Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier

Narang, Vishal S.; Fraga, Charles H.; Kumar, Narendra; Shen, Jun; Throm, Stacy L.; Stewart, Clinton F.; Waters, Christopher M.

doi:10.1152/ajpcell.00491.2007

Cited by 132 publications

(117 citation statements)

References 43 publications

(47 reference statements)

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“…This is in contrast to other substrates of P-gp such as dexamethasone and ritonavir (Gutmann et al, 2006;Narang et al, 2008;Perloff et al, 2004).…”

Section: And R-citalopram and Its Metabolites In Abcb1ab (-/-) Knocmentioning

confidence: 73%

Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment

Karlsson¹,

Carlsson²,

Hiemke³

et al. 2013

European Neuropsychopharmacology

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According to both in vitro and in vivo data P-glycoprotein (P-gp) may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. The therapeutic activity of citalopram resides in the S-enantiomer, whereas the R-enantiomer is practically devoid of serotonin reuptake potency. To date, no in vivo data are available that address whether the enantiomers of citalopram and its metabolites are substrates of P-gp. P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10 mg/kg) or escitalopram (5 mg/kg). Serum and brain samples were collected 1-6 h after the first or last i.p. injection for subsequent drug analysis by an enantioselective HPLC method. In brain, 3-fold higher concentrations of S-and R-citalopram, and its metabolites, were found in abcb1ab (-/-) mice than in abcb1ab (+/+) mice after both acute and chronic citalopram treatments. After escitalopram treatment, the S-citalopram brain concentration was 3-5 times higher in the knockout mice than in controls. The results provide novel evidence that the enantiomers of citalopram are substrates of P-gp. Possible clinical and toxicological implications of this finding need to be further elucidated.

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“…This is in contrast to other substrates of P-gp such as dexamethasone and ritonavir (Gutmann et al, 2006;Narang et al, 2008;Perloff et al, 2004).…”

Section: And R-citalopram and Its Metabolites In Abcb1ab (-/-) Knocmentioning

confidence: 73%

Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment

Karlsson¹,

Carlsson²,

Hiemke³

et al. 2013

European Neuropsychopharmacology

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“…In addition to PXR, other nuclear receptors are also expressed at the blood-brain barrier, where they control regulation of several transporters. Narang et al (2008) demonstrated that dexamethasone activation of the glucocorticoid receptor increased P-glycoprotein, Mrp2, and BCRP in rat brain endothelial cells and showed that PXR activation with PCN increased BCRP expression. In this context, the present study adds another mosaic to the picture that is emerging for the blood-brain barrier, that is, like in liver (Rosenfeld et al, 2003), a complex network of nuclear receptors controlling metabolizing enzymes and drug efflux transporters.…”

Section: Discussionmentioning

confidence: 96%

Pregnane X Receptor (PXR) Regulates P-Glycoprotein at the Blood-Brain Barrier: Functional Similarities between Pig and Human PXR

Ott

Fricker²,

Bauer³

2009

J Pharmacol Exp Ther

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Pharmacotherapy of central nervous system (CNS) disorders is impaired by the drug efflux transporter, P-glycoprotein, which limits drug penetration across the blood-brain barrier into the CNS. One strategy to increase brain drug levels is to modulate P-glycoprotein regulation. This approach requires understanding of the mechanisms that control transporter expression and function. One mechanism through which P-glycoprotein is regulated is the nuclear receptor, pregnane X receptor (PXR). Xenobiotics including drugs activate PXR and induce P-glycoprotein, which potentially affects pharmacokinetics/pharmacodynamics of coadministered drugs. Because rodent models are not suitable to predict xenobiotic interactions with human PXR, in a porcine model, we studied functional similarities between pig and human PXR. We used brain capillary endothelial cells from pig to study the effect of PXR activation on P-glycoprotein. To activate PXR, we used the PXR ligands, rifampicin, hyperforin, and pregnenolone-16␣-carbonitrile (PCN), and measured abcb1 mRNA with quantitative polymerase chain reaction, P-glycoprotein expression with Western blotting, and P-glycoprotein transport activity with a calcein assay. We provide first proof of principle that the human PXR ligands, rifampicin and hyperforin, but not the rodent PXR ligand, PCN, activate pig PXR at the bloodbrain barrier and induce mRNA, protein expression, and transport activity of P-glycoprotein. Our data indicate functional similarities between human and pig PXR that suggest the pig model could be useful for predicting xenobiotic-PXR interactions in humans. Because PXR is crucial in controlling drug efflux transporters, our findings will contribute to a better understanding of the regulation of blood-brain barrier function, which could potentially have important clinical implications for the treatment of CNS disorders.Pharmacotherapy of CNS disorders is greatly impaired by the blood-brain barrier. In this barrier, ATP-driven efflux transporters limit a large number of drugs from getting into the brain. P-glycoprotein (ABCB1, MDR1), the most prominent drug efflux transporter at the blood-brain barrier, plays an essential role in barrier function (Schinkel, 1999). For example, brain penetration of a large number of drugs is increased by 10-to 100-fold in P-glycoprotein-null mice compared with wild-type controls (Schinkel et al., 1994). Likewise, specific inhibition of P-glycoprotein in mice increases brain levels of paclitaxel, resulting in a 90% reduction of brain tumor volume (Fellner et al., 2002). On the other hand, up-regulation of P-glycoprotein, e.g., in drug-resistant epilepsy, CNS inflammation, or through oxidative stress selectively tightens the barrier for drugs that are P-glycoprotein substrates (Löscher and Potschka, 2005;Bauer et al., 2007;Hartz et al., 2008). In this regard, we have previously shown expression of the ligand-activated nuclear receptor, pregnane X receptor (PXR), in isolated rat brain capillaries and demonstrated PXR-mediated up-regulatio...

