Effect of Kupffer cell inactivation on ethanol-induced protein adducts in the liver.
Tissue deposition of protein adducts derived from ethanol metabolism and lipid peroxidation, has been suggested to play a role in the initiation of alcoholic liver disease. The mechanisms modulating adduct formation have, however, remained unclear. We used immunohistochemical methods to examine acetaldehyde (AA) and malondialdehyde (MDA) adducts and cytochrome P4502E1 and P4503A2 expression in rats after administration of (i) an ethanol-diet (n = 6), (ii) ethanol-diet plus gadolinium chloride (GdCl(3)), a selective Kupffer cell toxicant (n = 7), or (iii) control diet (n = 6). A 4 week ethanol treatment resulted in liver steatosis, necrosis, and inflammation and deposition of protein adducts with both AA and MDA, which colocalized with areas of fatty change. The intensities (mean +/- SD) of the immunohistochemical reactions for both AA (2.50 +/- 1.23) and MDA (3.00 +/- 1.10) adducts were significantly higher in the ethanol-fed animals than in the controls (0.083 +/- 0.20) (0.16 +/- 0.25) (p <.001). GdCl(3) prevented adduct accumulation, the mean immunohistochemistry scores being 0.86 +/- 1.07 for AA and 1.64 +/- 0.63 for MDA, the former showing a more striking reduction (p <.01). The hepatic cytochrome enzymes were not different in the ethanol-fed groups with or without GdCl(3). The data indicates that Kupffer cells are involved in the generation of protein adducts with both acetaldehyde and ethanol-induced lipid peroxidation products in alcoholic liver disease.
Niemelä
Onni
O
Laboratory Medicine, EP Central Hospital, Seinäjoki, Finland. onni.niemela@epshp.fi
Parkkila
Seppo
S
Bradford
Blair
B
Iimuro
Yuji
Y
Pasanen
Markku
M
Thurman
Ronald G
RG
D000079:Acetaldehyde / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D004338:Drug Combinations; D000431:Ethanol / Q000633:toxicity*; D005609:Free Radicals; D005682:Gadolinium; D007124:Immunoenzyme Techniques; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism*; D008565:Membrane Proteins; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
D004338:Drug Combinations; D005609:Free Radicals; D008565:Membrane Proteins; D000431:Ethanol; D008315:Malondialdehyde; D005682:Gadolinium; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D000079:Acetaldehyde; C038958:gadolinium chloride