Cytochromes P450 2A6, 2E1, and 3A and production of protein-aldehyde adducts in the liver of patients with alcoholic and non-alcoholic liver diseases.
OBJECTIVE
Interaction between CYP2E1, ethanol metabolites, and enhanced lipid peroxidation is linked to the pathogenesis of alcoholic liver disease. This study was conducted to compare the expression of various cytochrome enzymes and the appearance of aldehyde adducts in humans.


METHODS
Acetaldehyde- and lipid peroxidation-derived protein adducts and CYP2A6, 2E1, and 3A4/5 were examined immunohistochemically from liver specimens of 12 alcohol abusers with either mild (n=7) or severe (n=5) liver disease, and from nine non-drinking patients with non-alcoholic steatosis (n=4), or hepatitis (n=5).


RESULTS
Ethanol-inducible CYP2E1 was present in all alcoholic livers. While CYP2A6 in zone 3 hepatocytes was also abundant in the alcoholic patients with various degrees of liver disease, CYP3A415 was most prominent in alcoholic cirrhosis. The sites of CYP2E1 and CYP2A6 immunoreactivity co-localized with fatty deposits, and with the sites of acetaldehyde and lipid peroxidation-derived protein adducts. The CYP enzymes were also abundant in the centrilobular hepatocytes of patients with fatty liver due to obesity or diabetes.


CONCLUSIONS
Alcohol-induced liver damage is associated with a generalized induction of CYP2A6, CYP2E1 and CYP3A4 and generation of acetaldehyde and lipid peroxidation-derived protein-aldehyde adducts. However, CYP induction also occurred in patients with non-alcoholic steatosis.
Niemelä
O
O
Department of Clinical Chemistry, University of Oulu, Finland.
Parkkila
S
S
Juvonen
R O
RO
Viitala
K
K
Gelboin
H V
HV
Pasanen
M
M
D000079:Acetaldehyde / Q000378:metabolism; D000273:Adipose Tissue / Q000473:pathology; D000328:Adult; D000447:Aldehydes / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D048909:Diabetes Complications; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009765:Obesity / Q000150:complications; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D014018:Tissue Distribution
D000447:Aldehydes; D008054:Lipid Peroxides; D011506:Proteins; D008315:Malondialdehyde; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000079:Acetaldehyde