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“…In particular, gene amplification (Ross et al, 1999;Knutsen et al, 2000;Volk et al, 2002) has been shown to be an important mechanism for elevated ABCG2 expression in drug-resistant cancer cells. Recent studies have demonstrated that transcriptional factors [i.e., nuclear receptors (Ee et al, 2004b;Ebert et al, 2005;Szatmari et al, 2006;Honorat et al, 2008;Narang et al, 2008;Vore and Leggas, 2008;Wang et al, 2008b) and epigenetic factors Turner et al, 2006;Calcagno et al, 2008;Nakano et al, 2008;To et al, 2008a)] play important roles in the regulation of ABCG2 in different model systems. Potential regulation of ABCG2 at its 3Ј-untranslated region (3Ј-UTR) is just beginning to be explored .…”

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confidence: 99%

MicroRNA-328 Negatively Regulates the Expression of Breast Cancer Resistance Protein (BCRP/ABCG2) in Human Cancer Cells

2009

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Breast cancer resistance protein (BCRP/ABCG2) is a molecular determinant of pharmacokinetic properties of many drugs in humans. To understand post-transcriptional regulation of ABCG2 and the role of microRNAs (miRNAs) in drug disposition, we found that microRNA-328 (miR-328) might readily target the 3Ј-untranslated region (3Ј-UTR) of ABCG2 when considering target-site accessibility. We then noted 1) an inverse relation between the levels of miR-328 and ABCG2 in MCF-7 and MCF-7/MX100 breast cancer cells and 2) that miR-328 levels could be rescued in MCF-7/MX100 cells by transfection with miR-328 plasmid. Luciferase reporter assays showed that ABCG2 3Ј-UTR-luciferase activity was decreased more than 50% in MCF-7/MX100 cells after transfection with miR-328 plasmid, the activity was increased over 100% in MCF-7 cells transfected with a miR-328 antagomir, and disruption of miR-328 response element within ABCG2 3Ј-UTR led to a 3-fold increase in luciferase activity. Furthermore, the level of ABCG2 protein was down-regulated when miR-328 was over-expressed, and the level was up-regulated when miR-328 was inhibited by selective antagomir. Altered ABCG2 protein expression was associated with significantly declined or elevated levels of ABCG2 3Ј-UTR and coding sequence mRNAs, suggesting possible involvement of the mechanism of mRNA cleavage. Finally, miR-328-directed down-regulation of ABCG2 expression in MCF-7/MX100 cells resulted in an increased mitoxantrone sensitivity, as manifested by a significantly lower IC 50 value (2.46 Ϯ 1.64 M) compared with the control (151 Ϯ 32 M). Together, these findings suggest that miR-328 targets ABCG2 3Ј-UTR and, consequently, controls ABCG2 protein expression and influences drug disposition in human breast cancer cells.Breast cancer resistance protein BCRP/ABCG2 is an ATPbinding cassette membrane transporter expressed ubiquitously in humans, controlling the absorption, distribution and clearance of numerous xenobiotics, including pharmaceutical agents, dietary carcinogens and conjugated metabolites (Mao and Unadkat, 2005;van Herwaarden and Schinkel, 2006;Vore and Leggas, 2008). In addition, overexpression of ABCG2 and other drug transporters in tumorigenic stem cells represents an important mechanism for multidrug resistance (Dean et al., 2005). Because ABCG2 was discovered in drugresistant human cancer cells (e.g., MCF-7/AdrVp and S1MI80), these cell lines have been widely used for studying the function and regulation of ABCG2 and defining its role in drug disposition and multidrug resistance. In particular, gene amplification (Ross et al., 1999;Knutsen et al., 2000;Volk et al., 2002) has been shown to be an important mechanism for elevated ABCG2 expression in drug-resistant cancer cells. Recent studies have demonstrated that transcriptional factors [i.e., nuclear receptors (Ee et al.,

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Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier

Cited by 132 publications

References 43 publications

Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment

Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment

Pregnane X Receptor (PXR) Regulates P-Glycoprotein at the Blood-Brain Barrier: Functional Similarities between Pig and Human PXR

MicroRNA-328 Negatively Regulates the Expression of Breast Cancer Resistance Protein (BCRP/ABCG2) in Human Cancer Cells

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