Antiepileptic drug-induced multidrug resistance P-glycoprotein overexpression in astrocytes cultured from rat brains.

BACKGROUND

Intractable epilepsy may be due to multidrug resistance induced by conventional antiepileptic drugs. The phenomenon is sometimes associated with an overexpression of multidrug resistance gene 1 (MDR1). The purpose of this study was to determine if the overexpression of MDR1 could be induced in astrocytes from rat brains in vitro using antiepileptic drugs.

METHODS

Astrocyte cell cultures from postnatal Wistar rats (within 24 hours of birth) were established. Different concentrations of the antiepileptic drugs phenytoin, phenobarbital, carbamazepine, and valproic acid were added to the cultures for 10, 20, or 30 days. The expression of P-glycoprotein (Pgp), the protein product of MDR1, was investigated with immunocytochemistry.

RESULTS

Less than 5% of normal, untreated astrocytes had detectable Pgp staining at any time point. Phenytoin, phenobarbital, carbamazepine, and valproic acid induced the overexpression of Pgp in astrocytes in a dose- and time-dependent manner. Significantly higher levels of Pgp staining were detected at therapeutic concentrations of certain antiepileptic drugs (20 microg/ml phenobarbital, 40 microg/ml phenobarbital, and 20 microg/ml phenytoin) on day 30. Upregulation of Pgp was detected when using higher concentrations of phenytoin, phenobarbital, and valproic acid on day 20 and when using higher concentrations of any of the four antiepileptic drugs on day 30.

CONCLUSIONS

Treatment with antiepileptic drugs may contribute to the overexpression in astrocytes of MDR1 and its protein product, Pgp. The mechanism leading to MDR must be considered in patients undergoing long-term treatment with antiepileptic drugs.