Effects of valproate on xenobiotic biotransformation in rat liver
- 29 Downloads
Male Wistar rats werein vivo exposed for 2 weeks to 100 μg/ml sodium valproate by subcutaneous implantation of osmotic pumps and hepatocytes were isolated. As anin vitro model co-cultures of rat hepatocytes with epithelial cells were daily treated with valproate (25, 50, 100, 200μg/ml) for 2 weeks. In both models the cytochrome P-450 content and the enzymatic activities of 7-ethoxycoumarinO-deethylase, aldrin epoxidase and glutathioneS-transferase were determined in valproate-treated hepatocytes, in controls and in phenobarbital-induced cells. It appeared that in both systems the cytochrome P-450 content and the 7-ethoxycoumarinO-deethylase activity increased significantly after valproate treatment. On the other hand, the activities of aldrin epoxidase and glutathioneS-transferase decreased. A cDNA probe, encoding rat P450IIB2 was used to determine whether mRNAs encoding the P450IIB subfamily were induced by valproate. It became clear that the inducing effect of valproate was even more pronouncedin vitro thanin vivo.
KeywordsAldrin epoxidase 7-AlkoxycoumarinO-dealkylase Biotransformation Cytochrome P-450 Enzyme induction Glutathione transferases Hepatocytes Valproic acid
Unable to display preview. Download preview PDF.
- 1.Eadi MJ, Hooper WD, Dickinson RG. Valproate associated hepatotoxicity and its biochemical mechanisms. Med Toxicol 1988;3:85–106.Google Scholar
- 6.Jäger E, Rating D, Platzek T, Helge H. Induction of drug metabolism by antiepileptic drugs. Epilepsia 1980;21:196.Google Scholar
- 13.Dickens M, Parsons DN. The effect of lamotrigine, a novel anticonvulsant upon hepatic drug metabolising enzyme systems in the rat and the marmoset [abstract]. In: Proceedings of the International Symposium on Clinical and Basic Aspects of Enzyme Induction and Inhibition; 1985 Jul 5–6; Essen, 1985:35.Google Scholar
- 14.Jordan BJ, Shillingford JS, Steed KP. Preliminary observations on the protein binding and enzyme inducing properties of sodium valproate. In: Legg NJ, ed. Clinical and pharmacological aspects of sodium valproate in the treatment of epilepsy. London: MCS Consultants, 1984:112.Google Scholar
- 18.Rogiers V, Vandenberghe Y, Cornet M, Callaerts A, Sonck W, Guillourd A, et al. The use of cultures and cocultures of rat hepatocytes for the study of the effects of valproate on phase I and II biotransformation systems of xenobiotics. In: Woodhouse KW, Yelland C, James OFW, eds. The liver, metabolism and ageing. Amsterdam: Elsevier Biomedical Press, 1988:75–82.Google Scholar
- 22.Fourney RM, Miyakoshi J, Day RS, Paterson MC. Northern blotting efficient RNA staining and transfer. BRL Focus 1988;10:5–6.Google Scholar
- 27.Guillouzo A. Use of isolated and cultured hepatocytes for xenobiotic metabolism and cytotoxicity studies. In: Guillouzo A, Guguen-Guillouzo C, eds. Isolated and cultured hepatocytes. Paris: Les Éditions Inserm John Libbey Eurotext, 1986:313.Google Scholar