An overdose of
acetaminophen (
APAP) is the most frequent cause of
fulminant liver failure in the United States. Increasing evidence demonstrates that oxidative stress plays an important etiologic role in
APAP-induced liver injury.
S-Adenosylmethionine (SAMe) is a key intermediate in the hepatic trans-sulfuration pathway and serves as a precursor for
glutathione (GSH) as well as the methyl donor in most transmethylation reactions. In the present study, we investigated effects of SAMe on liver injury induced by
APAP administration in male C57BL/6 mice. Two related studies were performed. In the first experiment, SAMe (1g/kg BW) was injected intraperitoneally 4 h before
APAP (600 mg/kg BW) administration. In the second experiment, SAMe was injected intraperitoneally 1 h after
APAP administration. Our results showed that
APAP administration induced changes typical of confluent centrilobular
necrosis by histological examination and a marked elevation in serum
alanine aminotransferase (ALT) activity.
APAP administration induced significant decreases in both hepatic and blood SAMe concentrations. In addition,
APAP decreased intracellular (both cytosolic and mitochondrial) GSH concentrations along with increased lipid peroxidation in conjunction with
mitochondrial dysfunction as documented by Ca2+-induced mitochondrial permeability transition. SAMe treatment (both before and after
APAP) significantly attenuated the liver injury. Exogenous SAMe prevented the decrease in liver and blood SAMe concentrations. Moreover, SAMe treatment attenuated both cytosolic and mitochondrial GSH depletion as well as
mitochondrial dysfunction. We conclude that SAMe at least in part protects the liver from
APAP-induced injury by preventing intracellular GSH depletion and
mitochondrial dysfunction.