Role of Hepatocellular Regeneration in CCl<sub>4</sub> Autoprotection

Thakore, Kashyap N.; Mehendale, Harihara M.

doi:10.1177/019262339101900106

Cited by 75 publications

(64 citation statements)

References 32 publications

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“…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%

“…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.…”

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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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: Implications To Therapeutic Strategiesmentioning

confidence: 99%

mentioning

confidence: 99%

Role of tissue repair in toxicologic interactions among hepatotoxic organics.

Soni

Mehendale

1998

Environ Health Perspect

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“…Normally, most cells in the liver are in the resting phase (Go; Fig. 5A (13)(14)(15)(16)(17)(18)(19)30). Other studies (11,13,14,22,(31)(32)(33)(34)(35)(36) Figure 5.…”

Section: Resultsmentioning

confidence: 93%

“…Rats treated with a single dose of 50 mg/kg TA show non-neoplastic hepatocellular proliferation indicated by 3H-thymidine (3H-T) incorporation and cell cycle progression to mitosis after administration (9,(12)(13)(14). Hepatocellular regeneration and tissue repair mechanisms have been implicated in the ultimate outcome of toxicity, after injury from a variety of structurally and mechanistically dissimilar chemicals including carbon tetrachloride (15)(16)(17)(18), acetaminophen (14), and thioacetamide (19).…”

mentioning

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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“…At each time point, the majority of hepatocytes in the PCNA-GF were in the G, phase of the cell cycle (Fig. 3) (31). The increased sensitivity of PCNA-GF in our study was attributed to the detection of more cells in the cell cycle (G1 + S + G2 + M), as compared to PCNA-LI, in which only S-phase cells are quantified, thereby allowing a &dquo;larger window&dquo; of observation of the cell cycle ( 11 ).…”

Section: Introductionmentioning

confidence: 99%