Geranylgeranylacetone enhances expression of thioredoxin and suppresses ethanol-induced cytotoxicity in cultured hepatocytes.
Geranylgeranylacetone (GGA) has been introduced into the clinical field as an anti-ulcer drug. In addition to protective effects on gastric mucosal cells, GGA also has anti-apoptotic effects against ischemia and reperfusion injury in hepatocytes and intestinal cells. However, the molecular mechanisms of the cytoprotective or anti-apoptotic effect of GGA are largely unknown. To explore the molecular mechanism of GGA action, we focused on thioredoxin (TRX), an endogenous-redox-acting molecule. We have demonstrated that GGA induces the messenger RNA and protein of TRX and affects the activation of transcription factors, AP-1 and NF-kappaB, and that GGA blunted ethanol-induced cytotoxicity of cultured hepatocytes. These results provide evidence suggesting that a possible novel molecular mechanism of GGA is to protect cells via the induction of TRX and the activation of transcription factors such as NF-kappaB and AP-1.
Hirota
K
K
Department of Anesthesia, Kyoto University Hospital, Kyoto University, 54 Shogoin-Kawaharacho, Kyoto, Sakyo-Ku, 606-8507, Japan. khirota@kuhp.kyoto-u.ac.jp
Nakamura
H
H
Arai
T
T
Ishii
H
H
Bai
J
J
Itoh
T
T
Fukuda
K
K
Yodoi
J
J
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology*; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000897:Anti-Ulcer Agents; D004224:Diterpenes; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D013879:Thioredoxins; D013755:Tetradecanoylphorbol Acetate; C031049:geranylgeranylacetone