Aims:
Drug-induced liver injury, especially
acetaminophen (
APAP)-induced liver injury, is a leading cause of
liver failure worldwide. Mouse models were used to evaluate the effect of microelement
selenium levels on the cellular redox environment and consequent hepatotoxicity of
APAP. Results:
APAP treatment affected mouse liver
selenoprotein thioredoxin reductase (TrxR) activity and
glutathione (GSH) level in a dose- and time-dependent manner. Decrease of mouse liver TrxR activity and
glutathione level was an early event, and occurred concurrently with liver damage. The decreases in the GSH/
glutathione disulfide form (
GSSG) ratio and TrxR activity, and the increase of
protein S-glutathionylation were correlated with the
APAP-induced hepatotoxicity. Moreover, in
APAP-treated mice both mild deprivation and excess supplementation with
selenium increased the severity of liver injury compared with those observed in mice with normal dietary
selenium levels. An increase in the oxidation state of the TrxR-mediated system, including cytosolic thioredoxin1 (Trx1) and peroxiredoxin1/2 (Prx1/2), and mitochondrial Trx2 and Prx3, was found in the livers from mice reared on
selenium-deficient and excess
selenium-supplemented diets upon
APAP treatment. Innovation: This work demonstrates that both Trx and GSH systems are susceptible to
APAP toxicity in vivo, and that the
thiol-dependent redox environment is a key factor in determining the extent of
APAP-induced hepatotoxicity. Dietary
selenium and
selenoproteins play critical roles in protecting mice against
APAP overdose. Conclusion:
APAP treatment in mice interrupts the function of the Trx and GSH systems, which are the main enzymatic
antioxidant systems, in both the cytosol and mitochondria. Dietary
selenium deficiency and excess supplementation both increase the risk of
APAP-induced hepatotoxicity.