Effects of nonsteroidal anti-inflammatory drugs on the expression and function of P-Glycoprotein/MDR1 in Caco-2 cells

Takara, Kohji; Hayashi, Ryuhei; Kokufu, Misato; Yamamoto, Kazuhiro; Kitada, Noriaki; Ohnishi, Noriaki; Yokoyama, Teruyoshi

doi:10.1080/01480540903130658

Cited by 24 publications

(14 citation statements)

References 22 publications

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“…This rapid increase in p-gp upregulation was also reported by Ehret et al [23], who showed that venlafaxine increases the expression of MDR1 and MRP genes in caco-2 cells during an acute (1.5, 3 and 6 h) treatment period. Similar results were observed for another known p-gp inducer, rifampicin, and for several nonsteroidal anti-inflammatory drugs (NSAIDs), including diclofenac, fenbufen and indomethacin [24]. The present remarkable increases in p-gp expression levels induced by curcumin and tetrahydrocurcumin were not accompanied by proportional increases in p-gp transport activity.…”

Section: Discussionsupporting

confidence: 74%

“…Noteworthy, our data suggest that, for the screening of p-gp inducers, both p-gp expression and activity should be investigated, since an increase in the first may not be reflected in an increase in the second parameter. Similarly, Takara et al [24] noted that p-gp transport function remained unchanged in caco-2 cells exposed to several NSAIDs, in spite of the observed increase in MDR1 mRNA. One possible explanation for the differences noted between p-gp expression and activity levels in these cells is that caco-2 full differentiation into enterocytes could be needed to obtain fully functional p-gp.…”

Section: Discussionmentioning

confidence: 99%

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P-gp Induction by Curcumin: An Effective Antidotal Pathway

Wan-Hua¹

2013

J Bioequiv Availab

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

P-gp Induction by Curcumin: An Effective Antidotal Pathway

Wan-Hua¹

2013

J Bioequiv Availab

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“…Additionally, for all the tested compounds, a good correlation between the observed increases in P-gp expression and activity was demonstrated. In fact, it is known that increases in protein expression may not necessarily result in proportional increases in 1,2-Dihydroxy-9H-xanthen-9-one −7 Sousa et al (2013) 3,4-Dihydroxy-9H-xanthen-9-one −6.3 Sousa et al (2013) 1-Chloro-9-oxo-9H-thioxanthen-4-yl acetate −8.4 pump activity (Silva et al , 2014aTakara et al 2009;Vilas-Boas et al 2011). Using the same in vitro model, we have previously shown that the remarkable increase in P-gp expression caused by doxorubicin, a potent P-gp inducer, was not accompanied by a proportional increase in P-gp transport activity .…”

Section: Discussionmentioning

confidence: 97%

“…With this second protocol, it is possible to evaluate whether the increases in P-gp activity are due to the increased P-gp expression induced by the TXs, given that an increased protein expression does not necessarily translate into an increased transport activity (Silva et al 2014a;Takara et al 2009). The obtained results (Fig.…”

Section: P-glycoprotein Expressionmentioning

confidence: 99%

P-glycoprotein induction in Caco-2 cells by newly synthetized thioxanthones prevents paraquat cytotoxicity

et al. 2014

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The induction of P-glycoprotein (P-gp), an ATP-dependent efflux pump, has been proposed as a strategy against the toxicity induced by P-gp substrates such as the herbicide paraquat (PQ). The aim of this study was to screen five newly synthetized thioxanthonic derivatives, a group known to interact with P-gp, as potential inducers of the pump's expression and/or activity and to evaluate whether they would afford protection against PQ-induced toxicity in Caco-2 cells. All five thioxanthones (20 µM) caused a significant increase in both P-gp expression and activity as evaluated by flow cytometry using the UIC2 antibody and rhodamine 123, respectively. Additionally, it was demonstrated that the tested compounds, when present only during the efflux of rhodamine 123, rapidly induced an activation of P-gp. The tested compounds also increased P-gp ATPase activity in MDR1-Sf9 membrane vesicles, indicating that all derivatives acted as P-gp substrates. PQ cytotoxicity was significantly reduced in the presence of four thioxanthone derivatives, and this protective effect was reversed upon incubation with a specific P-gp inhibitor. In silico studies showed that all the tested thioxanthones fitted onto a previously described three-feature P-gp induction pharmacophore. Moreover, in silico interactions between thioxanthones and P-gp in the presence of PQ suggested that a co-transport mechanism may be operating. Based on the in vitro activation results, a pharmacophore model for P-gp activation was built, which will be of further use in the screening for new P-gp activators. In conclusion, the study demonstrated the potential of the tested thioxanthonic compounds in protecting against toxic effects induced by P-gp substrates through P-gp induction and activation.

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“…Jung et al (2011) showed that aspirin induces MDR1 mRNA and activity in intestinal cells in vitro and rat intestine in vivo. In another study, NSAIDs increased MDR1 mRNA expression in Caco-2 cells but not efflux activity (Takara et al, 2009). Thus, the use of NSAIDs to attenuate neuroinflammation and microglial activation may have the added benefit of partially restoring normal transporter function.…”

mentioning

confidence: 99%

Inflammatory Regulation of ATP Binding Cassette Efflux Transporter Expression and Function in Microglia

Gibson

Hossain

Richardson

et al. 2012

J Pharmacol Exp Ther

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ATP-binding cassette (ABC) efflux transporters, including multidrug resistance protein 1 (Mdr1), breast cancer resistance protein (Bcrp), and multidrug resistance-associated proteins (Mrps) extrude chemicals from the brain. Although ABC transporters are critical for blood-brain barrier integrity, less attention has been placed on the regulation of these proteins in brain parenchymal cells such as microglia. Prior studies demonstrate that inflammation after lipopolysaccharide (LPS) treatment alters transporter expression in the livers of mice. Here, we sought to determine the effects of inflammation on the expression and function of transporters in microglia. To test this, the expression and function of ABC efflux transport proteins were quantified in mouse BV-2 microglial cells in response to activation with LPS. Intracellular retention of fluorescent rhodamine 123, Hoechst 33342, and calcein acetoxymethyl ester was increased in LPS-treated microglia, suggesting that the functions of Mdr1, Bcrp, and Mrps were decreased, respectively. LPS reduced Mdr1, Bcrp, and Mrp4 mRNA and protein expression between 40 and 70%. Conversely, LPS increased expression of Mrp1 and Mrp5 mRNA and protein. Immunofluorescent staining confirmed reduced Bcrp and Mrp4 and elevated Mrp1 and Mrp5 protein in activated microglia. Pharmacological inhibition of nuclear factor B (NF-B) transcriptional signaling attenuated down-regulation of Mdr1a mRNA and potentiated up-regulation of Mrp5 mRNA in LPS-treated cells. Together, these data suggest that LPS stimulates microglia and impairs efflux of prototypical ABC transporter substrates by altering mRNA and protein expression, in part through NF-B signaling. Decreased transporter efflux function in microglia may lead to the retention of toxic chemicals and aberrant cell-cell communication during neuroinflammation.

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Effects of nonsteroidal anti-inflammatory drugs on the expression and function of P-Glycoprotein/MDR1 in Caco-2 cells

Cited by 24 publications

References 22 publications

P-gp Induction by Curcumin: An Effective Antidotal Pathway

P-gp Induction by Curcumin: An Effective Antidotal Pathway

P-glycoprotein induction in Caco-2 cells by newly synthetized thioxanthones prevents paraquat cytotoxicity

Inflammatory Regulation of ATP Binding Cassette Efflux Transporter Expression and Function in Microglia

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