Effect of ethanol on cytochrome P450 2E1 (CYP2E1), lipid peroxidation, and serum protein adduct formation in relation to liver pathology pathogenesis.
It is well established that chronic ethanol ingestion enhances lipid peroxidation in the liver in vivo and in vitro. The relationship of lipid peroxidation and protein adduct formation to morphologically assessed liver damage remains problematic. To help determine if a relationship exists between lipid peroxidation and liver pathology rats were fed ethanol and a high fat diet by continuous intragastric tube feeding for 72 days, maintaining the blood alcohol levels above 200 mg/dl. This model induced a fatty liver with focal necrosis and fibrosis. This pathology was associated with an increased total cytochrome P450, an increased cytochrome P450 2E1 isoenzyme (CYP2E1), a decrease in the NADPH-cytochrome P450 reductase activity, an increased rate of NADPH oxidation and an increased NADPH-dependent lipid peroxidation in liver microsomes compared to controls. Serum protein adducts with malondialdehyde 4-hydroxynonenal were significantly increased. Thus, the alcohol-induced liver pathology was associated with the induction of CYP2EI, lipid peroxidation, and protein adduct formation. When isoniazid (INH) in therapeutic doses was fed to rats with ethanol these parameters were changed in that central-central bridging fibrosis was increased, as was lipid peroxidation, whereas INH reduced the ethanol-induced decrease in the reductase, the increase in total P450 and CYP2EI, as well as the NADPH oxidation rate and the elevation of serum transaminase levels. The results tend to link central-central bridging fibrosis with increased lipid peroxidation and aldehyde-protein adduct formation caused by ethanol.
French
S W
SW
Harbor-UCLA Medical Center, Torrance, California 90509.
Wong
K
K
Jui
L
L
Albano
E
E
Hagbjork
A L
AL
Ingelman-Sundberg
M
M
D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004041:Dietary Fats / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology; D050356:Lipid Metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism*; D008854:Microscopy, Electron; D008862:Microsomes, Liver / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000637:Transaminases / Q000097:blood / Q000378:metabolism
D000447:Aldehydes; D001798:Blood Proteins; D004041:Dietary Fats; D000431:Ethanol; D008315:Malondialdehyde; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; C071207:1,2-dimethylhydrazine demethylase; D010089:Oxidoreductases, N-Demethylating; D000637:Transaminases; C027576:4-hydroxy-2-nonenal; D007538:Isoniazid