Acinar distribution of rat liver arylamine N-acetyltransferase: effect of chronic ethanol and endotoxin exposure.
The expression of most drug-metabolising enzymes is highest in the perivenous region of the liver, where drug-induced damage is commonly initiated. Arylamine N-acetyltransferase plays an important role in activation or detoxification of many drugs, carcinogens, pesticides and other xenobiotics, but its acinar distribution is unknown. In this study we have analysed the activity of N-acetyltransferase in cell lysates obtained from the periportal or perivenous region by digitonin treatment during in situ liver perfusion. Livers from control animals were compared with rats chronically exposed either to ethanol by liquid diet or to lipopolysaccharide (endotoxin) by intravenous administration. The activity of N-acetyltransferase in the perivenous region was slightly (+ 20%) higher than in the periportal region. Although chronic ethanol exposure did not change total activity, the acinar distribution was reversed to a higher activity in the periportal region. In contrast, chronic endotoxin significantly increased N-acetyltransferase activity, but did not affect the acinar distribution. This increase was counteracted by simultaneous ethanol treatment. N-Acetyltransferase activity in perivenous lysates was significantly reduced after the co-administration of ethanol and endotoxin compared to that after endotoxin alone. Thus, the perivenous zonation of liver N-acetyltransferase is moderate compared to other transferases or P450 isozymes, and the cellular capacity for N-acetylation in the perivenous region, where xenobiotic activation to reactive intermediates dominates, may be insufficient.
Pronko
Pavel S
PS
Institute of Biochemistry, National Academy of Sciences of Belarus, Grodno. val@biochem.unibel.by
Järveläinen
Harri A
HA
Lindros
Kai O
KO
D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004731:Endotoxins / Q000493:pharmacokinetics / Q000633:toxicity*; D000431:Ethanol / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011169:Portal Vein / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D004731:Endotoxins; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D001191:Arylamine N-Acetyltransferase