TEMPORAL CHANGES IN TISSUE-REPAIR UPON REPEATED EXPOSURE TO THIOACETAMIDE

In an earlier study it was reported that a single low dose of thioacet amide (TA, 50 mg/kg) administered 36 h prior to challenge with a high dose of 400 mg/kg offers protection from lethality of high dose (Mangi pudy et al., Pharmacol. Toxicol. 77, 1995). The mechanism underlying t his protection was found to be preplaced hepatocellular division and t issue repair that peaked by 36 h following the low-dose treatment. In a separate study using the dose-response paradigm, it was established that the rate and the extent of the tissue repair response following i nfliction of injury after acute exposure has a critical bearing on the ultimate outcome of toxicity (Mangipudy et al., Environ. Health Persp ect. 103, 1995). The objective of this study was to investigate the ce ll proliferation dynamics after repeated exposure to TA (50 mg/kg ip). Male Sprague-Dawley rats (200-225 g) were administered TA at interval s of 96 h. Liver injury and tissue repair were studied over a time cou rse following each treatment. Tissue repair was estimated by S-phase D NA synthesis measuring H-3-thymidine incorporation into hepatonuclear DNA while liver injury was estimated by serum alanine aminotransferase activity. After the first dose of 50 mg/kg, peak S-phase DNA synthesi s was observed at 36 h. This returned to control values by 96 h at whi ch time the rats are known to overcome liver injury. A second dose of TA (repeated dose 1, RD1) resulted in peak S-phase DNA synthesis 12 h later at 48 h. Following the third dose (RD2) a dramatic increase in S -phase DNA synthesis was noted from as early as 12 h. Much higher peak was observed at 72 h. Interestingly, following the fourth dose (RD3) S-phase stimulation did not occur. Instead, a significant latency was observed for cells in the S-phase DNA synthesis even at time points as late as 144 h following the treatment. Liver injury on the other hand exhibited no significant differences between repetitions until RD2. H owever, injury was sustained in the rats treated with the fourth dose (RD3) while it returned to control levels in the earlier three instanc es. Sustained prolongation of liver injury after the fourth dose is pr esumably because tissue repair was not operational. Thus repeated expo sure to TA causes a significant increase in tissue repair response alt hough it is temporally delayed until a threshold is reached. Repetitio n beyond the threshold results in a marked attenuation of the repair r esponse. These findings suggest that toxicodynamics of cell proliferat ion are altered after repeated exposure. (C) 1998 Academic Press.