DIET RESTRICTION ENHANCES COMPENSATORY LIVER-TISSUE REPAIR AND SURVIVAL FOLLOWING ADMINISTRATION OF LETHAL DOSE OF THIOACETAMIDE

Diet restriction is known to prevent a plethora of age-associated dise ases including cancer. However, the effects of diet restriction on non cancer end points are not known. The objective of this study was to in vestigate whether diet restriction protects against hepatotoxicity of thioacetamide (TB), and if so, to investigate the underlying mechanism . Male Sprague-Dawley rats (250-275 g) were maintained on 65% of their ad libitum (AL) food consumption for a period of 3 weeks and then tre ated with a single low dose of 50 mg TA/kg ip. plasma enzymes (ALT and SDH), hepatic glycogen levels, and H-3-thymidine incorporation into h epatocellular nuclear DNA were measured during a time course (0-120 h) after TA administration. fiver sections were examined for histopathol ogy, and cell-cycle progression was assessed by proliferating cell nuc lear antigen (PCNA) immunohistochemistry. In Ak rats hepatic necrosis was evident at 12 h, peaked at 36 h, persisted up to 72 h, and was res olved by 96 h. in the diet-restricted (DR) group hepatic necrosis was observed at 12 h, peaked at 24 h, persisted tip 72 h, and was resolved by 96 h, Maximal injury indicated by enzyme elevation occurred in DR rats and was approximately sixfold greater than that observed in the A k group. Histopathological examination of the liver sections revealed liver injury concordant with plasma enzyme elevations. There was a hig her and sustained S-phase synthesis in the DR rats compared to AL grou p. S-phase stimulation was evident at 36 h, peaked at 48 h, and persis ted until 96 h in the DR rats, whereas in the AL rats peak S-phase sti mulation occurred at 36 h and subsided by 72 h. PCNA studies revealed a corresponding stimulation of cell-cycle progression indicating highl y stimulated compensatory tissue repair. The 14-day lethality experime nts (600 mg TA/kg ip) indicated 70% survival in the DR rats compared t o 10% survival in the AL group. Although diet restriction increases he patotoxic injury of TA, it protects from the lethal outcome by enhance d liver tissue repair. Comparison of liver injury and tissue repair em ploying an equitoxic dose (600 mg TA/kg in AL rats yields similar live r injury as observed with 50 mg TA/kg in DR rats) revealed that in spi te of near equal injury up to 36 h, tissue repair response in DR rats is much higher. The compensatory tissue repair allows the DR rats to e scape death in contrast to much lower compensation in AL rats leading to progression of liver injury culminating in death. (C) 1998 Academic Press.