Temporal changes in tissue repair upon repeated exposure to thioacetamide

In an earlier study it was reported that a single low dose of thioacetamide (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 (Mangipudy et al., Pharmacol. Toxicol. 77, 1995). The mechanism underlying this protection was found to be preplaced hepatocellular division and tissue 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 infliction of injury after acute exposure has a critical bearing on the ultimate outcome of toxicity (Mangipudy et al., Environ. Health Perspect. 103, 1995). The objective of this study was to investigate the cell proliferation dynamics after repeated exposure to TA (50 mg/kg i.p.). Male Sprague-Dawley rats (200-225 g) were administered TA at intervals of 96 h. Liver injury and tissue repair were studied over a time course following each treatment. Tissue repair was estimated by S-phase DNA synthesis measuring 3H-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 synthesis was observed at 36 h. This returned to control values by 96 h at which 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. However, injury was sustained in the rats treated with the fourth dose (RD3) while it returned to control levels in the earlier three instances. Sustained prolongation of liver injury after the fourth dose is presumably because tissue repair was not operational. Thus repeated exposure to TA causes a significant increase in tissue repair response although it is temporally delayed until a threshold is reached. Repetition beyond the threshold results in a marked attenuation of the repair response. These findings suggest that toxicodynamics of cell proliferation are altered after repeated exposure.