Overdose of
acetaminophen (
APAP) can cause severe liver injury. Although alcohol is considered a risk factor for
APAP toxicity, the mechanism underlying the interaction between alcohol and
APAP remains unclear. Binge alcohol (5 g/kg every 12 h, 3 doses) reduced the concentration of
cysteine and
glutathione (GSH) and decreased expression of
cystathionine β-synthase (CβS),
cystathionine γ-
lyase (CγL), and
glutamate cysteine ligase catalytic subunit (GCLC) in the livers of male C57BL/6 mice. Furthermore, the levels of GSH S-
transferase (GST) and GSH
peroxidase (GPx) were decreased. To evaluate the effect of
binge drinking on
APAP-induced liver injury, 300 mg
APAP was administered following alcohol binges.
APAP in the binge group significantly amplified the serum ALT more than two fold and enhanced the
pro-apoptotic proteins with a severe centrilobular
necrosis compared to
APAP alone.
APAP treatment after alcohol binges caused lower levels of hepatic
cysteine and GSH than
APAP alone over 24 h, indicating that alcohol binges reduced GSH regenerating potential. Exposure to
APAP after binge treatment significantly increased oxidative stress (lipid peroxidation) and endoplasmic reticulum (ER) stress (
Grp78 and ATF6) markers at 6 h
after treatment. Notably, the IRE1α/ASK1/MKK4/JNK pathway was activated, whereas CHOP expression was reduced by
APAP administration in mice with pre-exposed alcohol binges compared with
APAP alone. Thus, pretreatment with binge alcohol decreases GSH-mediated
antioxidant capacity and contributes to augmentation of liver injury caused by subsequent
APAP administration through differential ER stress signaling pathway.