Effect of an antimitotic agent colchicine on thioacetamide hepatotoxicity.

Abstract

In an earlier study we established that timely and adequate tissue repair response following the administration of a six-fold dose-range of thioacetamide (TA; 50, 150, and 300 mg/kg) prevented progression of injury and led to recovery and animal survival. Delayed and attenuated repair response after the 600 mg/kg TA dose resulted in a marked progression of injury and 100% lethality. The objective of the present study was to further scrutinize this concept in an experimental protocol in which we hypothesized that a selective ablation of the tissue repair response should lead to lethality from the nonlethal, moderately toxic doses 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 injury by serum enzyme elevations and histopathology. Tissue regeneration response was measured by 3H-thymidine incorporation into hepatonuclear DNA and by proliferating cell nuclear antigen (PCNA) assay. S-Phase stimulation, as indicated by 3H-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 following treatment. Therefore, two doses of CLC (30 hr and 42 hr, 1 mg/kg, ip) were administered to the 150 mg/kg treated group while a single dose of CLC (42 hr, 1 mg/kg, ip) was administered to the 300 mg/kg group. CLC treatment resulted in 100% lethality in both groups. Thus, CLC administration converted nonlethal doses into lethal doses. The 150 mg/kg TA dose was then chosen to further investigate the underlying mechanism. Rats treated with TA alone recovered from injury by 36-48 hr while CLC treatment resulted in a progression of injury as indicated by serum enzyme elevation and histopathology. Tissue repair, as evidenced by 3H-thymidine incorporation and PCNA studies explained this dichotomy. Antimitotic intervention with CLC resulted in a significantly diminished repair response leading to unrestrained progression of injury and lethality even from nonlethal doses. This model demonstrates the critical role of tissue repair response in determining the final outcome of toxicity. Images Figure 1. Figure 2. Figure 3. Figure 3. Figure 3. Figure 3. Figure 3. Figure 3. Figure 5. Figure 5. Figure 5. Figure 5. Figure 5. Figure 5. Figure 4. Figure 6.

Colchicine antimitosis causes progression of S-(1,2-dichlorovinyl)-l-cysteine-induced injury leading to acute renal failure and death in mice

“…Similar observations have been made by different investigators from dose-response studies conducted for injury and repair using different toxicants in extrarenal tissues like liver (Kulkarni et al, 1997;Mangipudy et al, 1996;Rao et al, 1997;Mehendale, 2005) and red blood cells (Sivarao and Mehendale, 1995). However, the critical role of this nephrogenic tissue repair in protecting mice from DCVC-nephrotoxicity has not been examined in detail.…”

“…The role of tissue repair in the final outcome of hepatotoxic injury by various toxicants such as carbon tetrachloride (CCl 4 ), thioacetamide (TA), and 1,2-dichlorobenzene (1,2-DCB) has been previously investigated (Kulkarni et al, 1997;Mangipudy et al, 1996;Rao and Mehendale, 1993;Rao et al, 1997;Mehendale, 2005). These studies have examined the critical role of tissue repair by inhibiting tissue repair using antimitotic agents like colchicine (CLC).…”

Extent and Timeliness of Tissue Repair Determines the Dose-Related Hepatotoxicity of Chloroform

“…Prior administration of a small dose of same toxicant (autoprotection) or different toxicant (heteroprotection) will rescue the animals from lethal dose of hepatotoxicants (Mangipudy, Chanda, and Mehendale 1995b;Thakore and Mehendale 1994;Sivarao and Mehendale 1995;. When the liver regeneration is abolished by the antimitotic agent cochicine, even the minimal initial injury results in lethality (Kulkarni et al 1997;Rao, Mangipudy, and Mehendale 1997;Mangipudy, Rao, and Mehendale 1996). These results underscore the significance of the newly dividing cells.…”

“…Previous studies with several hepatotoxicants have established that stimulation of cell division and tissue repair is a predictable response (Soni and Mehendale 1999). This response occurs irrespective of the mechanism and regiospecificity of infliction of injury, and determines the ultimate outcome of hepatotoxicity, i.e., progression or regression of injury depends on timely and adequate appearance of cell division Rao, Mangipudy, and Mehendale 1997;Mehendale 1995a, 1995b;Mangipudy, Rao, and Mehendale 1996;. Attenuation and delay in tissue repair are observed at higher doses of toxicants, leading to progression of injury culminating in hepatic failure and animal death (Purushotham, Lockard, and Mehendale 1988;Mehendale 1994;Mangipudy, Chanda, and Mehendale 1995a;Kulkarni et al 1996).…”

Mechanisms of inhibited liver tissue repair in toxicant challenged type 2 diabetic rats

“…Many studies have now shown that factors other than bioactivation and/or detoxification mechanisms, such as liver tissue repair, are involved in determining the final outcome of toxicity (Mangipudy et al, 1995a(Mangipudy et al, ,b, 1996Soni and Mehendale, 1998;Wang et al, 2000aWang et al, ,b, 2001Sawant et al, 2004Sawant et al, , 2006Mehendale, 2005). Literature suggests that inhibited liver cell division and tissue repair by lethal doses of model toxicants or antimitotic intervention with colchicine after low to moderate doses of toxicants results in progression of liver injury, hepatic failure, and mortality (Mangipudy et al, 1995b(Mangipudy et al, , 1996Kulkarni et al, 1997;Dalu et al, 1998;Soni and Mehendale, 1998;Mehendale, 2005). Furthermore, pre-placed and higher tissue repair stimulated by low (priming) dose of a hepatotoxicant protect from the subsequently administered lethal dose of same or different hepatotoxicants Mangipudy et al, 1995a;Calabrese and Mehendale, 1996;Mehendale, 2005).…”