RGD Reference Report - Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. - Rat Genome Database

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Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity.

Authors: Potschka, H  Fedrowitz, M  Loscher, W 
Citation: Potschka H, etal., J Pharmacol Exp Ther 2003 Jul;306(1):124-31.
RGD ID: 704399
Pubmed: PMID:12663688   (View Abstract at PubMed)
DOI: DOI:10.1124/jpet.103.049858   (Journal Full-text)

The blood-brain barrier (BBB) is a physical and metabolic barrier between the brain and the systemic circulation, which functions to protect the brain from circulating drugs, toxins, and xenobiotics. ATP-dependent multidrug transporters such as P-glycoprotein (Pgp; ABCB1), which are found in the apical (luminal) membranes of brain capillary endothelial cells, are thought to play an important role in BBB function by limiting drug penetration into the brain. More recently, the multidrug resistance protein MRP2 (ABCC2) has been found in the luminal surface of brain capillary endothelium of different species, including humans. In endothelial cells from patients with drug-resistant epilepsy, MRP2 was shown to be overexpressed, indicating that it may be critically involved in multidrug resistance of such patients. However, the role of MRP2 in drug disposition into the brain is defined poorly. Herein, we used different strategies to study the contribution of MRP2 to BBB function. First, the MRP inhibitor probenecid was shown to increase extracellular brain levels of the major antiepileptic drug phenytoin in rats, indicating that phenytoin is a substrate of MRP2 in the BBB. This was substantiated by using MRP2-deficient TR- rats, in which extracellular brain levels of phenytoin were significantly higher compared with the normal background strain. In the kindling model of epilepsy, coadministration of probenecid significantly increased the anticonvulsant activity of phenytoin. In kindled MRP2-deficient rats, phenytoin exerted a markedly higher anticonvulsant activity than in normal rats. These data indicate that MRP2 substantially contributes to BBB function.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
visual epilepsy treatmentISOAbcc2 (Rattus norvegicus)704399; 704399 RGD 
visual epilepsy treatmentIMP 704399 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
transepithelial transport involved_inIMP 704399PMID:12663688ARUK-UCL 
xenobiotic transport across blood-brain barrier involved_inIMP 704399PMID:12663688ARUK-UCL 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal blood-brain barrier function  IAGP 704399 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Abcc2  (ATP binding cassette subfamily C member 2)

Genes (Mus musculus)
Abcc2  (ATP-binding cassette, sub-family member 2)

Genes (Homo sapiens)
ABCC2  (ATP binding cassette subfamily C member 2)


Additional Information