The CYP inhibitor 1-aminobenzotriazole does not prevent oxidative stress associated with alcohol-induced liver injury in rats and mice.
Cytochrome P450 (CYP) 2E1 is induced by ethanol and is postulated to be a source of reactive oxygen species during alcoholic liver disease. However, there was no difference in liver pathology and radical formation between wild-type and CYP2E1 knockout mice fed ethanol. Other CYP isoforms may contribute these effects if CYP2E1 is inhibited or absent. The purpose of this study was, therefore, to determine if blocking most of the P450 isoforms with 1-aminobenzotriazole (ABT; 100 mg/kg i.g.), has any effect on liver damage and oxidative stress due to alcohol in rats and mice. Male C57BL/6 mice and Wistar rats were fed either high-fat control or ethanol-containing enteral diet for 4 weeks. ABT had a significant inhibitory effect on many P450 isoforms independent of concomitant alcohol administration. However, ABT did not protect against liver damage due to alcohol in either species. Indices of oxidative stress and inflammation were also similar in livers from vehicle-treated and ABT-treated animals fed ethanol. In summary, suppression of P450 activity with ABT had no apparent effect on oxidative stress caused by alcohol in both rats and mice. These data support the hypothesis that oxidative stress and liver damage can occur independently of CYP activities in both rats and mice during early alcohol-induced liver injury.
Isayama
Fuyumi
F
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, the University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Froh
Matthias
M
Bradford
Blair U
BU
McKim
Stephen E
SE
Kadiiska
Maria B
MB
Connor
Henry D
HD
Mason
Ronald P
RP
Koop
Dennis R
DR
Wheeler
Michael D
MD
Arteel
Gavin E
GE
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis / Q000235:genetics; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004578:Electron Spin Resonance Spectroscopy; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000431:Ethanol / Q000633:toxicity*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014230:Triazoles / Q000494:pharmacology*
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014230:Triazoles; C033020:1-aminobenzotriazole; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D000410:Alanine Transaminase