Acetaminophen (
APAP) hepatotoxicity was investigated in rats fed
ethanol and
isopentanol alone or in combination in a liquid diet for 7 days. Serum levels of
aspartate aminotransferase (AST) and histological examination of liver slices were used to assess hepatotoxicity. At 7 hr after intragastric administration of 0.5 or 1.0 g
APAP/kg, there was no significant increase in serum levels of AST in rats treated with
APAP alone, or in rats pretreated with
ethanol or
isopentanol alone followed by
APAP. There was mild central lobular congestion in the livers of rats pretreated with
ethanol alone followed by
APAP. In contrast, in rats pretreated with the combination of
ethanol and
isopentanol, administration of
APAP caused a dramatic increase in serum levels of AST, along with marked central lobular
necrosis, including steatosis and ischemic changes. Hepatic
glutathione levels were decreased to 40-50% of control values in
APAP-treated rats that had been pretreated with
ethanol either alone or in combination with
isopentanol. The serum concentrations of
APAP were significantly lower in rats pretreated with the combination of
ethanol and
isopentanol followed by 1 g
APAP/kg than in rats treated with
APAP alone, suggesting a greater rate of
APAP metabolism. We had reported previously that combined treatment of rats with
ethanol and
isopentanol resulted in additive to synergistic increases in
CYP3A, with no further increases in CYP2E than that caused by
ethanol alone.
CYP3A may, therefore, be responsible for the increased
APAP hepatotoxicity caused by the combined alcohol treatment.