Abstracts

Antiepileptic drugs are usually taken orally and drug availability may therefore be markedly influenced by [quot]first-pass[quot] metabolism/elimination in the liver. An increase in the expression of multidrug transporters (MDTs), including multidrug resistant 2 (MDR2) and multidrug resistance related protein 2 (MRP2 or cMoat) in the liver have been proposed as a possible factor responsible for therapy resistant seizures. Hepatic expression of enzymes involved in drug metabolism, exemplified here by glutathione S-transferase A2 (GSTA2) and NAD(P)H:quinone oxidoreductase (QOR or DT-diphorase) have also been implicated in therapy resistance in epilepsy. Kainic acid (KA) is used in animals to model human temporal lobe epilepsy. We examined the effect of prolonged KA-induced seizure activity ([ge] 3.5 hours) on the expression of MDR2, MRP2, GSTA2 and QOR mRNAs in rat liver. KA-induced seizures were achieved by the method of Hellier et. al. (1998). Animals were given a 5 mg/kg intra-peritoneal injection every hour until marked, repeated stage 4/5 (Racine, 1972) seizures were achieved. Saline-treated animals were used as controls. Total RNA was isolated from liver tissue and the level of MRP2, GSTA2, and QOR mRNA assessed by Northern blot analysis at 24 hours and ten weeks after KA-induced seizure activity. The level of MDR2 mRNA was assessed by real-time PCR at 24 hours and ten weeks after KA-induced seizure activity using a Roche lightcycler. Significant elevations of MRP2, MDR2, GSTA2 and QOR mRNAs were detected in the liver ten weeks after kainic acid induced seizure activity. 24 hours after KA-induced seizure activity only QOR mRNA was significantly increased. KA-induced seizure activity has been reported to cause induction of MDR2, MRP2, and QOR mRNA in the brain. Our results indicate that KA-induced seizure activity also causes increased expression of these mRNAs in the liver. The increase in the liver was detected ten weeks after KA treatment, suggesting that it might be the seizures themselves causing mRNA induction. The multidrug transporter mRNAs examined in this study are all involved in the elimination of antiepileptic drugs. The fact that these genes have human homologues and that the mRNA induction occurs in the liver, a major organ in drug metabolism, has implications for therapy resistance. (Supported by NS-42311)