Ethanol withdrawal induced CYP2E1 degradation in vivo, blocked by proteasomal inhibitor PS-341.
The aim of this study was to characterize CYP2E1 degradation in vivo using PS-341, a potent proteasome inhibitor. Previously, only in vitro evidence showed that CYP2E1 induced by ethanol is degraded by the proteasome. Male Wistar rats were given ethanol intragastrically for 30 d. Ethanol was withdrawn at the same time that PS-341 was injected, 24 h before the rats were sacrificed. The liver proteasomal chymotrypsin-like activity (ChT-L) in rats fed ethanol was inhibited. After ethanol withdrawal, the proteasomal ChT-L activity returned to control levels. In the ethanol-withdrawn rats injected with PS-341, the ChT-L activity was significantly inhibited before withdrawal (p <.001). Ethanol treatment induced a 3-fold increase in CYP2E1 levels determined by Western blot. When ethanol was withdrawn, CYP2E1 decreased to control levels. In ethanol-withdrawn rats injected with PS-341, CYP2E1 remained at the induced level. These results show, for the first time, that the proteasome is responsible for ethanol-induced CYP2E1 degradation in vivo.
Bardag-Gorce
Fawzia
F
Department of Pathology, Harbor UCLA Medical Center, 1000 W. Carson Street, Torrance, CA 90509, USA.
Li
Jun
J
French
Barbara Alan
BA
French
Samuel William
SW
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D053818:Chymases; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000201:enzymology* / Q000378:metabolism
D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000431:Ethanol; D000069286:Bortezomib; D019392:Cytochrome P-450 CYP2E1; D012697:Serine Endopeptidases; D053818:Chymases