LAUSR

Thioredoxin‐1 (Trx‐1) is a potent therapeutic agent against a variety of diseases because of its actions as an antioxidant and regulator of apoptosis. N‐acetyl‐p‐aminophenol (APAP), commonly known as acetaminophen, generates excessive oxidative stress and triggers hepatocyte cell death, exemplified by regulated necrosis. In the present study, we investigated whether APAP‐induced liver injury in a mouse model is associated with “necroptosis,” and if pretreatment with recombinant Trx‐1 prevents the hepatic injury caused by APAP overdose. We also explored the mechanism underlying the preventive action of Trx‐1 against APAP‐induced hepatic injury. In a prevention study, C3H/he mice received different doses (0, 10, 50 or 100 mg kg–1 body weight) of recombinant human Trx‐1 intraperitoneally, followed by a single oral dose of 300 mg kg–1 of APAP. In this experimental paradigm, liver injury and lethality were markedly decreased in rhTrx‐1–pretreated mice. In survival experiments, mice received rhTrx‐1 followed by oral administration of a lethal dose of APAP. APAP overdose caused a series of liver toxicity‐associated events, beginning with overexpression of c‐fos, excessive production of reactive oxygen species and reactive nitrogen species (RNS) and leading to decreased endogenous Trx‐1 expression and activation of JNK signaling pathways. Pretreatment with rhTrx‐1 inhibited all of these toxicological manifestations of APAP. In addition, rhTrx‐1 significantly reduced the expression of RIP‐3, a critical necrosome component. Taken together, our findings indicate that rhTrx‐1 prevents APAP‐induced liver injury through multiple action mechanisms, including scavenging reactive oxygen species and reactive nitrogen species, restoring endogenous Trx‐1 levels and inhibiting RIP‐3 overexpression.