Abstracts

Polychlorinated biphenyls (PCBs) are man-made ubiquitous environmental contaminants, found as mixtures of more than 200 individual compounds. PCBs are known to cause the induction of drug metabolizing and multidrug transporter enzymes including multidrug resistant 1 (MDR1). We examined the effect of PCB exposure on the expression of MDR1a and MDR1b mRNAs in the rat liver and kidney. The effect of PCB exposure on the effectiveness of phenytoin in the maximal electroshock (MES) test was also examined., Animals were treated with either corn oil or PCBs (25 mg/kg, i.p.). After 48 hours, groups of animals were dosed with phenytoin (60 mg/kg, p.o.) and subjected to the MES test (bilateral corneal electrical stimulation 150 mA, 0.3 sec.) after two hours. Additional groups of PCB treated animals were pre-treated with clotrimazole (75 mg/kg, i.p.) 2.5 hours prior to phenytoin treatment (to inhibit cytochrome P450 activity) and subjected to the MES test, two hours after phenytoin treatment. The serum level of phenytoin was determined by HPLC analysis. Total RNA was isolated from liver and kidney tissue and the level of MDR1a, MDR1b mRNAs determined by real-time PCR analysis., Significant elevations of MDR1a and MDR1b mRNAs were detected in the liver of PCB treated animals, while only MDR1a mRNA was elevated in the kidney. In the MES test, 7/8 animals were protected by phenytoin in the corn oil control group, while only 2/8 animals were protected in the PCB treated group. HPLC analysis indicated a significant decrease in the level of phenytoin in the serum of the PCB treated animals. Clotrimazole treatment did not affect the number of animals protected against MES by phenytoin (7/8 protected). In PCB treated animals clotrimazole did not fully restore the protection by phenytoin (only 5/8 protected)., The results indicate that exposure to PCBs causes an increase in the expression of MDR1a mRNA in the liver and kidney, and MDR1b in the liver. PCB exposure also causes a significant decrease in the effectiveness of phenytoin in the MES test. Despite inhibition of cytochrome P450 activity, PCB treatment caused a decrease in the number of animals protected from MES by phenytoin, suggesting a potential role for transporters in the PCB effect. Environmental contaminants may contribute to therapy resistance in epilepsy by multiple mechanisms., (Supported by NO1-NS-4-2359.)