Participation of lipid transport and fatty acid metabolism in valproate sodium-induced hepatotoxicity in HepG2 cells.
The hepatotoxicity induced by valproic acid (VPA) has been described in many clinical studies and the related mechanism has been partly elucidated. The objective of this study is to investigate the hepatotoxicity and its underlying mechanism of valproic acid on human hepatoma carcinoma cell line HepG2. The cell viability was evaluated by 3-(4,5-dimethyltyiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in the medium were detected using spectrophotometry. The gene expressions of cytochrome P450 1 A1 (CYP1A1), ATP-binding cassette transporter G1 (ABCG1) and carnitine palmitoyltransferase 1 (CPT1A), related to lipid transport and fatty acid metabolism, were measured by quantitative real-time reverse transcriptase-PCR. Treatment with valproate sodium obviously decreased the viability of HepG2 cells, accompanied by the increased leakages of ALT, AST and LDH in a dose-dependent manner. Furthermore, the gene expressions of CYP1A1, ABCG1 and CPT1A were almost up-regulated in the treated groups. In conclusion, these data suggest that VPA-induced hepatotoxicity was critically enhanced with the elevation of valproate sodium, which may be correlated with up-regulated gene expressions of CYP1A1, ABCG1 and CPT1A.
Ji
Qiaoli
Q
Department of Pharmacology and Pharmacy, Key Laboratory of Environment and Genes Related to Diseases, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
Shi
Xiaolian
X
Lin
Rong
R
Mao
Youhua
Y
Zhai
Xiaogang
X
Lin
Qinqin
Q
Zhang
Jiye
J
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000410:Alanine Transaminase / Q000378:metabolism; D000927:Anticonvulsants / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D018675:Toxicity Tests; D014635:Valproic Acid / Q000633:toxicity*
C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000927:Anticonvulsants; D005227:Fatty Acids; D014635:Valproic Acid; D007770:L-Lactate Dehydrogenase; D019363:Cytochrome P-450 CYP1A1; D002334:Carnitine O-Palmitoyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase