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H M Mehendale

Publications and source records attributed to H M Mehendale.

At least 19 recordsLinked to original sources
PubMed1995

Pristane-induced effects on cytochrome P-4501A, ornithine decarboxylase and putrescine in rats.

The effects of pristane (2,6,10,14-tetramethylpentadecane) on cytochrome P-4501A (cP4501A) activity in microsomes, as well as on ornithine decarboxylase (ODC) activity and concomitant putrescine levels were examined in Copenhagen rats. In general, pristane treatment led to increased cP4501A levels when compared to basal levels, while co-treatment with 3-methylcholanthrene (3-MC) and pristane elicited augmented cP4501A responses when compared to responses induced by 3-MC alone. Increases in both ODC activity and putrescine levels were also observed in pristane treated rats. Collectively, these results indicate that pristane influences cP4501A activity and elicits promoter-like responses as reflected in elevated ODC activity and increased amount of putrescine.

Animals↗
PubMed1995

The uptake and metabolism of cystamine and taurine by isolated perfused rat and rabbit lungs.

Cystamine has been reported to be taken up and metabolized to taurine by the rat lung slices. The objectives of the present study were to compare the uptake and metabolism of cystamine and taurine in isolated perfused lungs of rats and rabbits and examine the action of glutathione (GSH) on these processes. The uptake and metabolism of [14C]cystamine and [14C]taurine were studied at 20 microM concentrations each in isolated, ventilated, perfused rat and rabbit lungs. In some experiments, 1 microM GSH was included in the perfusate prior to the addition of cystamine. The perfusate and lung homogenate samples were analyzed for cystamine and its metabolites. [14C]cystamine uptake with and without GSH was 13 and 14% in rat lungs and 37 and 32% in rabbit lungs. [14C]taurine uptake was 10% in rat and 37% in rabbit lungs. The levels of radiolabeled cystamine and its metabolites were (nmol/g lung): 20.0 +/- 10.0 and 11.5 +/- 7.0 cystamine, 4.7 +/- 0.5 and 3.2 +/- 0.5 hypotaurine and 56.0 +/- 16.0 and 49.4 +/- 6.0 taurine, for rat and rabbit lungs, respectively, when perfused without GSH; and 18.0 +/- 1.0 and 2.5 +/- 0.5 cystamine, 6.6 +/- 0.5 and 18 +/- 10 hypotaurine and 60.0 +/- 12.0 and 33.6 +/- 9.0 taurine, when perfused with GSH, for rats and rabbit lungs, respectively. Taurine did not undergo any further metabolism in either of the lungs. These studies show that cystamine is taken up and metabolized to taurine via hypotaurine by both rat and rabbit lungs in a manner similar to that seen in rat lung slices. However, rat lungs have much greater capacity to metabolize cystamine to taurine than rabbit. Inclusion of GSH did not significantly alter the ability of lungs to sequester cystamine from the perfusate but the metabolism of hypotaurine to taurine was markedly decreased in rabbit lungs. Taurine was not metabolized any further. It is concluded that rat and rabbit lungs take up cystamine from the systemic circulation, metabolize it via hypotaurine to taurine, and effuse most of the latter in to the circulation.

Animals↗
PubMed1995

Age-related susceptibility to chlordecone-potentiated carbon tetrachloride hepatotoxicity and lethality is due to hepatic quiescence.

Previous studies revealed that postnatally developing rats are resilient to the lethal effects of chlordecone (CD) + carbon tetrachloride (CCl4) 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) and adult (60-d) male Sprague-Dawley rats were challenged with a nontoxic single dose of CCl4 (100 microL/kg, i.p.) or corn oil after pretreatment with either dietary CD (10 ppm) or normal diet (ND) for 15 d. Hepatocellular injury was assessed by measuring serum enzymes [alanine transaminase (ALT), sorbitol dehydrogenase (SDH)], and bilirubin, as well as by histopathologic examination of liver sections during a time course of 0-96 h after the administration of CCl4 or corn oil. Hepatocellular regeneration was assessed by [3H]thymidine ([3H]T) incorporation into hepatic nuclear DNA. In CD+CCl4 treatment, ALT, SDH, and bilirubin levels peaked between 36 and 48 h after CCl4. All 20-d-old rats survived the challenge of CD+CCl4. CD-potentiated hepatotoxicity and lethality of CCl4 begin to be manifested in 45-d-old rats at 48 h and later times (25% mortality), whereas adult rats experience progressive hepatotoxic injury and 100% mortality by 72 h. In contrast, regardless of pretreatment, 20-d-old rats recover fully from injury by 72 h after CCl4 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Tissue repair response as a function of dose in thioacetamide hepatotoxicity.

