Age-Related Susceptibility to Chlordecone-Potentiated Carbon Tetrachloride Hepatotoxicity and Lethality Is Due to Hepatic Quiescence

Abstract

Previous studies revealed that postnatally developing rats are resilient to the lethal effects of chlordecone (CD) + carbon tetrachloride (CCI,) combination. The objective of this study was to investigate the underlying mechanism. We hypothesized that ongoing cell division and cell cycle progression as well as additional toxicant-induced stimulation of tissue repair help in restraining the progression of injury on the one hand, and in recovery through speedy healing on the other. Postnatally developing (20-and 45-d) (2), galactosamine (6), and acetaminophen (7). Most interestingly, young rats survive exposure to individually nontoxic combination of C D + CCl, (9, known to cause 100% mortality in adult rats (8,9).Because there is a need to understand the mechanisms underlying this age-related difference in toxicity, and because the C D + CC1, model offers a unique opportunity to investigate these mechanisms, this model was used in the present studies.CCl, is bioactivated by cytochrome P450 to CCl, free radical, which is further converted to a peroxy radical, CCl,O; (10). These free radicals readily react with polyunsaturated fatty acids of the endoplasmic reticulum and other hepatocel-

Colchicine Antimitosis Abolishes Resiliency of Postnatally Developing Rats to Chlordecone-Amplified Carbon Tetrachloride Hepatotoxicity and Lethality

“…These findings underscore the importance of ongoing and toxicant-stimulated cell division and tissue repair meanisms in hepatotoxidty, and the need for the inclusion of age factors in (1). Recent studies have revealed that neonates and young rats are resilient to a wide variety of structurally and mechanistically dissimilar hepatotoxicants such as CC14 (2)(3)(4)(5)(6), allyl alcohol (7), galactosamine (8), and acetaminophen (9). Furthermore, young rats are resilient to the combination of chlordecone (CD) and CC14 (4)(5)(6), which is known to cause fulminant hepatic failure (10) and 100% mortality in adult rats (10)(11)(12).…”

Colchicine antimitosis abolishes resiliency of postnatally developing rats to chlordecone-amplified carbon tetrachloride hepatotoxicity and lethality.

“…The lethality study was conducted to examine if stimulated cell division is critical in the resiliency of postnatally developing rats to CD-potentiated CCl4 hepatotoxicity and lethality. This concept was tested in 45-day-old rats using CLC antimitosis because this age group is known to exhibit partial sensitivity (25% mortality) to CD + CCl4 (4,5). The administration of CLC (1 mg/kg, ip) to the ND + CCl4 group did not result in any mortality (Table 1 12 and 36 hr after the administration of CCl4 (Fig.…”

“…It is also known that exposure to a combination of CD and CC14 results in suppression of this compensatory tissue repair in rats, allowing progression of liver injury, culminating in liver failure and animal death (10)(11)(12)17,(34)(35)(36). In contrast, young rats are resilient to CD-potentiated CC14 hepatotoxicity and lethality primarily because of ongoing liver cell division replacing dead or dying cells, thereby suppressing the progression of liver injury (4)(5)(6). Furthermore Table 2.)…”

“…However, recent 3H-T incorporation and proliferating cell nuclear antigen (PCNA) studies indicate that younger rats (45 days old) exhibit resiliency not only to CCl4 alone, but also to the lethal combination of CD and CC14. This resiliency was closely associated with enhanced plasticity in hepatocellular regeneration and efficient tissue repair mechanisms in the younger animals (4)(5)(6), rather than due to differences in cytochrome P450 levels or bioactivation-dependent mechanisms (4). Furthermore, young rats are also resilient to hepatotoxicants such as galactosamine, which do not depend on cytochrome P450 bioactivation to inflict liver injury (8).…”

“…Recent studies have revealed that neonates and young rats are resilient to a wide variety of structurally and mechanistically dissimilar hepatotoxicants such as CC14 (2)(3)(4)(5)(6), allyl alcohol (7), galactosamine (8), and acetaminophen (9). Furthermore, young rats are resilient to the combination of chlordecone (CD) and CC14 (4)(5)(6), which is known to cause fulminant hepatic failure (10) and 100% mortality in adult rats (10)(11)(12).…”