Inhibition of ethanol-induced liver disease in the intragastric feeding rat model by chlormethiazole.
The purpose of this investigation was to assess the effect of chlormethiazole treatment on liver damage in the experimental rat intragastric ethanol-feeding model of alcoholic liver disease. Chlormethiazole has been used in the treatment of alcoholic withdrawal and has been shown to inhibit cytochrome P4502E1. Since treatment of experimental alcoholic liver disease with CYP2E1 inhibitors had an ameliorating effect on liver injury in the rat, chlormethiazole was used to see if it had a similar effect. Rats fed ethanol for 2 months had significantly less liver injury when chlormethiazole was added to the diet, fed intragastrically. The CYP2E1 apoprotein levels, which were increased by ethanol feeding, were also increased when chlormethiazole was fed with ethanol. Chlormethiazole inhibited the increase in the ethanol-induced CYP2E1 activity in vivo, as measured by chlorzoxazone 6-hydroxylation, but did not affect the level of CYP2E1 apoprotein. Likewise, the reduction in proteasome proteolytic enzyme activity produced by ethanol feeding was blunted in chlormethiazole-fed rats. These results support the conclusion that chlormethiazole treatment partially protects the liver from injury by inhibiting CYP2E1 activity in vivo.
Gouillon
Z
Z
Department of Pathology, Harbor-UCLA Medical Center, Torrance, California 90509, USA.
Lucas
D
D
Li
J
J
Hagbjork
A L
AL
French
B A
BA
Fu
P
P
Fang
C
C
Ingelman-Sundberg
M
M
Donohue
T M
TM
French
S W
SW
D000818:Animals; D001051:Apoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002719:Chlormethiazole / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002753:Chlorzoxazone / Q000031:analogs & derivatives / Q000378:metabolism; D002918:Chymotrypsin / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006900:Hydroxylation / Q000187:drug effects; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014357:Trypsin / Q000378:metabolism
D001051:Apoenzymes; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D009097:Multienzyme Complexes; D017392:Thiobarbituric Acid Reactive Substances; D002719:Chlormethiazole; C039289:6-hydroxychlorzoxazone; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D002918:Chymotrypsin; D014357:Trypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D002753:Chlorzoxazone