CYP2E1 inhibition enhances mallory body formation.
Mallory body (MB) formation is a complex phenomenon seen in chronic liver disease. CYP2E1 may play a role in preventing MB formation since it is involved in the elimination of toxic drugs and chemicals. When mice were fed with diethyl-1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) for 10 weeks, Mallory bodies (MBs) developed in the liver at the end of this period. When DDC feeding was combined with CMZ (an efficient in vivo CYP2E1 inhibitor), more MBs formed compared to DDC feeding alone. DDC was shown to be a suicide inhibitor of CYP2E1. The level of CYP2E1 protein in the liver was further reduced by the DDC and CMZ treatment when measured by Western blot. To test whether CYP2E1 reduced MB formation, CYP2E1 knockout mice and CYP2E1 overexpressed mice were fed with DDC or DDC and CMZ for 10 weeks. MB formation increased markedly in the liver of CYP2E1 knockout mice when fed with DDC only. CYP2E1 overexpressed mice showed an increase in MB formation when the mice were fed with the combination of DDC and CMZ where the amount of CYP2E1 was reduced to levels seen in wild type mice. It was concluded that CYP2E1 inhibits MB formation by increasing the rate of elimination of DDC and/or its toxic intermediates.
Bardag-Gorce
Fawzia
F
Harbor UCLA Medical Center, L.A. Biomed, 1000 W. Carson Street, Torrance, CA 90502, USA.
Wilson
L
L
Nan
Li
L
Li
Jun
J
French
Barbara A
BA
Morgan
Timothy R
TR
Morgan
Kengathevy
K
French
Samuel W
SW
D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury; D002719:Chlormethiazole / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004095:Dihydropyridines / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D025801:Ubiquitin / Q000378:metabolism
D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D025801:Ubiquitin; D002719:Chlormethiazole; C061879:diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate; D019392:Cytochrome P-450 CYP2E1