Constitutive androstane receptor upregulates Abcb1 and Abcg2 at the blood–brain barrier after CITCO activation

Lemmen, Julia; Tozakidis, Iasson E. P.; Bele, Prachee; Galla, Hans‐Joachim

doi:10.1016/j.brainres.2013.01.025

Cited by 42 publications

(34 citation statements)

References 45 publications

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“…However, the fluxes of mannitol remained stable through the experiments in spite of this breakdown, but the partial breakdown may be the reason for our apparent TEER cut-off value of 500 Ω·cm 2 , which is higher than previously reported [69]. A method to decrease the apparent decline in paracellular tightness could be to run the experiments directly in the incubator, as shown by Lemmen et al who performed 20-h transport experiments across pig endothelial cells in the incubator with real-time TEER monitoring demonstrating polarized transport of Hoechst dye and stable TEER values throughout the experiment [70,71]. This method may not be applicable for short-term transport studies with shaking and frequent sampling, where a gradual decline in TEER can be anticipated.…”

Section: Polarized Transport Of Efflux Transporter Substrates May Be mentioning

confidence: 62%

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

Helms

Hersom

Kuhlmann

et al. 2014

AAPS J

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Abstract. Efflux transporters of the ATP-binding cassette superfamily including breast cancer resistance protein (Bcrp/Abcg2), P-glycoprotein (P-gp/Abcb1) and multidrug resistance-associated proteins (Mrp's/ Abcc's) are expressed in the blood-brain barrier (BBB). The aim of this study was to investigate if a bovine endothelial/rat astrocyte in vitro BBB co-culture model displayed polarized transport of known efflux transporter substrates. The co-culture model displayed low mannitol permeabilities of 0.95±0.1·10 H-etoposide revealed polarized transport favouring the brain-to-blood direction for all substrates. Steady state efflux ratios of 2.5±0.2 for digoxin, 4.4±0.5 for estrone-3-sulphate and 2.4±0.1 for etoposide were observed. These were reduced to 1.1±0.08, 1.4±0.2 and 1.5±0.1, by addition of verapamil (digoxin), Ko143 (estrone-3-sulphate) or zosuquidar+reversan (etoposide), respectively. Brain-toblood permeability of all substrates was investigated in the presence of the efflux transporter inhibitors verapamil, Ko143, zosuquidar, reversan and MK 571 alone or in combinations. Digoxin was mainly transported via P-gp, estrone-3-sulphate via Bcrp and Mrp's and etoposide via P-gp and Mrp's. The expression of P-gp, Bcrp and Mrp-1 was confirmed using immunocytochemistry. The findings indicate that P-gp, Bcrp and at least one isoform of Mrp are functionally expressed in our bovine/rat co-culture model and that the model is suitable for investigations of small molecule transport.KEY WORDS: blood-brain barrier; breast cancer resistance protein; multidrug resistance-associated protein; p-glycoprotein; polarized small molecule transport.

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Section: Polarized Transport Of Efflux Transporter Substrates May Be mentioning

confidence: 62%

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

Helms

Hersom

Kuhlmann

et al. 2014

AAPS J

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“…Accumulating evidence shows that CAR is necessary for normal function in tissues in which the expression of CAR is relatively low. The human CAR agonist CITCO induces the expression of drug transporters at the blood-brain barrier, indicating that the expression of CAR in endothelial cells is important for drug resistance [107][108][109] . The association of CAR single-nucleotide polymorphisms with bone mineral density was also reported, and loss of CAR increased bone mass, suggesting that CAR is essential for osteoblast/osteoclast homeostasis [110,111] .…”

Section: Discussionmentioning

confidence: 99%

Deciphering the roles of the constitutive androstane receptor in energy metabolism

et al. 2014

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The constitutive androstane receptor (CAR) is initially defined as a xenobiotic nuclear receptor that protects the liver from injury. Detoxification of damaging chemicals is achieved by CAR-mediated induction of drug-metabolizing enzymes and transporters. More recent research has implicated CAR in energy metabolism, suggesting a therapeutic potential for CAR in metabolic diseases, such as type 2 diabetes and obesity. A better understanding of the mechanisms by which CAR regulates energy metabolism will allow us to take advantage of its effectiveness while avoiding its side effects. This review summarizes the current progress on the regulation of CAR nuclear translocation, upstream modulators of CAR activity, and the crosstalk between CAR and other transcriptional factors, with the aim of elucidating how CAR regulates glucose and lipid metabolism.

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“…CAR (phenobarbital, CITCO) and PXR (rifampicin and 2-acetylaminofluorene) ligands can thus increase ABCG2 expression in vitro (Jigorel et al, 2006;Lemmen et al, 2013). Other transcription factors can also induce ABCG2, and its promoter contains hypoxia, estrogen, progesterone, PPARg, and aryl hydrocarbon receptor response elements (Ebert et al, 2005;Szatmari et al, 2006;Robey et al, 2011;To et al, 2011).…”

Section: Abcg2mentioning

confidence: 99%

“…Its agonists (e.g., rifampicin) consequently decreased the intestinal uptake (bioavailability) and increased the (biliary/renal) elimination of ABCB1 ligands in healthy volunteers (Chen, 2010). CAR agonists (e.g., CITCO [6-(4-chlorophenyl)-imidazo[2,1-b][1,3] thiazole-5-carbaldehyde]) induced ABCB1 expression in brain capillary cells (Chen, 2010;Lemmen et al, 2013). VDR activation, via 1,25-dihydroxyvitamin D3, induced ABCB1 in the kidney and brain of mice (Chow et al, 2011).…”

Section: Abcb1mentioning

confidence: 99%

The Role of Canalicular ABC Transporters in Cholestasis

Cuperus

Claudel

Gautherot

et al. 2014

Drug Metabolism and Disposition

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Cholestasis, a hallmark feature of hepatobiliary disease, is characterized by the retention of biliary constituents. Some of these constituents, such as bile acids, inflict damage to hepatocytes and bile duct cells. This damage may lead to inflammation, fibrosis, cirrhosis, and eventually carcinogenesis, sequelae that aggravate the underlying disease and deteriorate clinical outcome. Canalicular ATP-binding cassette (ABC) transporters, which mediate the excretion of individual bile constituents, play a key role in bile formation and cholestasis. The study of these transporters and their regulatory nuclear receptors has revolutionized our understanding of cholestatic disease. This knowledge has served as a template to develop novel treatment strategies, some of which are currently already undergoing phase III clinical trials. In this review we aim to provide an overview of the structure, function, and regulation of canalicular ABC transporters. In addition, we will focus on the role of these transporters in the pathogenesis and treatment of cholestatic bile duct and liver diseases.

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Constitutive androstane receptor upregulates Abcb1 and Abcg2 at the blood–brain barrier after CITCO activation

Cited by 42 publications

References 45 publications

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

Deciphering the roles of the constitutive androstane receptor in energy metabolism

The Role of Canalicular ABC Transporters in Cholestasis

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