QTAP) approach. Furthermore, the general morphological appearance of the liver was assessed by immunohistochemistry, and lipid content was visualized using Oil Red O staining. The small intestines of APP/PS1 mice exhibited a significant 2.3-fold increase in multidrug resistance-associated protein 2 (Mrp2), a 1.9-fold decrease in monocarboxylate transporter 1 (Mct1), and a 3.6-fold increase in UDP-glucuronosyltransferase (Ugt) 2b5 relative to those from WT mice based on QTAP analysis. While the liver from APP/PS1 mice exhibited no changes in drug transporter expression, there was a 1.3-fold elevation in cytochrome P450 (Cyp) 51a1 and a 1.2-fold reduction in Cyp2c29 protein expression, and this was associated with morphological alterations including accumulation of hepatocyte lipids. These studies are the first to demonstrate that the protein expression of transporters and metabolizing enzymes important in oral drug absorption are modified in a mouse model of familial AD, which may lead to altered disposition of some orally administered drugs in AD.

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Section: Discussionmentioning

confidence: 99%

Altered Expression of Small Intestinal Drug Transporters and Hepatic Metabolic Enzymes in a Mouse Model of Familial Alzheimer’s Disease

et al. 2018

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“…In the present study, we focused on the uptake of Fe 3 O 4 NPs by intestinal epithelial cells under inflammatory conditions. The intestinal tract is the primary physiological barrier for the oral absorption of multiple substances [ 28 , 29 ]. Lehr et al [ 30 , 31 ] reported that in the inflamed colon, an increased adherence of particles was observed in the thicker mucus layer.…”

Section: Resultsmentioning

confidence: 99%

Enhanced Uptake of Fe3O4 Nanoparticles by Intestinal Epithelial Cells in a State of Inflammation

et al. 2017

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Fe3O4 nanoparticles (Fe3O4 NPs) have been used for medical and drug applications, although the mechanisms of cellular uptake and transport need to be further evaluated under inflammatory conditions. In the present study, we investigated the uptake of Fe3O4 NPs (20, 50, 100, and 200 nm) by intestinal epithelial cells under inflammatory conditions via the light scattering of flow cytometry and inductively coupled plasma mass spectrometry (ICP-MS) techniques. The results of the correlation analysis indicated that the uptake ratios of Fe3O4 NPs by intestinal epithelial cells under inflammatory conditions were higher than those under the control conditions. The transportation ratios of NPs by inflammatory Caco-2 cells increased almost 0.8–1.2 fold compared to the control. The internalization of the Fe3O4 NPs in Caco-2 cells was mediated by clathrin-related routes in both the control and an interleukin-1β (IL-1β)-induced inflammatory condition. The level of mRNA of clathrin expressed in Caco-2 cells that were stimulated by IL-1β was almost three times more than the control. Consistently with the mRNA expression, the level of protein in the clathrin was upregulated. Additionally, it was verified for the first time that the expression of clathrin was upregulated in IL-1β-stimulated Caco-2 cells. Collectively, these results provided a further potential understanding about the mechanism of Fe3O4 NPs’ uptake by intestinal epithelial cells under inflammatory conditions.

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“…Expression of drug efflux transporters was investigated in the intestine of poultry by Haritova et al (). They found that multidrug resistance‐associated protein 2 (MRP2) mRNA transporters localised at the apical membrane of enterocytes act as an important mechanism against intestinal absorption of xenobiotics (Arana, Tocchetti, Rigalli, Mottino, & Villanueva, ). The fact that we found low concentrations of thymol in the ileum could be due to low MRP2 transporter activity, so thymol and/or thymol metabolites could be absorbed into enterocytes and effectively transported to the blood circulation.…”

Section: Discussionmentioning

confidence: 99%

Thymol in the intestinal tract of broiler chickens after sustained administration of thyme essential oil in feed

Ocelova

Chizzola

Battelli

et al. 2018

Animal Physiology Nutrition

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Plant compounds occurring in phytogenic feed additives are involved in different pharmacological activities in the animal organism. Since the digestive tract acts as a first line of defence against foreign compounds, it is necessary to outline its response to dietary supplementation with bioactive plant components. Little information is available on the bioactivity of thymol as the main bioactive compound of Thymus vulgaris L. essential oil (TEO). The main objective of the present study was to provide a detailed view of the concentrations of thymol in plasma and the content of individual intestinal segments (duodenum, jejunum, ileum, caecum and colon) of broiler chickens after 4 weeks of dietary supplementation with different TEO concentrations. 32 one‐day old Ross 308 hybrid broilers were randomly divided into four dietary treatment groups (0.00%, 0.01%, 0.05%, 0.1% w/w of TEO in the diet). Thymol concentrations in the duodenal chyme presented around 7% on average from the thymol amount administered in the feed. A significantly increased thymol amount was observed after 0.1% TEO addition to the diet compared with 0.01% TEO enrichment in the duodenal wall and gut content of jejunum, ileum, caecum and colon (p < 0.05). Thymol levels in the colon were significantly higher than in the ileum and about 1.7 times higher on average than those in the caecum. Significant coefficient of correlation was observed between thymol concentrations in plasma and feed, gut content of all intestinal segments as well as duodenal wall. Our results point to intensive thymol absorption in the initial sections of the digestive tract. In the current study, the role of intestine in biotransformation of thymol was observed, and it would be desirable to investigate whether thymol itself or thymol metabolites are responsible for beneficial effects in intestine.

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Physiological and pathophysiological factors affecting the expression and activity of the drug transporter MRP2 in intestine. Impact on its function as membrane barrier

Cited by 22 publications

References 150 publications

Altered Expression of Small Intestinal Drug Transporters and Hepatic Metabolic Enzymes in a Mouse Model of Familial Alzheimer’s Disease

Altered Expression of Small Intestinal Drug Transporters and Hepatic Metabolic Enzymes in a Mouse Model of Familial Alzheimer’s Disease

Enhanced Uptake of Fe3O4 Nanoparticles by Intestinal Epithelial Cells in a State of Inflammation

Thymol in the intestinal tract of broiler chickens after sustained administration of thyme essential oil in feed

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