Mitochondrial
oxidant stress and
peroxynitrite formation have been implicated in the pathophysiology of
acetaminophen-induced (
AAP-induced) liver injury. Therefore, we tested the hypothesis that lipid peroxidation (LPO) might be involved in the injury mechanism. Male C3Heb/FeJ mice fed a diet high in
vitamin E (1 g
d-alpha-tocopheryl acetate/kg diet) for 1 week had 6.7-fold higher hepatic
tocopherol levels than animals on the control diet (8.2 +/- 0.1 nmol/g liver). Treatment of fasted mice with 300 mg/kg
AAP caused centrilobular
necrosis with high plasma
alanine aminotransferase (ALT) activities at 6 h (3280 +/- 570 U/l) but no evidence of LPO (hepatic
malondialdehyde, 4-hydroxynonenal). Animals on the
vitamin E diet had similar injury and LPO as mice on the control diet. To verify a potential effect of the
vitamin E diet on
drug-induced liver injury, animals were pretreated with a combination of
phorone, FeSO4, and
allyl alcohol. We observed, 2 h after
allyl alcohol, massive LPO and liver cell injury in the livers of animals on the control diet, as indicated by a 32-fold increase in
malondialdehyde levels, extensive staining for
4-hydroxynonenal, and ALT activities of 2310 +/- 340 U/l. Animals on the
vitamin E diet had 40% lower hepatic
malondialdehyde levels and 85% lower ALT values. Similar results were obtained when animals were treated for 3 days with alpha- or
gamma-tocopherol (0.19 mmol/kg, ip). Both treatments reduced LPO and injury after
allyl alcohol but had no effect on
AAP hepatotoxicity. Thus, despite the previously shown mitochondrial
oxidant stress and
peroxynitrite formation, LPO does not appear to be a critical event in
AAP-induced hepatotoxicity.