Geranylgeranylacetone protects against acetaminophen-induced hepatotoxicity by inducing heat shock protein 70.
Geranylgeranylacetone (GGA), an anti-ulcer drug, has been reported to induce heat shock protein (HSP) 70 in several animal organs. The present study was performed to determine whether GGA protects mouse liver against acetaminophen (APAP)-induced injury and whether it has potential as a therapeutic agent for APAP overdose. Hepatic damage was induced by single oral administration of APAP (500 mg/kg). GGA at 400 mg/kg was given orally 4 or 8h before, or 0.5h after APAP administration. Treatment of mice with GGA 4h before or 0.5h after APAP administration suppressed increases in transaminase activities and ammonia content in blood as well as hepatic necrosis. Such GGA treatment significantly increased hepatic HSP70 accumulation after APAP administration. Furthermore, GGA inhibited increases in hepatic lipid peroxide content and hepatic myeloperoxidase activity after APAP administration. In contrast, GGA neither inhibited hepatic cytochrome P450 2E1 activity nor suppressed hepatic glutathione depletion after APAP administration. The protective effect of GGA treatment 4h before APAP on hepatotoxicity induced by APAP was completely inhibited with quercetin, known as an HSP inhibitor. In conclusion, GGA has been identified as a new antidote to APAP injury, acting by induction of HSP70. The potential of GGA as a therapeutic tool is strongly supported by its ability to inhibit hepatic injury even when administered after ingestion of APAP.
Nishida
Tadashi
T
Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.
Matsura
Tatsuya
T
Nakada
Junya
J
Togawa
Aki
A
Kai
Masachika
M
Sumioka
Isao
I
Minami
Yukari
Y
Inagaki
Yoshimi
Y
Ishibe
Yuichi
Y
Ito
Hisao
H
Ohta
Yoshiji
Y
Yamada
Kazuo
K
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000410:Alanine Transaminase / Q000378:metabolism; D000641:Ammonia / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D004224:Diterpenes / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009336:Necrosis; D009195:Peroxidase / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D000897:Anti-Ulcer Agents; D004224:Diterpenes; D018840:HSP70 Heat-Shock Proteins; D000082:Acetaminophen; D000641:Ammonia; D009195:Peroxidase; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; C031049:geranylgeranylacetone