Neotrofin Is Transported Out of Brain by a Saturable Mechanism: Possible Involvement of Multidrug Resistance and Monocarboxylic Acid Transporters

Yan, Rongzi; Taylor, Eve M.

doi:10.1124/dmd.30.5.513

Cited by 7 publications

(4 citation statements)

References 34 publications

(39 reference statements)

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“…However, as seen when PGP1 was expressed in yeast, PGP1‐mediated net 3 H‐BA efflux was also observed when 3 H‐BA was supplied at higher concentrations (Figure 6b). Background efflux of 3 H‐BA in empty vector controls was higher than with 3 H‐IAA, presumably due to endogenous mammalian benzoate/monocarboxylic acid transport activity (Yan and Taylor, 2002). Expression of PGP1 in HeLa cells resulted in more auxin substrate specificity than when PGP1 was expressed in yeast, as PGP1‐mediated net efflux of 3 H‐BA decreased to zero when 3 H‐BA concentration was reduced to 10 n m , while 3 H‐IAA efflux was unaffected (Figure 6b).…”

Section: Resultsmentioning

confidence: 99%

Cellular efflux of auxin catalyzed by the Arabidopsis MDR/PGP transporter AtPGP1

et al. 2005

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SummaryDirectional transport of the phytohormone auxin is required for the establishment and maintenance of plant polarity, but the underlying molecular mechanisms have not been fully elucidated. Plant homologs of human multiple drug resistance/P-glycoproteins (MDR/PGPs) have been implicated in auxin transport, as defects in MDR1 (AtPGP19) and AtPGP1 result in reductions of growth and auxin transport in Arabidopsis (atpgp1, atpgp19), maize (brachytic2) and sorghum (dwarf3). Here we examine the localization, activity, substrate specificity and inhibitor sensitivity of AtPGP1. AtPGP1 exhibits non-polar plasma membrane localization at the shoot and root apices, as well as polar localization above the root apex. Protoplasts from Arabidopsis pgp1 leaf mesophyll cells exhibit reduced efflux of natural and synthetic auxins with reduced sensitivity to auxin efflux inhibitors. Expression of AtPGP1 in yeast and in the standard mammalian expression system used to analyze human MDR-type proteins results in enhanced efflux of indole-3-acetic acid (IAA) and the synthetic auxin 1-naphthalene acetic acid (1-NAA), but not the inactive auxin 2-NAA. AtPGP1-mediated efflux is sensitive to auxin efflux and ABC transporter inhibitors. As is seen in planta, AtPGP1 also appears to mediate some efflux of IAA oxidative breakdown products associated with apical sites of high auxin accumulation. However, unlike what is seen in planta, some additional transport of the benzoic acid is observed in yeast and mammalian cells expressing AtPGP1, suggesting that other factors present in plant tissues confer enhanced auxin specificity to PGP-mediated transport.

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Section: Resultsmentioning

confidence: 99%

Cellular efflux of auxin catalyzed by the Arabidopsis MDR/PGP transporter AtPGP1

et al. 2005

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“…A key component of the protective mechanism of the BCSFB is the expression of a variety of ATP-Binding Cassette (ABC) transporter proteins (14)(15)(16)(17)(18), which play a significant role in drug transport across the BCSFB. A key member of the ABC family of transporters is the breast cancer resistance protein (BCRP/ABCP/MXR).…”

Section: Introductionmentioning

confidence: 99%

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Kaur

Badhan

2015

J Pharm Pharm Sci

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-PURPOSE: Breast cancer resistance protein (BCRP/ABCG2) is a drug efflux transporter expressed at the blood cerebrospinal fluid barrier (BCSFB), and influences distribution of drugs into the central nervous systems (CNS). Current inhibitors have failed clinically due to neurotoxicity. Novel approaches are needed to identify new modulators to enhance CNS delivery. This study examines 18 compounds (mainly phytoestrogens) as modulators of the expression/function of BCRP in an in vitro rat choroid plexus BCSFB model. METHODS: Modulators were initially subject to cytotoxicity (MTT) assessment to determine optimal non-toxic concentrations. Reverse-transcriptase PCR and confocal microscopy were used to identify the presence of BCRP in Z310 cells. Thereafter modulation of the intracellular accumulation of the fluorescent BCRP probe substrate Hoechst 33342 (H33342), changes in protein expression of BCRP (western blotting) and the functional activity of BCRP (membrane insert model) were assessed under modulator exposure. RESULTS: A 24 hour cytotoxicity assay (0.001 µM-1000 µM) demonstrated the majority of modulators possessed a cellular viability IC50 > 148 µM. Intracellular accumulation of H33342 was significantly increased in the presence of the known BCRP inhibitor Ko143 and, following a 24 hour pre-incubation, all modulators demonstrated statistically significant increases in H33342 accumulation (P < 0.001), when compared to control and Ko143. After a 24 hour pre-incubation with modulators alone, a 0.16-2.5 -fold change in BCRP expression was observed for test compounds. The functional consequences of this were confirmed in a permeable insert model of the BCSFB which demonstrated that 17-β-estradiol, naringin and silymarin (down-regulators) and baicalin (up-regulator) can modulate BCRP-mediated transport function at the BCSFB. CONCLUSION: We have successfully confirmed the gene and protein expression of BCRP in Z310 cells and demonstrated the potential for phytoestrogen modulators to influence the functionality of BCRP at the BCSFB and thereby potentially allowing manipulation of CNS drug disposition.

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“…Then it is transported out of the brain by a mechanism that likely comprises, at least in part, multidrug resistance and monocarboxylic acid transporters [18] . Furthermore, Chu-LaGraff et al [19] found that AIT-082 enhances NGF mRNA levels in the hippocampus in a time-and dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Effects of AIT-082, a Purine Derivative, on Tremor Induced by Arecoline or Oxotremorine in Mice

Nannan¹,

Yang²,

Lin³

et al. 2007

Pharmacology

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The effects of AIT-082, a hypoxanthine derivative, on tremor in mice were investigated. The mice received intragastric administration of AIT-082 for consecutive 60 days at doses of 150, 300 and 600 mg·kg^–1. The results showed that AIT-082 not only effectively inhibited the tremor induced by arecoline or oxotremorine, but also alleviated the tremor intensity and significantly shortened the tremor durations. The inhibition of tremor was perhaps associated with the central cholinergic nerve depressant effects as well as the stimulation of proliferation and differentiation of nerve cells.

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Neotrofin Is Transported Out of Brain by a Saturable Mechanism: Possible Involvement of Multidrug Resistance and Monocarboxylic Acid Transporters

Cited by 7 publications

References 34 publications

Cellular efflux of auxin catalyzed by the Arabidopsis MDR/PGP transporter AtPGP1

Cellular efflux of auxin catalyzed by the Arabidopsis MDR/PGP transporter AtPGP1

Phytoestrogens Modulate Breast Cancer Resistance Protein Expression and Function at the Blood-Cerebrospinal Fluid Barrier

Effects of AIT-082, a Purine Derivative, on Tremor Induced by Arecoline or Oxotremorine in Mice

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