Role of hepatocellular regeneration in chlordecone potentiated hepatotoxicity of carbon tetrachloride

Kodavanti, Prasada Rao S.; Joshi, Urmila M.; Young, Robert A.; Bell, Andrea N.; Mehendale, Harihara M.

doi:10.1007/bf00303125

Cited by 42 publications

(32 citation statements)

References 28 publications

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“…On the other hand, evidence from histomorphometric studies (12,13) and from subsequent investigations using 3H-T pulselabeling and autoradiography techniques and the partially hepatectomized animal model (14)(15)(16)(17) are supportive of a novel hypothesis (4) that normally hepatocellular regeneration and repair of the hepatolobular architecture enable the animals to overcome and recover from injury initiated by a low dose of CCI4. These studies (14)(15)(16)(17) also revealed that suppression of hepatocellular regeneration and tissue repair are responsible for the amplified hepatotoxicity of the same low dose of CC14 by prior exposure to CD.…”

mentioning

confidence: 99%

Resiliency to Amplification of Carbon Tetrachloride Hepatotoxicity by Chlordecone during Postnatal Development in Rats

Cai

Mehendale

1993

Pediatr Res

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ABSTRACT. The interactive hepatotoxicity of C C 4 and chlordecone, at an individually nontoxic dosage, was studied in neonatal and young developing rats. The well-documented amplification of CCI4 (100 pL/kg) hepatotoxicity and lethality by prior dietary exposure to chlordecone (10 ppm, for 1 5 d) was absent in neonatal and developing rats through 3 5 d of age. The chlordecone-potentiated hepatotoxicity and lethality of C C 4 was partially expressed in 45-d-old rats and fully expressed in 60-d-old rats. Although hepatic microsomal cytochrome P-450 content in 2-or 5-d-old rats was significantly lower than that in older age groups, the cytochrome P-450 content was not significantly different between 35-, 45-, and 60-d-old chlordeconetreated rats. During postnatal development, the ongoing hepatocellular proliferation declined in a biphasic manner, more rapidly up to 20 d and slowly thereafter, as indicated by %-thymidine incorporation in hepatic nuclear DNA. This pattern of postnatal liver proliferation and growth was not altered by exposure to chlordecone. In vivo metabolism of CC14, in terms of I4CO2 production derived from I4CCl4 and I4CCl4 metabolites bound to hepatic tissue, was not significantly different between 35-, 45-, and 60-d-old chlordecone-treated rats, whereas CC14-stimulated hepatocellular regeneration in 35-d-old chlordecone-treated rats was significantly higher than in 45-or 60-d-old chlordecone-treated rats, as indicated by 3H-thymidine incorporation into hepatic DNA and histomorphometric analysis. These data suggest that the absence of potentiation of CC14 toxicity by chlordecone in postnatally developing rats is well correiated with the presence of ongoing and itimulatable hepatocellular regenerative activity. (Pediatr Res 33: 225-232,1993) Abbreviations CD, chlordecone PB, phenobarbital %I-T, 3H-thymidine ALT, alanine transaminase ND, normal diet TGF, transforming growth factorThe remarkable potentiation of CCI4 hepatotoxicity by prior exposure to nontoxic levels of CD (10 ppm in diet for 15 d) is well documented in male and female adult rats, as indicated by greatly increased hepatotoxicity and lethality of CCI4 at ordinarily nontoxic doses in CD-treated rats (1-3). A number of candidate mechanisms for this interaction have been considered (4). Increased bioactivation of CCI4 followed by increased lipid peroxidation is the foremost of these mechanisms in view of their wide acceptance with respect to PB, alcohol, ketone, and other xenobiotic-induced enhancement of CC14 toxicity (5-7). Studies of in vitro (8) and in vivo (9) metabolism of CC14 in rats indicated that, although enhanced metabolism of CCI4 induced by cytochrome P-450 inducers such as PB and CD resulted in increased hepatotoxic effects of CCI4 initially, the alterations in CCI4 metabolism in PB-and CD-pretreated rats were not paralleled by the increase of C C 4 lethal effects. These studies revealed that a 3-fold increase in CC14 metabolism with a statistically nonsignificant 1.7-fold increase in CCI4 lethality for PB rats was c...

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confidence: 99%

Resiliency to Amplification of Carbon Tetrachloride Hepatotoxicity by Chlordecone during Postnatal Development in Rats

Cai

Mehendale

1993

Pediatr Res

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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).…”

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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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“…Rats receiving a low dose of CCl, (100 pL1kg) alone exhibit very limited liver injury as evidenced by histopathologic observations at 6 h after the administration of CCl,. This injury is progressive up to 12 h, followed by recovery by 24 h (11,13). Prior exposure to a nontoxic dose of CD (10 ppm in diet for 15 d) is known to amplify hepatotoxicity and lethality of CCl, in male (8) and female (9) adult rats.…”

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confidence: 99%

“…Prior exposure to a nontoxic dose of CD (10 ppm in diet for 15 d) is known to amplify hepatotoxicity and lethality of CCl, in male (8) and female (9) adult rats. Studies have revealed that the CD + CCl, combination inhibits CC1,-induced liver cell division and tissue repair, thereby permitting unrestrained progression of injury leading to hepatic failure and death (8,9,(13)(14)(15)(16)(17).…”

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confidence: 99%

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

et al. 1995

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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-

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Role of hepatocellular regeneration in chlordecone potentiated hepatotoxicity of carbon tetrachloride

Cited by 42 publications

References 28 publications

Resiliency to Amplification of Carbon Tetrachloride Hepatotoxicity by Chlordecone during Postnatal Development in Rats

Resiliency to Amplification of Carbon Tetrachloride Hepatotoxicity by Chlordecone during Postnatal Development in Rats

Effect of an antimitotic agent colchicine on thioacetamide hepatotoxicity.

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

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