Mechanism of hepatotoxicity in periportal regions of the liver lobule due to allyl alcohol: studies on thiols and energy status.
The possible involvement of thiols and adenine nucleotides in the selective toxicity to periportal regions by allyl alcohol was evaluated in isolated perfused rat livers. Infusion of allyl alcohol (350 microM) for 20 min depleted hepatic glutathione content by 95% in both regions of the liver lobule yet damage was undetectable as indexed by release of lactate dehydrogenase or uptake of trypan blue. Perfusion for an additional 40 min in the absence of allyl alcohol resulted in lactate dehydrogenase release (2400 U/l) and uptake of trypan blue by 75% of hepatocytes in periportal regions of the liver lobule; however, dye was not taken up by cells in pericentral areas. Because thiol content was depleted in the undamaged pericentral area, it was concluded that thiol depletion alone cannot explain local toxicity to periportal regions by allyl alcohol. Perfusion with dithioerythritol (1.5 mM) prevented damage due to allyl alcohol totally. In contrast, addition of dithioerythritol 20 min after allyl alcohol did not prevent allyl alcohol-induced damage to periportal regions indicating that irreversible changes occur during the first 20 min which ultimately lead to damage. Fasting or pretreatment of rats with diethylmaleate (0.7 g/kg; 1 hr) to deplete glutathione decreased the T1/2 required for release of lactate dehydrogenase from 45 to 35 and 22 min, respectively. When methionine was infused into livers from diethylmaleate-treated rats, the T1/2 for release of lactate dehydrogenase by allyl alcohol was increased to 45 min. Infusion of allyl alcohol for 60 min also produced a significant decrease in ATP content and in the ATP/ADP ratio in periportal but not pericentral regions of the liver lobule.(ABSTRACT TRUNCATED AT 250 WORDS)
D000433:1-Propanol / Q000633:toxicity; D000227:Adenine Nucleotides / Q000032:analysis; D000818:Animals; D004229:Dithiothreitol / Q000494:pharmacology; D004734:Energy Metabolism; D005260:Female; D005978:Glutathione / Q000032:analysis*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008298:Maleates / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D020005:Propanols; D051381:Rats; D011919:Rats, Inbred Strains; D014343:Trypan Blue / Q000378:metabolism
D000227:Adenine Nucleotides; D008298:Maleates; D020005:Propanols; C006463:allyl alcohol; D000433:1-Propanol; D007770:L-Lactate Dehydrogenase; C014476:diethyl maleate; D005978:Glutathione; D014343:Trypan Blue; D004229:Dithiothreitol