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The thioredoxin reductase system is a critical factor in mediating acetaminophen‐induced liver damage
Author(s) -
Carlson Bradley A,
Patterson Andrew D,
Yoo MinHyuk,
Conrad Marcus,
Gonzalez Frank J,
Hatfield Dolph L
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.100.6
Subject(s) - acetaminophen , glutathione , pharmacology , chemistry , liver injury , hepatocyte , toxicity , thioredoxin reductase , medicine , biochemistry , enzyme , organic chemistry , in vitro
Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the US. When taken in excess, APAP is converted to the reactive metabolite NAPQI causing rapid glutathione (GSH) depletion and leading to liver necrosis. These events are initiated by ROS formation in mitochondria which leads to the activation of apoptosis signaling‐regulating kinase 1 (ASK1) and the c‐Jun N‐terminal kinase (JNK) pathway. Since thioredoxin reductase 1 (TR1) is important for attenuating the activation of ASK1 through thioredoxin, the role of TR1 in APAP‐induced liver damage was investigated. Hepatocyte‐specific TR1 knockout (KO) mice were generated and treated with a toxic dose of APAP. Liver toxicity was assessed by measuring the aminotransferase (ALT and AST) activities in serum, and by histological analysis of liver sections. Surprisingly, TR1 KO mice were resistant to APAP toxicity. GSH levels decreased as expected in APAP‐treated control mice, yet were largely unaffected in TR1 KO mice. Unexpectedly, JNK was phosphorylated to a similar extent in TR1 KO mice as APAP‐treated control mice. These results demonstrate an important role for TR1 in modulating APAP‐induced liver damage and provide new insights into APAP‐induced liver toxicity. This research was supported by the Intramural Research Program of the NIH, NCI, CCR.