EFFECT OF AN ANTIMITOTIC AGENT COLCHICINE ON THIOACETAMIDE HEPATOTOXICITY

In an earlier study we established that timely and adequate tissue rep air response following the administration of six-fold dose-range of th ioacetamide (TA; 50, 150, and 300 mg/kg) prevented progression of inju ry and led to recovery and animal survival. Delayed and attenuated rep air response after the 600 mg/kg TA dose resulted in a marked progress ion of injury and 100% lethality. The objective of the present study w as to further scrutinize this concept in an experimental protocol in w hich we hypothesized that a selective ablation of the tissue repair re sponse should lead to lethality from the nonlethal, moderately toxic d oses of 150 and 300 mg/kg TA. In this study we investigated the effect of the antimitotic agent colchicine (CLC, 1 mg/kg) on the outcome of TA hepatotoxicity. Male Sprague-Dawley rats (175-225 g) were injected intraperitoneally (ip) with 150 and 300 mg/kg TA. We assessed liver in jury by serum enzyme elevations and histopathology. Tissue regeneratio n response was measured by H-3-thymidine incorporation into hepatonucl ear DNA and by proliferating cell nuclear antigen (PCNA) assay. S-Phas e stimulation, as indicated by H-3-thymidine incorporation, was noted at 36 and 48 hr following the administration of 150 mg/kg TA, whereas with the 300 mg/kg TA S-phase stimulation was elicited at 48 hr follow ing treatment. Therefore, two doses of CLC (30 hr and 42 hr, 1 mg/kg, ip) were administered to 150 mg/kg treated group while a single dose o f CLC (42 hr, 1 mg/kg, ip) was administered to the 300 mg/kg group. CL C treatment resulted in 100% lethality in both groups. Thus, CLC admin istration converted nonlethal doses into lethal doses. The 150 mg/kg T A dose was then chosen to further investigate the underlying mechanism . Rats treated with TA alone recovered from injury by 36-48 hr while C LC treatment resulted in a progression of injury as indicated by serum enzyme elevation and histopathology. Tissue repair, as evidenced by H -3-thymidine incorporation and PCNA studies explained this dichotomy. Antimitotic intervention with CLC resulted in a significantly diminish ed repair response leading to unrestrained progression of injury and l ethality even from nonlethal doses. This model demonstrates the critic al role of tissue repair response in determining the final outcome of toxicity.