title: Involvement of fatty acid metabolism in the hepatotoxicity induced by divalproex sodium.
abstract: Divalproex sodium is an antiepileptic drug. Hepatotoxicity is one of the most common side effects induced by divalproex sodium. Impaired fatty acid metabolism is considered to play an important role in the drug-induced hepatotoxicity. The sterol regulatory element-binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor α (PPARα) are two key transcription factors involved, respectively, in fatty acid synthesis and degradation in liver. In the present study, we investigated the hepatotoxicity induced by divalproex sodium and its potential mechanism. The results indicated that divalproex sodium significantly decreased the cell viability and increased lactate dehydrogenase leakage in hepatocytes. The activities of alanine aminotransferase and aspartate transaminase were increased in hepatocytes treated with divalproex sodium. Furthermore, divalproex sodium activated SREBP-1c and increased the mRNA expressions of acetyl-CoA carboxylase 1, fatty acid synthase and stearoyl-CoA desaturase 1. Divalproex sodium also inhibited PPARα and decreased the messenger RNA expressions of 3-hydroxy-3-methylglutaryl-CoA synthase 2 and carnitine palmitoyltransferase 1A. These results suggest that the hepatotoxicity induced by divalproex sodium may be related with fatty acid synthesis and degradation mediated by SREBP-1c and PPARα in hepatocytes.
authors.affiliation: Department of Pharmacology, Key Laboratory of Environment and Genes Related to Diseases, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: R
authors.initials: R
authors.lastname: Lin
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Mao
authors.forename: X
authors.initials: X
authors.lastname: Bu
authors.forename: Q
authors.initials: Q
authors.lastname: Ji
authors.forename: X
authors.initials: X
authors.lastname: Zhai
authors.forename: Q
authors.initials: Q
authors.lastname: Lin
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: K
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D047493:PPAR alpha / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D005227:Fatty Acids; D047493:PPAR alpha; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D014635:Valproic Acid; D007770:L-Lactate Dehydrogenase; D013230:Stearoyl-CoA Desaturase; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase; D064429:Fatty Acid Synthases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase