TEMPORAL CHANGES IN TISSUE-REPAIR PERMIT SURVIVAL OF DIET-RESTRICTED RATS FROM AN ACUTE LETHAL DOSE OF THIOACETAMIDE

Although, diet restriction (DR) has been shown to substantially increa se longevity while reducing or delaying the onset of age-related disea ses, little is known about the mechanisms underlying the beneficial ef fects of DR on acute toxic outcomes. An earlier study (S. K. Ramaiah c t at, 1998, Toxicol. Appl. Pharmacol. 150, 12-21) revealed that a 35% DR compared to ad libitum (AL) feeding leads to a substantial increase in liver injury of thioacetamide (TA) at a low dose (50 mg/kg, ip). H igher liver injury was accompanied by enhanced survival. A prompt and enhanced tissue repair response in DR rats at the low dose (sixfold hi gher liver injury) occurred, whereas at equitoxic doses (50 mg/kg in D R and 600 mg/kg in AL rats) tissue repair in AL rats was substantially diminished and delayed. The extent of liver injury did not appear to be closely related to the extent of stimulated tissue repair response, The purpose of the present study was to investigate the time course ( 0-120 h) of liver injury and liver tissue repair at the high dose (600 mg TA/kg, ip, lethal in AL rats) in AL and DR rats. Male Sprague-Dawl ey rats (225-275 g) were 35% diet restricted compared to their AL coho rts for 21 days and on day 22 they received a single dose of TA (600 m g/kg, ip). Liver injury was assessed by plasma ALT and by histopatholo gical examination of liver sections. Tissue repair was assessed by [H- 3]thymidine incorporation into hepatonuclear DNA and proliferating cel l nuclear antigen (PCNA) immunohistochemistry during 0-120 h after TA injection. In AL-fed rats hepatic necrosis was evident at 12 h, peaked at 60 h. and persisted thereafter until mortality (3 to 6 days). Peak liver injury was approximately twofold higher in DR rats compared to that seen in AL rats. Hepatic necrosis was evident at 36 h, peaked at 48 h, persisted until 96 h, and returned to normal by 120 h, Light mic roscopy of liver sections revealed progression of hepatic injury in AL rats whereas injury regressed completely leading to recovery of DR ra ts by 120 h. Progression of injury led to 90% mortality in AL rats vs 30% mortality in DR group. In the surviving AL rats, S-phase DNA synth esis was evident at 60 h, peaked at 72 h, and declined to base level b y 120 h, whereas in DR rats S-phase DNA synthesis was evident at 36 h and was consistently higher until 96 h reaching control levels by 120 h. PCNA studies showed a corresponding increase in cells in S and M ph ase in the AL and DR groups. DR resulted in abolition of the delay in tissue repair associated with the lethal dose of TA in ad libitum rats . Temporal changes and higher tissue repair response in DR rats (earli er and prolonged) are the conduits that anew a significant number of d iet restricted rats to escape lethal consequence. (C) 1998 Society of Toxicology.