Modulation of ethanol-mediated CYP2E1 induction by clofibrate and L-carnitine in rat liver.
To understand the effects of lipid-lowering agents on the ethanol-induction of hepatic CYP2E1, clofibrate and L-carnitine were administered to adult male rats. The administration of ethanol in the diet (containing 21% calories as ethanol, given for 3 weeks) increased levels of hepatic CYP2E1 protein (1.9-fold that of untreated controls) and mRNA (2.1-fold). In contrast, the administration of clofibrate (0.1%v/v) in an ethanol-containing diet did not significantly increase either CYP2E1 protein (1.1-fold) or mRNA (0.8-fold), in spite of the significant increases in blood ketone bodies. Administration of L-carnitine alone had no clear effect on CYP2E1 and blood ketone body levels. Co-administration of L-carnitine, however, increased liver microsomal CYP2E1 protein (2.5-fold) in rats given an ethanol-containing diet. No difference was observed in the mRNA levels in rats receiving ethanol with and without L-carnitine. These results indicate that clofibrate and L-carnitine modulate ethanol-mediated induction of hepatic CYP2E1 independent of blood levels of ketone bodies. It is also suggested that these lipid-lowering agents affected hepatic CYP2E1 through particular mechanisms, suppression of the specific mRNA and post-translation stabilization.
Tainaka
H
H
Institute for Production, Nikka Whisky Distilling Co., Ltd., Kashiwa, Japan.
Naito
T
T
Murayama
N
N
Yamazoe
Y
Y
Kato
R
R
D000818:Animals; D002331:Carnitine / Q000494:pharmacology*; D002994:Clofibrate / Q000494:pharmacology*; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004357:Drug Synergism; D004790:Enzyme Induction; D000431:Ethanol / Q000494:pharmacology*; D006900:Hydroxylation; D007657:Ketone Bodies / Q000097:blood; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009596:Nitrophenols / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism
D007657:Ketone Bodies; D009596:Nitrophenols; D012333:RNA, Messenger; D014280:Triglycerides; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D002994:Clofibrate; D002331:Carnitine; C024836:4-nitrophenol