Protective effects of asiatic acid against D-galactosamine/lipopolysaccharide-induced hepatotoxicity in hepatocytes and kupffer cells co-cultured system via redox-regulated leukotriene C4 synthase expression pathway.
Asiatic acid is a triterpenoid component possessing antioxidative, anti-inflammatory and hepatoprotective activity. In this issue, we explored the protective effects of asiatic acid and the relative mechanism in the D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced hepatotoxicity in hepatocytes and kupffer cells co-cultured system. The cultures were pretreated with asiatic acid for 12 h, followed by D-GalN/LPS exposure for 12 h. Asiatic acid reduced aspartate aminotransferase and lactate dehydrogenase generation and increased cell viability in a concentration-dependent manner. Meanwhile, the effects of asiatic acid in leukotriene C(4) synthase (LTC(4)S) expression and cellular redox status including reactive oxygen species and GSH content were detected. The results showed that D-GalN/LPS induced the increase of reactive oxygen species followed by extracellular signal-regulated kinase 1/2 (ERK 1/2) and nuclear factor-kappaB (NF-kappaB) activation. Treatment with ERK 1/2 specific inhibitor 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (U0126) abolished the ERK1/2 protein phosphorylation and blunted LTC(4)S expression. Reactive oxygen species signaling pathway inhibitor pyrrolidine dithiocarbamate (PDTC) inhibited reactive oxygen species generation and NF-kappaB activation, which in turn blocked LTC(4)S expression and attenuated the injury. Asiatic acid can protect the hepatocytes against D-GalN/LPS-induced hepatotoxicity. During which, the cell redox was ameliorated and increased expression of LTC(4)S was reversed by the pretreatment of asiatic acid. Taken together, asiatic acid can protect against D-GalN/LPS-induced hepatotoxicity partly via redox-regulated LTC(4)S expression pathway.
Ma
Kuifen
K
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences and Biochemical Pharmaceutics, Zhejiang University, Hangzhou, China.
Zhang
Yuyu
Y
Zhu
Danyan
D
Lou
Yijia
Y
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D018920:Coculture Techniques; D004789:Enzyme Activation / Q000187:drug effects; D005688:Galactosamine / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017997:Leukotriene C4 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D053978:Pentacyclic Triterpenes; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors; D014315:Triterpenes / Q000494:pharmacology*
D002070:Butadienes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009570:Nitriles; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; D014315:Triterpenes; C113580:U 0126; C066229:prolinedithiocarbamate; D017997:Leukotriene C4; D005688:Galactosamine; D011392:Proline; C017032:asiatic acid; D005982:Glutathione Transferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C041116:leukotriene-C4 synthase