Role of tissue repair in toxicologic interactions among hepatotoxic organics.

Abstract

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

Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

“…Body weight was significantly decreased in the 154 kcal group, suggesting an overall decrease in total body water and volume of distribution; this could be a cause of the increased UECs in that group. Compensatory tissue repair is known to influence the final outcome of hepatotoxicity (8,31,44), and it is known that nutritional factors may modulate the tissue repair response in addition to altering the metabolic activation of hepatotoxicants (32). Timely onset of cell division and sustained continuation of the cell proliferative response are of pivotal importance for survival in the face of liver injury; however, such a sustained increase in the hepatocyte proliferative rate will also increase the risk of carcinogenesis (15).…”

Hepatocyte Proliferation is the Possible Mechanism for the Transient Decrease in Liver Injury During Steatosis Stage of Alcoholic Liver Disease

“…A timely stimulated and sustained hepatocyte division after toxicant treatment, such as CCl 4 , thioacetamide, acetaminophen, and galactosamine, leads to regression of injury, and restoration of structure and function of the liver (Chanda et al, 1995;Soni and Mehendale, 1998;Shayiq et al, 1999;Galum et al, 2000). Therefore, it was hypothesized that the decrease in liver injury following chronic EtOH consumption is predominantly due to increase in compensatory hepatocyte division.…”

“…It appears that lower doses of EtOH may actually stimulate liver regeneration (Minuk et al, 1991;Zhang et al, 1998Zhang et al, , 2000Zhang et al, , 2003. The extent of liver regeneration may also depend on the extent of liver injury (Ramaiah et al, 1998;Soni and Mehendale, 1998;Apte et al, 2002;Zhang et al, 2003). Based on these reports and our findings, a reasonable assumption can be made that hepatocyte proliferation following EtOH ingestion is modulated in a dose dependent manner and is reliant on the extent and the type of liver injury.…”

Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

“…36 In a broader sense, Ppar␣-null mice respond adversely to a number of inducers of hepatocyte damage and compensatory growth. For example, they are more sensitive to the liver toxicants acetaminophen, 37 trichloroethylene (Laughter et al, unpublished data), and carbon tetrachloride (Xiao et al, manuscript in preparation). Moreover, wild-type mice pretreated with a PP are resistant to several other hepatotoxicants (summarized in Chen et al 38 ).…”