EXPRESSION OF LIVER FUNCTIONS FOLLOWING SUBLETHAL AND NONLETHAL DOSESOF ALLYL ALCOHOL AND ACETAMINOPHEN IN THE RAT

Background/Aims: To relate severity of intoxication with allyl alcohol and acetaminophen to modulated hepatic gene expression of liver funct ions and regeneration. Methods: Rats fasted for 12 h received acetamin ophen 3.5 or 5.6 g per kg body weight, or allyl alcohol 100 or 125 mu l by gastric tube, doses producing no and about 30% mortality, respect ively, within 2 days. In the morning 2, 6, 12, 24, and 36 h after into xication, RNA was extracted from liver tissue. By slot blot hybridizat ion mRNA levels was determined for acute phase proteins, enzymes invol ved in ammonia elimination and urea synthesis, and for proteins relate d to liver regeneration. Results: After allyl alcohol, mRNA of ''posit ive'' acute phase proteins was higher than after acetaminophen and inc reased with the dose, whereas after acetaminophen it decreased with th e dose. The mRNA of the urea cycle enzymes and glutamine synthetase wa s uniformly reduced by allyl alcohol, whereas that of most urea cycle enzymes was above the controls after the non-lethal, but not after the sub-lethal, dose of acetaminophen. The mRNA of glutamine synthetase w as significantly more reduced by acetaminophen than by allyl alcohol. The mRNA of cell-cycle dependent proteins was greatly reduced after bo th toxins, more after the higher dose. Conclusions: The study shows th at acetaminophen intoxication inhibits or fails to induce the expressi on of acute phase proteins in contrast to allyl alcohol intoxication. Allyl alcohol suppressed the expression of urea cycle enzymes, whereas that of the rate limiting enzymes carbamoylphosphate synthase and arg ininosuccinate synthetase was increased by the non-lethal but not by t he sub-lethal dose of acetaminophen. The expression of the cell-cycle dependent proteins was more suppressed after the sub-lethal than after the non-lethal dose of both toxins. The data support the view that a fatal outcome of the intoxications depends more on the ability to rege nerate than on the maintenance of liver-specific functions.