Autoprotection in acetaminophen intoxication in rats: The role of liver regeneration

Autoprotection by acetaminophen, i.e, increased resistance to toxic effects caused by pretreatment, is a well-known phenomenon. The purpose of the pre sent work was to identify mechanisms for increased acetaminophen tolerance induced by pretreatment of rats. One group of female Wistar rats (pretreate d rats) received acetaminophen orally in increasing doses (1 to 4.3 g/kg) t wice a week for 3 weeks, one group (naive rats) received the vehicle. At ti me zero pretreated rats received a toxic dose of 7.5 g/kg (100% lethal in n aive rats), and naive rats received a toxic dose of 4.3 g/ kg. Blood and li ver tissue were collected before and 12, 24, 36, and 45 hr after the toxic dose and were analysed for hepatic glutathione and cysteine contents, hepat ic glutathione-S-transferase and blood alanine aminotransferase activity, a s well as acetaminophen concentration in plasma. Steady-slate mRNA levels o f proteins involved in acetaminophen detoxification. cell division and acut e phase response were measured, liver tissue was examined for proliferating cell nuclear antigen and degree of hepatocyte necrosis. Six naive rats not receiving acetaminophen served as controls. The mortality was the same in pre-treated and naive rats (33 percent). Thus, pretreatment increased the t olerance twice. Before the toxic dose pretreated rats compared to control r ats had higher activity of glutathione-S-transferase (liver) and alanine am inotransferase (serum), higher hepatic mRNA level of glutathione-S-transfer ase and gamma -glutamylcysteine synthetase heavy and light chain subunits, and lower hepatic concentration of glutathione, cysteine and mRNA of CYP1A2 than cont;ol rats. After the toxic dose, the mRNA levels of glutathione-S- transferase, gamma -glutamylcysteine synthetase heavy and light chain subun its, and CYP1A2 in naive rats rose, approaching those of pretreated rats. P roliferating cell nuclear antigen labelling was high in pretreated rats, wh ile only slightly increased in a few of the naive rats. Necrotic hepatocyte s were found at all time intervals in pretreated rats, and in naive rats th ey appeared after 12 hr, peaking after 36 hr. Pretreatment increased the to lerance to acetaminophen toxicity twice, as estimated by mortality. The dat a indicate that pretreatment may reduce the relative production of toxic me tabolites, but it primarily enhances the protection against these metabolit es by regenerating hepatocytes.