Colchicine Antimitosis Abolishes CCl4 Autoprotection

Rao, Vaman C.; Mehendale, Harihara M.

doi:10.1177/019262339101900405

Cited by 43 publications

(39 citation statements)

References 36 publications

(63 reference statements)

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“…Stimulation of tissue repair speeds up recovery, whereas inhibition of tissue repair leads to progression of injury and animal death. Models are from references (39,36,14,15,35,3,11,3,9,20,19), respectively. binary mixtures ( Figure 6). Whenever tissue repair induced by one chemical is further enhanced by the binary combination of chemicals, the toxic outcome is survival.…”

Section: Resiliency Ofpostnatally Developing Ratsmentioning

confidence: 99%

“…Because toxicant-stimulated tissue repair response is critically involved in the ultimate outcome of toxicity, inhibition or enhancement of tissue repair by other chemicals may lead to unrestrained progression of injury and mortality or arrested progression of injury and recovery from injury and survival, respectively. Examples of both situations are available (9)(10)(11)(12)(13)(14)(15)(16). In the highly amplified toxicity of CC14 by chlordecone, tissue repair is inhibited (1,2), which results in unrestrained progression of liver injury leading to 67-fold amplification of CC14 toxicity by chlordecone.…”

Section: Implications To Therapeutic Strategiesmentioning

confidence: 99%

“…These findings suggest that even though massive (and ordinarily lethal) injury may occur because of modulation of stage one, enhanced tissue repair in stage two can compensate, thereby allowing the reversal of injury. Antimitotic intervention of cell division by colchicine administration after the mechanistic processes of infliction of injury (stage one) leads to progression of even limited injury culminating in lethal outcome from ordinarily nonlethal doses of hepatotoxicants (9,11,79).…”

Section: Implications To Therapeutic Strategiesmentioning

confidence: 99%

“…Several studies suggest that the rate and extent of tissue repair as a response to the injury inflicted by toxicants determines the ultimate outcome of hepatotoxicity (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Blockage of the tissue repair leads to progression of injury, culminating in hepatic failure and death (9)(10)(11)(12)(13)(14)(15)(16). Because stimulation of tissue repair is a biologic response that accompanies injury, quantifying this response in addition to measuring injury might be helpful in predictive toxicology.…”

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confidence: 99%

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Role of tissue repair in toxicologic interactions among hepatotoxic organics.

Soni

Mehendale

1998

Environ Health Perspect

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It is widely recognized that exposure to combinations or mixtures of chemicals may result in highly exaggerated toxicity even though individual chemicals might not be toxic at low doses. Chemical mixtures may also cause additive or less than additive toxicity. From the perspective of public health, highly exaggerated toxicity is of significant concern. Assessment of risk from exposure to chemical mixtures requires knowledge of the underlying mechanisms. Previous studies from this laboratory have shown that nontoxic doses of chlordecone (10 ppm, 15 days) and carbon tetrachloride (CCl4) (100 microliters/kg) interact at the biologic interface, resulting in potentiated liver injury and 67-fold amplification of CCl4 lethality. In contrast, although interaction between phenobarbital and CCl4 leads to even higher injury, animal survival is unaffected because of highly stimulated compensatory tissue repair. A wide variety of additional experimental evidence confirms the central role of stimulated tissue repair as a decisive determinant of the final outcome of liver injury inflicted by hepatotoxicants. These findings led us to propose a two-stage model of toxicity. In this model, tissue injury is inflicted in stage one by the well-described mechanisms of toxicity, whereas in stage two the ultimate toxic outcome is determined by whether timely and sufficient tissue repair response accompanies this injury. In an attempt to validate this model, dose-response relationships for injury and tissue repair as opposing responses have been developed for model hepatotoxicants. Results of these studies suggest that tissue repair increases in a dose-dependent manner, restraining injury up to a threshold dose, whereupon it is inhibited, allowing an unrestrained progression of injury. These findings indicate that tissue repair is a quantifiable response to toxic injury and that inclusion of this response in risk assessment may help in fine-tuning prediction of toxicity outcomes. Images Figure 3 Figure 4 Figure 6

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Section: Resiliency Ofpostnatally Developing Ratsmentioning

confidence: 99%

Section: Implications To Therapeutic Strategiesmentioning

confidence: 99%

Section: Implications To Therapeutic Strategiesmentioning

confidence: 99%

mentioning

confidence: 99%

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Role of tissue repair in toxicologic interactions among hepatotoxic organics.

Soni

Mehendale

1998

Environ Health Perspect

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“…Intervention with the repair processes has been reported to result in unrestrained progression of hepatic injury leading to hepatic failure and animal death (20,21). Colchicine (CLC) is a widely used antimitotic agent (20)(21)(22)(23).…”

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confidence: 99%

Effect of an antimitotic agent colchicine on thioacetamide hepatotoxicity.

Mangipudy

Rao

Mehendale

1996

Environ Health Perspect

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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.

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Stimulated hepatic tissue repair underlies heteroprotection by thioacetamide against acetaminophen-induced lethality

et al. 1995

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Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that causes massive centrilobular hepatic necrosis at high doses, leading to death. The objectives of this study were to test our working hypothesis that preplaced cell division and hepatic tissue repair by prior thioacetamide (TA) administration provides protection against APAP-induced lethality and to investigate the underlying mechanism. Male Sprague-Dawley rats were treated with a low dose of TA (50 mg/kg, intraperitoneally [i.p.]) before challenge with a 90% lethal dose (1,800 mg/kg, i.p.) of APAP. This protocol resulted in a 100% protection against the lethal effect of APAP. Because TA caused a 23% decrease of hepatic microsomal cytochromes P-450, the possibility that TA protection may be caused by decreased bioactivation of APAP was examined. A 30% decrease in cytochromes P-450 induced by cobalt chloride failed to provide protection against APAP lethality. Time course of serum enzyme elevations (alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase) indicated that actual infliction of liver injury by APAP peaked between 12 to 24 hours after the administration of APAP, whereas the ultimate outcome of that injury depended on the biological events thereafter. Although liver injury progressed in rats receiving only APAP, it regressed in rats pretreated with TA. Acetaminophen t1/2 was not altered in TA-treated rats, indicating that significant changes in APAP disposition and bioactivation are unlikely. Moreover, hepatic glutathione was decreased to a similar extent regardless of TA pretreatment, suggesting that decreased bioactivation of APAP is unlikely to be the mechanism underlying TA protection. [3H]Thymidine incorporation studies confirmed the expected stimulation of S-phase synthesis, and proliferating cell nuclear antigen studies showed a corresponding stimulation of cell division through accelerated cell cycle progression. Intervention with TA-induced cell division by colchicine antimitosis ended the TA protection in the absence of significant changes in the time course of serum enzyme elevations during the inflictive phase of APAP hepatotoxicity. These studies suggest that hepatocyte division and tissue repair induced by TA facilitate sustained hepatic tissue repair after subsequent APAP-induced liver injury, producing recovery from liver injury and protection against APAP lethality.

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Colchicine Antimitosis Abolishes CCl4 Autoprotection

Cited by 43 publications

References 36 publications

Role of tissue repair in toxicologic interactions among hepatotoxic organics.

Role of tissue repair in toxicologic interactions among hepatotoxic organics.

Effect of an antimitotic agent colchicine on thioacetamide hepatotoxicity.

Stimulated hepatic tissue repair underlies heteroprotection by thioacetamide against acetaminophen-induced lethality

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