CYP2E1 has been reported to have an essential role in alcohol-mediated increases in hepatic steatosis and
acetaminophen hepatotoxicity. We found that pretreatment of
Cyp2e1(-/-) mice with
ethanol plus
isopentanol, the predominant
alcohols in alcoholic beverages, for 7 days resulted in micro- and macrovesicular steatosis in the livers of all mice, as well as a dramatic increase in
acetaminophen hepatotoxicity. In
Cyp2e1(-/-) mice administered up to 600 mg
acetaminophen/kg alone and euthanized 7 h later, there was no increase in serum levels of ALT. In
Cyp2e1(-/-) mice pretreated with
ethanol and
isopentanol, subsequent exposure to 400 or 600 mg
acetaminophen/kg resulted in centrilobular
necrosis in all mice with maximal elevation in serum levels of ALT.
Acetaminophen-mediated liver damage was similar in males and females. Hepatic microsomal levels of
APAP activation in untreated females were similar to those in males treated with the
alcohols. However, the females, like the males, required pretreatment with the
alcohols in order to increase
APAP hepatotoxicity. These findings suggest that, in the
Cyp2e1(-/-) mice, the alcohol-mediated increase in
acetaminophen hepatotoxicity involves the contribution of other factors, in addition to induction of CYP(s) that activate
acetaminophen. Alternatively, CYP-mediated activation of
acetaminophen measured in vitro may not reflect the actual activity in vivo. Our findings that a 7-day treatment with
ethanol and
isopentanol causes extensive hepatic steatosis and increases
acetaminophen hepatotoxicity in Cyp2e(-/-) mice indicate that
CYP2E1 is not essential for either response.