Short-term treatment with alcohols causes hepatic steatosis and enhances acetaminophen hepatotoxicity in Cyp2e1(-/-) mice.
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.
Sinclair
J F
JF
Veterans Administration Medical Center, White River Junction, Vermont, 05009, USA. JSINC@dartmouth.edu
Szakacs
J G
JG
Wood
S G
SG
Walton
H S
HS
Bement
J L
JL
Gonzalez
F J
FJ
Jeffery
E H
EH
Wrighton
S A
SA
Bement
W J
WJ
Sinclair
P R
PR
D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D000431:Ethanol / Q000633:toxicity*; D005235:Fatty Liver, Alcoholic / Q000201:enzymology / Q000209:etiology*; D005260:Female; D007097:Imines / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000439:Pentanols / Q000633:toxicity*; D012737:Sex Factors
D018712:Analgesics, Non-Narcotic; D016227:Benzoquinones; D007097:Imines; D000439:Pentanols; D000082:Acetaminophen; D000431:Ethanol; C029683:isopentyl alcohol; D019392:Cytochrome P-450 CYP2E1; C028473:N-acetyl-4-benzoquinoneimine