MDR1 gene expression in brain of patients with medically intractable epilepsy.
Why some patients with seizures are successfully treated with antiepileptic drugs (AEDs) and others prove medically intractable is not known. Inadequate intraparenchymal drug concentration is a possible mechanism of resistance to AEDs. The multiple drug resistance gene (MDR1) encodes P-glycoprotein, an energy-dependent efflux pump that exports planar hydrophobic molecules from the cell. If P-glycoprotein is expressed in brain of some patients with intractable epilepsy and AEDs are exported by P-glycoprotein, lower intraparenchymal drug concentrations could contribute to lack of drug response in such patients. Eleven of 19 brain specimens removed from patients during operation for intractable epilepsy had MDR1 mRNA levels > 10 times greater than those in normal brain, as determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. Immunohistochemistry for P-glycoprotein from 14 of the patients showed increased staining in capillary endothelium in samples from epileptic patients as compared with staining in normal brain samples. In epileptic brain specimens with high MDR1 mRNA levels, expression of P-glycoprotein in astrocytes also was identified. Last, steady-state intracellular phenytoin (PHT) concentrations in MDR1 expressing neuroectodermal cells was one fourth that in MDR1-negative cells. MDR1 expression is increased in brain of some patients with medically intractable epilepsy, suggesting that the patients' lack of response to medication may be caused by inadequate accumulation of AED in brain.
Tishler
D M
DM
Division of Hematology/Oncology, Childrens Hospital of Los Angeles, California.
Weinberg
K I
KI
Hinton
D R
DR
Barbaro
N
N
Annett
G M
GM
Raffel
C
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D002648:Child; D018432:Drug Resistance, Multiple / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use; D016133:Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D010672:Phenytoin