Resistance to acetaminophen-induced hepatotoxicity in glutathione S-transferase Mu 1-null mice.
We investigated the role of glutathione S-transferases Mu 1 (GSTM1) in acetaminophen (APAP)-induced hepatotoxicity using Gstm1-null mice. A single oral administration of APAP resulted in a marked increase in plasma alanine aminotransferase accompanied by hepatocyte necrosis 24 hr after administration in wild-type mice, but its magnitude was unexpectedly attenuated in Gstm1-null mice. Therefore, it is suggested that Gstm1-null mice are resistant to APAP-induced hepatotoxicity. To examine the mechanism of this resistance in Gstm1-null mice, we measured phosphorylation of c-jun N-terminal kinase (JNK), which mediates the signal of APAP-induced hepatocyte necrosis, by Western blot analysis 2 and 6 hr after APAP administration. A marked increase in phosphorylated JNK was observed in wild-type mice, but the increase was markedly suppressed in Gstm1-null mice. Therefore, it is suggested that suppressed phosphorylation of JNK may be a main mechanism of the resistance to APAP-induced hepatotoxicity in Gstm1-null mice, although other possibilities of the mechanism cannot be eliminated. Additionally, phosphorylation of glycogen synthase kinase-3β and mitogen-activated protein kinase kinase 4, which are upstream kinases of JNK in APAP-induced hepatotoxicity, were also suppressed in Gstm1-null mice. A decrease in liver total glutathione 2 hr after APAP administration, which is an indicator for exposure to N-acetyl-p-benzoquinoneimine, the reactive metabolite of APAP, were similar in wild-type and Gstm1-null mice. In conclusion, Gstm1-null mice are considered to be resistant to APAP-induced hepatotoxicity perhaps by the suppression of JNK phosphorylation. This study indicates the novel role of GSTM1 as a factor mediating the cellular signal for APAP-induced hepatotoxicity.
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd, Shizuoka, Japan. arakawa.shingo.z6@daiichisankyo.co.jp
Shingo
S
Arakawa
Takanori
T
Maejima
Kazunori
K
Fujimoto
Takashi
T
Yamaguchi
Masae
M
Yagi
Tomomi
T
Sugiura
Ryo
R
Atsumi
Yasushi
Y
Yamazoe
D000082:Acetaminophen / Q000008:administration & dosage* / Q000633:toxicity*; D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D016227:Benzoquinones / Q000633:toxicity; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology*; D005260:Female; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007097:Imines / Q000633:toxicity; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation
D000082:Acetaminophen; D000410:Alanine Transaminase; D016227:Benzoquinones; D005978:Glutathione; D005982:Glutathione Transferase; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007097:Imines; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C000605507:Gsk3b protein, mouse; C028473:N-acetyl-4-benzoquinoneimine