STIMULATED HEPATIC TISSUE-REPAIR UNDERLIES HETEROPROTECTION BY THIOACETAMIDE AGAINST ACETAMINOPHEN-INDUCED LETHALITY

Acetaminophen (APAP) is a widely used analgesia and antipyretic drug t hat causes massive centrilobular hepatic necrosis at high doses, leadi ng to death. The objectives of this study were to test our working hyp othesis that preplaced cell division and hepatic tissue repair by prio r thioacetamide (TA) administration provides protection against APAP-i nduced lethality and to investigate the underlying mechanism. Male Spr ague-Dawley rats were treated with a low dose of TA (50 mg/kg, intrape ritoneally [i.p.]) before challenge with a 90% lethal dose (1,800 mg/k g, i.p.) of APAP. This protocol resulted in a 100% protection against the lethal effect of APAP. Because TA caused a 23% decrease of hepatic microsomal cytochromes P-450, the possibility that TA protection may be caused by decreased bioactivation of APAP was examined. A 30% decre ase in cytochromes P-450 induced by cobalt chloride failed to provide protection against APAP lethality. Time course of serum enzyme elevati ons (alanine aminotransferase, aspartate aminotransferase, and sorbito l dehydrogenase) indicated that actual indiction of liver injury by AP AP peaked between 12 to 24 hours after the administration of APAP, whe reas the ultimate outcome of that injury depended on the biological ev ents thereafter. Although liver injury progressed in rats receiving on ly APAP, it regressed in rats pretreated with TA. Acetaminophen t(1/2) was not altered in TA-treated rats, indicating that significant chang es in APAP disposition and bioactivation are unlikely. Moreover, hepat ic glutathione was decreased to a similar extent regardless of TA pret reatment, suggesting that decreased bioactivation of APAP is unlikely to be the mechanism underlying TA protection, [H-3]Thymidine incorpora tion studies confirmed the expected stimulation of S-phase synthesis, and proliferating cell nuclear antigen studies showed a corresponding stimulation of cell division through accelerated cell cycle progressio n. Intervention with TA induced cell division by colchicine antimitosi s ended the TA protection in the absence of significant changes in the time course of serum enzyme elevations during the inflictive phase of APAP hepatotoxicity. These studies suggest that hepatocyte division a nd tissue repair induced by TA facilitate sustained hepatic tissue rep air after subsequent APAP-induced liver injury, producing recovery fro m fiver injury and protection against APAP lethality.