Induction of CYP2E1 in liver, kidney, brain and intestine during chronic ethanol administration and withdrawal: evidence that CYP2E1 possesses a rapid phase half-life of 6 hours or less.
Controversy exists as to whether the induction of CYP2E1 by ethanol occurs via increased protein synthesis or protein stabilization. To address these issues in vivo, we chronically administered ethanol to rats and determined levels of immunoreactive CYP2E1 in liver, kidney, brain and upper gastro-intestinal tract (GI). Our data shows that chronic ethanol administration induces hepatic (5-6-fold over pair-fed controls) and extra-hepatic CYP2E1, an effect which is strikingly absent 12 hours after ethanol withdrawal. No changes in CYP2E1 mRNA were observed at any time, suggesting these changes are mainly post-translational at a blood ethanol concentration of 0.15% w/v. Our experimental data indicates that CYP2E1 possesses a half-life of 6 hours or less in the liver and is rapidly degraded following the removal of ethanol. This pattern of CYP2E1 turnover was also observed in other tissues, suggestive of a similar mode of regulation.
Roberts
B J
BJ
Laboratory of Clinical Studies, National Institute of Alcohol Abuse and Alcoholism, Rockville, MD 20892.
Shoaf
S E
SE
Jeong
K S
KS
Song
B J
BJ
D000096:Acetone / Q000633:toxicity; D000204:Activity Cycles; D000437:Alcoholism / Q000201:enzymology*; D000818:Animals; D015152:Blotting, Northern; D001921:Brain / Q000201:enzymology*; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D006207:Half-Life; D007421:Intestine, Small / Q000201:enzymology*; D007668:Kidney / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000201:enzymology*
D012333:RNA, Messenger; D000096:Acetone; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating