Multidrug Resistance-Associated Proteins: Expression and Function in the Central Nervous System

Dallas, Shannon; Miller, David S.; Bendayan, Reina

doi:10.1124/pr.58.2.3

Cited by 269 publications

(211 citation statements)

References 254 publications

(327 reference statements)

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“…The literature reports that the membrane localization and function of Mrps are still controversial (Dallas et al, 2006;Hoffmann et al, 2006). Available data show the functional importance of Mrps at the BCSFB but not at the BBB.…”

Section: What Is the In Vivo Significance Of Bcrp (Abcg2) Mrps (Abccmentioning

confidence: 99%

Progress in Brain Penetration Evaluation in Drug Discovery and Development

Liu¹,

Chen²,

Smith³

2008

J Pharmacol Exp Ther

165

156

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This review discusses strategies to optimize brain penetration from the perspective of drug discovery and development. Brain penetration kinetics can be described by the extent and time to reach brain equilibrium. The extent is defined as the ratio of free brain concentration to free plasma concentration at steady state. For all central nervous system (CNS) drug discovery programs, optimization of the extent of brain penetration should focus on designing and selecting compounds having low efflux transport at the blood-brain barrier (BBB). The time to reach brain equilibrium is determined by both BBB permeability and brain tissue binding. Rapid brain penetration can be achieved by increasing passive permeability and reducing brain tissue binding. Although many drug transporters have been identified at the BBB, the available literature demonstrates only the in vivo functional importance of P-glycoprotein (P-gp) in limiting brain penetration of its substrates. Drug-drug interactions mediated by P-gp at the BBB are possible due to inhibition or induction of P-gp. For newly identified drug transporters at the BBB, more research is needed to reveal their in vivo significance. We propose the following strategies for addressing drug transporters at the BBB. 1) Drug discovery screens should be used to eliminate good P-gp substrates for CNS targets. Special consideration could be given to moderate P-gp substrates as potential CNS drugs based on a high unmet medical need and the presence of a large safety margin. 2) Selection of P-gp substrates as drug candidates for non-CNS targets can reduce their CNS-mediated side effects.Brain is separated from the systemic circulation by two barriers: the blood-brain barrier (BBB) and the blood-cerebrospinal-fluid barrier (BCSFB). The BBB is composed of cerebral endothelial cells that differ from those in the rest of the body by the presence of extensive tight junctions, absence of fenestrations, and sparse pinocytotic vesicular transport. The BCSFB is formed by a continuous layer of polarized epithelial cells that line the choroid plexus. The BBB and BCSFB exhibit very low paracellular permeability and express multiple drug transporters. These characteristics restrict the entry of hydrophilic compounds or efflux transport substrates into brain (Davson and Segal, 1995). In this review, we will summarize recent published data relevant to assess drug brain penetration and present the authors' opinions on how to effectively address BBB issues in drug discovery and development.

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Section: What Is the In Vivo Significance Of Bcrp (Abcg2) Mrps (Abccmentioning

confidence: 99%

Progress in Brain Penetration Evaluation in Drug Discovery and Development

Liu¹,

Chen²,

Smith³

2008

J Pharmacol Exp Ther

165

156

View full text Add to dashboard Cite

show abstract

“…Another study has revealed that MRP1 and MRP5 are more abundant in various brain cells than the other family members though MRP3 and MRP4 could also be detected in astrocytes [103]. MRP proteins may thus contribute to the resistance of the brain to several cytotoxic and antiviral drugs [104].…”

Section: Abc Transporters In the Brainmentioning

confidence: 99%

ABC transporters, neural stem cells and neurogenesis – a different perspective

2006

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“…MRP4 mRNA is intermediately expressed in heart (43); however, there is no evidence of MRP4 protein expression in heart tissue. In addition, MRP4 has a low affinity for E 2 17G (K m = 30.3 Amol/L), and there are no reports of MRP4-mediated LTC 4 transport (47,48). Similarly, Bcrp1/ABCG2 is expressed in heart; however, the affinity of ABCG2 for E 2 17G is 44. a MRP-specific inhibitor, was an effective inhibitor of LTC 4 transport in sarcolemma vesicles.…”

Section: Discussionmentioning

confidence: 99%

Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice

Jungsuwadee¹,

Cole²,

Sultana

et al. 2006

Molecular Cancer Therapeutics

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Multidrug resistance-associated protein 1 (MRP1) mediates the ATP-dependent efflux of endobiotics and xenobiotics, including estradiol 17-(B-D-glucuronide), leukotriene C 4 , and the reduced glutathione conjugate of 4-hydroxy-2-nonenal (HNE), a highly reactive product of lipid peroxidation. Adriamycin is an effective cancer chemotherapeutic drug whose use is limited by cardiotoxicity. Adriamycin induces oxidative stress and production of HNE in cardiac tissue, which may contribute to cardiomyopathy. We investigated the role of Mrp1 in Adriamycin-induced oxidative stress in cardiac tissue. Mice were treated with Adriamycin (20 mg/kg, i.p.), and heart homogenate and sarcolemma membranes were assayed for Mrp1 expression and ATP-dependent transport activity. Expression of Mrp1 was increased at 6 and 24 hours after Adriamycin treatment compared with saline treatment. HNE-adducted proteins were significantly increased (P < 0.001) in the homogenates at 6 hours after Adriamycin treatment and accumulated further with time; HNE adduction of a 190-kDa protein was evident 3 days after Adriamycin treatment. Mrp1 was localized predominately in sarcolemma as shown by confocal and Western blot analysis. Sarcolemma membrane vesicles transported leukotriene C 4 with a K m and V max of 51.8 nmol/L and 94.1 pmol/min/mg, respectively, and MK571 (10 Mmol/L) inhibited the transport activity by 65%.Exposure of HEK Mrp1 membranes to HNE (10 Mmol/L) significantly decreased the V max for estradiol 17-(B-Dglucuronide) transport by 50%. These results show that expression of Mrp1 in the mouse heart is localized predominantly in sarcolemma. Adriamycin treatment increased Mrp1 expression and HNE adduction of Mrp1. Cardiac Mrp1 may play a role in protecting the heart from Adriamycin-induced cardiomyopathy by effluxing HNE conjugates.

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Multidrug Resistance-Associated Proteins: Expression and Function in the Central Nervous System

Cited by 269 publications

References 254 publications

Progress in Brain Penetration Evaluation in Drug Discovery and Development

Progress in Brain Penetration Evaluation in Drug Discovery and Development

ABC transporters, neural stem cells and neurogenesis – a different perspective

Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice

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