Abstracts

Multidrug resistance (MDR) transporters are overexpressed in the blood-brain barrier of patients with refractory epilepsy and in the brains and livers of rodents following induced seizures (Kwan and Brodie, [italic]Epilepsia[/italic] 2005;46:224-35; Lamb et al., [italic]Epilepsia[/italic] 2004;45(Suppl.7):12-3. The expression of P-gp, the prototypic MDR transporter, can be regulated by xenobiotics which activate nuclear receptors, such as dexamethasone (Dex) and by altering chromatin ultrastructure (Scotto, [italic]Oncogene[/italic] 2003;22:7496-511). In this study we assessed the effects of valproic acid (VPA), a histone deacetylases (HDACs) inhibitor, and its amide valpromide (VPD), a non-HDACs inhibitor (Phiel et al., [italic]J Biol Chem[/italic] 276:36734-41) on P-gp expression [italic]in vitro[/italic] and in rat liver, in comparison to the HDACs inhibitor butyric acid (BuA) and Dex. The effects of the tested compounds on MDR1 expression and function in SW620 and KG1a cells were assessed using flow cytometry. To evaluate the effects of these compounds on mdr1a and mdr1b [italic]in vivo[/italic], adult male rats were treated twice daily for 7 days with VPA (150mg/kg), VPD (150mg/kg), BuA (600mg/kg), dexamethasone (50mg/kg) or vehicle. Accumulation of the acetylated histone H3 in livers was evaluated using a specific antibody. Hepatic expression of [italic]mdr1a[/italic] was determined by real-time polymerase chain reaction. In the human cell lines, VPA, but not VPD, induced P-gp expression and function 2-4 fold when compared to control. Our preliminary results indicate that in rat liver VPA and BuA induced histone hyperacetylation (3.5 and 3.3 fold of control, respectively) and mdr1a expression (4.7 and 7.1 fold of control, respectively). VPD did not increase histone acetylation, and its effect on mdr1a was less than that of VPA (2.5 fold). Our results show that VPA can induce the expression of P-gp in cell lines and in rat liver. Although VPA is not a substrate for P-gp, the increase in P-gp expression could contribute to lower plasma and perhaps brain levels of those AEDs that are P-gp substrates; i.e., phenytoin carbamazepine and topiramate. (Supported by unrestricted funds of Profs. Bialer and White.)