Effects of long-term administration of the antiepileptic drug--sodium valproate upon the ultrastructure of hepatocytes in rats.
Chronic intragastric application (1, 3, 6, 9 and 12 months) of the antiepileptic drug--sodium valproate (VPA; Vupral "Polfa") to rats in the effective dose of 200 mg/kg b.w./day exerts hepatotoxic effect after 9 and 12 months of the experiment. The first ultrastructural changes in hepatocytes were observed after 3 months of the drug administration. These became more intense in the subsequent stages of the experiment, to be most pronounced after 12 months. The most striking changes were in the mitochondria (significant swelling, an increase in their number, degeneration of matrix and cristae, disruption of the outer mitochondrial membrane) and in peroxisomes (proliferation, enlargement and the presence of distinct nucleoids). Further alterations in hepatocytes manifested themselves in: microvesicular fatty change with cholesterolosis (cholesterol clefts), damage to the cellular membrane of the sinusoidal pole with dilation of the perisinusoidal space of Disse, presence of cystern-like cytoplasmic vacuoles in the sinusoidal region, filled with plasma-like material and focal cytoplasmic necrosis. The changes in hepatocytes coexisted with the swelling and activation of sinusoidal cells, endothelial cells and Kupffer cells. The author suggests that mitochondria and peroxisomes considerably contribute to the morphogenesis of hepatocyte damage by VPA in the chronic experimental model.
Sobaniec-Lotowska
M E
ME
Department of Pathological Anatomy, Medical Academy Bialystok, Poland.
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury; D008099:Liver / Q000187:drug effects* / Q000648:ultrastructure*; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000648:ultrastructure; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
D000927:Anticonvulsants; D014635:Valproic Acid