Expression of multidrug transporters MRP1, MRP2, and BCRP shortly after status epilepticus, during the latent period, and in chronic epileptic rats.
OBJECTIVE
Overexpression of multidrug transporters may play a role in the development of pharmacoresistance by decreasing extracellular drug levels in the brain. However, it is not known whether overexpression is due to an initial insult or evolves more gradually because of recurrent spontaneous seizures. In the present study, we investigated the expression of different multidrug transporters during epileptogenesis in the rat. In addition, we determined whether these transporters affected phenytoin (PHT) distribution in the brain.


METHODS
Expression of multidrug resistance-associated proteins MRP1 and MRP2 and breast cancer-resistance protein (BCRP) was examined after electrically induced status epilepticus (SE) by immunocytochemistry and Western blot analysis. Brain/blood PHT levels were determined by high-performance liquid chromatography (HPLC) analysis in the presence and absence of the MRP inhibitor probenecid.


RESULTS
Shortly after SE, MRP1, MRP2, and BCRP were upregulated in astrocytes within several limbic structures, including hippocampus. In chronic epileptic rats, these proteins were overexpressed in the parahippocampal cortex, specifically in blood vessels and astrocytes surrounding these vessels. Overexpression was related to the occurrence of SE and was present mainly in rats with a high seizure frequency. Brain PHT levels were significantly lower in epileptic rats compared with control rats, but pharmacologic inhibition of MRPs increased the PHT levels.


CONCLUSIONS
Overexpression of MRP and BCRP was induced by SE as well as recurrent seizures. Moreover, overexpression was associated with lower PHT levels in the brain, which was reversed through inhibition of MRPs. These data suggest that administration of antiepileptic drugs in combination with specific inhibitors for multidrug transporters may be a promising therapeutic strategy in pharmacoresistant patients.
van Vliet
Erwin A
EA
Epilepsy Institute of the Netherlands (SEIN), Heemstede, the Netherlands.
Redeker
Sandra
S
Aronica
Eleonora
E
Edelbroek
Peter M
PM
Gorter
Jan A
JA
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism*; D002908:Chronic Disease; D018432:Drug Resistance, Multiple; D004558:Electric Stimulation; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D010672:Phenytoin / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D013226:Status Epilepticus / Q000378:metabolism; D014018:Tissue Distribution
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000927:Anticonvulsants; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010672:Phenytoin; D011339:Probenecid; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1