Mechanism of hepatotoxicity to periportal regions of the liver lobule due to allyl alcohol: role of oxygen and lipid peroxidation.

The objective of this study was to evaluate the role of local oxygen tension in the zone-specific hepatotoxicity due to allyl alcohol. Infusion of allyl alcohol (350 microM) for 60 min into livers from normal fed rats perfused in the anterograde direction damaged virtually all cells in periportal areas of the liver lobule as indexed by trypan blue uptake (half-maximal uptake at 38 min). Under these conditions, oxygen uptake was inhibited only in periportal hepatocytes. Increasing the time of infusion of allyl alcohol to 90 min, however, caused dye uptake in virtually all cells across the liver lobule, with half-maximal staining in pericentral regions occurring at 70 min, indicating that hepatocytes in pericentral areas are not immune to damage by allyl alcohol. In livers from diethylmaleate-treated rats, the half-time for staining of periportal and pericentral regions was 27 and 39 min, respectively. Perfusion in the retrograde direction reverses the oxygen gradient in the liver. When allyl alcohol was infused in the retrograde direction for 60 min, cells in pericentral regions took up trypan blue whereas those in periportal areas were not damaged. Concomitantly, oxygen uptake was decreased only in pericentral regions. Infusion of allyl alcohol in oxygen-saturated perfusate in either direction caused release of lactate dehydrogenase and malondialdehyde. If oxygen tension was decreased by lowering the flow rate or perfusing with air-saturated buffer in the anterograde direction, however, malondialdehyde release and dye uptake due to allyl alcohol was reduced markedly.(ABSTRACT TRUNCATED AT 250 WORDS)