The effect of ethanol-induced cytochrome p4502E1 on the inhibition of proteasome activity by alcohol

The present investigation was undertaken to determine the effect of CYP2E1 induction by ethanol on the inhibition of proteasomal activity in wild-type and CYP2E1 knockout C57 black mice. The proteasomal chymotrypsin-like acti vity decreased significantly in ethanol-fed wild-type mice liver, but was n ot reduced in ethanol-fed knockout mice liver, The 26S proteasomal activity was decreased more by ethanol feeding than was the 20S proteasomal fractio n. Individual hepatocytes lost immunostaining of the proteasomes in the cen trilobular zone in the livers of ethanol-fed wild-type mice and the knockou t mouse liver, There was increased product of protein oxidation in the live r in the wild type but not in the knockout mice given ethanol, Taken togeth er, these results suggest that CYP2E1 induction was responsible for the dec rease in proteasome activity seen in the wild-type mice which head to the a ccumulation of oxidized proteins which were increased as the result of free radicals generated by CYP2E1 metabolism of ethanol. (C) 2000 Academic Pres s.