Role of CYP3A and CYP2E1 in alcohol-mediated increases in acetaminophen hepatotoxicity: comparison of wild-type and Cyp2e1(-/-) mice.
CYP2E1 is widely accepted as the sole form of cytochrome P450 responsible for alcohol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, we previously found that alcohol [ethanol and isopentanol (EIP)] causes increases in APAP hepatotoxicity in Cyp2e1(-/-) mice, indicating that CYP2E1 is not essential. Here, using wild-type and Cyp2e1(-/-) mice, we investigated the relative roles of CYP2E1 and CYP3A in EIP-mediated increases in APAP hepatotoxicity. We found that EIP-mediated increases in APAP hepatotoxicity occurred at lower APAP doses in wild-type mice (300 mg/kg) than in Cyp2e1(-/-) mice (600 mg/kg). Although this result suggests that CYP2E1 has a role in the different susceptibilities of these mouse lines, our findings that EIP-mediated increases in CYP3A activities were greater in wild-type mice compared with Cyp2e1(-/-) mice raises the possibility that differential increases in CYP3A may also contribute to the greater APAP sensitivity in EIP-pretreated wild-type mice. At the time of APAP administration, which followed an 11 h withdrawal from the alcohols, alcohol-induced levels of CYP3A were sustained in both mouse lines, whereas CYP2E1 was decreased to constitutive levels in wild-type mice. The CYP3A inhibitor triacetyloleandomycin (TAO) decreased APAP hepatotoxicity in EIP-pretreated wild-type and Cyp2e1(-/-) mice. TAO treatment in vivo resulted in inhibition of microsomal CYP3A-catalyzed activity, measured in vitro, with no inhibition of CYP1A2 and CYP2E1 activities. In conclusion, these findings suggest that both CYP3A and CYP2E1 contribute to APAP hepatotoxicity in alcohol-treated mice.
Wolf
Kristina K
KK
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, USA.
Wood
Sheryl G
SG
Allard
Jenna L
JL
Hunt
Jane A
JA
Gorman
Nadia
N
Walton-Strong
Brooke W
BW
Szakacs
Juliana G
JG
Duan
Su X
SX
Hao
Qin
Q
Court
Michael H
MH
von Moltke
Lisa L
LL
Greenblatt
David J
DJ
Kostrubsky
Vsevolod
V
Jeffery
Elizabeth H
EH
Wrighton
Steven A
SA
Gonzalez
Frank J
FJ
Sinclair
Peter R
PR
Sinclair
Jacqueline F
JF
D000082:Acetaminophen; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000633:toxicity*; D020719:Glucuronides / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006900:Hydroxylation; D007097:Imines / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000439:Pentanols / Q000633:toxicity*; D012720:Severity of Illness Index; D013739:Testosterone / Q000378:metabolism; D014217:Troleandomycin / Q000494:pharmacology; D008565:Membrane Proteins
D000082:Acetaminophen; D000410:Alanine Transaminase; D016227:Benzoquinones; D019388:Cytochrome P-450 CYP1A2; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004791:Enzyme Inhibitors; D000431:Ethanol; D020719:Glucuronides; D005978:Glutathione; D007097:Imines; D000439:Pentanols; D013739:Testosterone; D014217:Troleandomycin; C029683:isopentyl alcohol; C028473:N-acetyl-4-benzoquinoneimine; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins