Expression of liver functions following sub-lethal and non-lethal doses of 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 functions and regeneration. Methods: Rats fasted for 12 h received acetaminophen 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, respectively, within 2 days. In the morning 2, 6, 12, 24, and 36 h after intoxication, RNA was extracted from liver tissue. By slot blot hybridization mRNA levels was determined for acute phase proteins, enzymes involved in ammonia elimination and urea synthesis, and for proteins related to liver regeneration. Results: After allyl alcohol, mRNA of "positive" acute phase proteins was higher than after acetaminophen and increased with the dose, whereas after acetaminophen it decreased with the dose. The mRNA of the urea cycle enzymes and glutamine synthetase was 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 was significantly more reduced by acetaminophen than by allyl alcohol. The mRNA of cell-cycle dependent proteins was greatly reduced after both toxins, more after the higher dose. Conclusions: The study shows that acetaminophen intoxication inhibits or fails to induce the expression 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 argininosuccinate synthetase was increased by the non-lethal but not by the 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 regenerate than on the maintenance of liver-specific functions.