Mitogen-activated Protein Kinase Phosphatase (Mkp)-1 Protects Mice against Acetaminophen-induced Hepatic Injury
In: Toxicologic Pathology, Jg. 40 (2012-05-23), S. 1095-1105
Online
unknown
Zugriff:
c-Jun N-terminal kinase (JNK) activation promotes hepatocyte death during acetaminophen overdose, a common cause of drug-induced liver failure. While mitogen-activated protein kinase (MAPK) phosphatase (Mkp)-1 is a critical negative regulator of JNK MAPK, little is known about the role of Mkp-1 during hepatotoxicity. In this study, we evaluated the role of Mkp-1 during acute acetaminophen toxicity. Mkp-1+/+ and Mkp-1−/− mice were dosed ip with vehicle or acetaminophen at 300 mg/kg (for mechanistic studies) or 400 mg/kg (for survival studies). Tissues were collected 1–6 hr post 300 mg/kg dosing to assess glutathione levels, organ damage, and MAPK activation. Mkp-1−/− mice exhibited more rapid plasma clearance of acetaminophen than did Mkp-1+/+ mice, indicated by a quicker decline of plasma acetaminophen level. Moreover, Mkp-1−/− mice suffered more severe liver injury, indicated by higher plasma alanine transaminase activity and more extensive centrilobular apoptosis and necrosis. Hepatic JNK activity in Mkp-1−/− mice was higher than in Mkp-1+/+ mice. Finally, Mkp-1−/− mice displayed a lower overall survival rate and shorter median survival time after dosing with 400 mg/kg acetaminophen. The more severe phenotype exhibited by Mkp-1−/−mice indicates that Mkp-1 plays a protective role during acute acetaminophen overdose, potentially through regulation of JNK.
Titel: |
Mitogen-activated Protein Kinase Phosphatase (Mkp)-1 Protects Mice against Acetaminophen-induced Hepatic Injury
|
---|---|
Autor/in / Beteiligte Person: | Rogers, Lynette K. ; Wancket, Lyn M. ; Meng, Xiaomei ; Liu, Yusen |
Link: | |
Zeitschrift: | Toxicologic Pathology, Jg. 40 (2012-05-23), S. 1095-1105 |
Veröffentlichung: | SAGE Publications, 2012 |
Medientyp: | unknown |
ISSN: | 1533-1601 (print) ; 0192-6233 (print) |
DOI: | 10.1177/0192623312447551 |
Schlagwort: |
|
Sonstiges: |
|