The purpose of the present study was to establish a dose-response relationship for thioacetamide (TA), where tissue regeneration as well as liver injury were two simultaneous but opposing responses. Male Sprague-Dawley rats were injected intraperitioneally with a 12-fold dose range of TA, and both liver injury and tissue repair were measured. Liver injury was assessed by serum enzyme elevations. Serum alanine aminotransferase (ALT) elevation did not show any dose response over a 12-fold dose range up to 24 hr. A dramatic ALT elevation was evident after 24 hr and only for the highest dose (600 mg/kg). Tissue regeneration response was measured by 3H-thymidine (3H-T) incorporation into hepatocellular DNA and by proliferating cell nuclear antigen (PCNA) procedure during a time course (6, 12, 24, 36, 48, 72, and 96 hr). Tissue regeneration, as indicated by 3H-T incorporation, peaked at 36 hr after administration of a low dose of TA (50 mg/kg). With increasing doses, a greater but delayed stimulation of cell division was observed until a threshold was reached (300 mg/kg). Above the tissue repair threshold (600 mg/kg), because stimulated tissue repair as revealed by 3H-T incorporation in hepatonuclear DNA was significantly delayed and attenuated, injury assessed by serum enzyme elevations was remarkably accelerated, indicating unrestrained progression of injury leading to animal death. These findings suggest that, in addition to the magnitude of tissue repair response, the time at which this occurs is critical in restraining the progression of injury, thereby determining the ultimate outcome of toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1995

Nutritional impact on the final outcome of liver injury inflicted by model hepatotoxicants: effect of glucose loading.

Fifteen percent glucose in drinking water for 7 days increased lethality of four structurally and mechanistically different model centrilobular hepatotoxicants (acetaminophen, thioacetamide, chloroform, and carbon tetrachloride) in male Sprague-Dawley rats (n = 10/group). A nonlethal injection of thioacetamide was lethal in glucose loaded rats and therefore was chosen for further studies. Serum enzyme elevations and liver histopathology revealed that actual infliction of liver injury peaked between 36 to 48 h after thioacetamide injection; however, the liver injury progressed in rats receiving glucose, whereas it regressed in rats maintained on normal diet and drinking water without glucose supplement. Glucose loading did not increase the hepatic microsomal cytochrome P450. [3H]thymidine incorporation studies along with proliferating cell nuclear antigen immunohistochemical analysis of liver sections revealed inhibition of S-phase stimulation and decelerated cell cycle progression. These findings suggest that glucose loading inhibits cellular regeneration and tissue repair resulting in accelerated progression of liver injury inflicted by thioacetamide culminating in increased death of animals receiving a moderately hepatotoxic dose of thioacetamide.

Acetaminophen↗
PubMed1995

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

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.

Acetaminophen↗
PubMed1994

Autoprotection: stimulated tissue repair permits recovery from injury.

Autoprotection is a phenomenon whereby prior exposure to a small dose of a chemical results in protection against a subsequently administered lethal dose of the same compound. While CCl4 autoprotection has been studied the most, it has also been demonstrated for other chemicals. Recent studies indicate that the prevailing concept of decreased bioactivation of the normally lethal dose of CCl4 owing to decreased hepatic microsomal cytochrome P-450 content cannot be supported by direct end points of liver injury such as necrosis. These findings suggest a pivotal role for hepatocellular division and tissue healing processes stimulated by the protective dose in the mechanism of autoprotection. Augmentation of hepatocellular regeneration and tissue repair, stimulated by the protective dose, appears to permit timely recovery and restoration of hepatic structure and function. In the absence of the protective dose, hepatocellular division is substantially deficient and it occurs too late to tip the delicate balance between recovery from injury and progression of massive injury in favor of recovery. Abolition of autoprotection by colchicine antimitosis, under conditions where metabolism and disposition of CCl4 are not altered, is supportive of this concept. Selective colchicine antimitotic suppression of the early phase of hepatocellular division and tissue repair induced by a low dose of CCl4 results in progression of toxic liver injury, leading to hepatic failure and mortality. Studies have shown that pretreatment with phenobarbital results in postponed low-dose CCl4-stimulated cell division by 24 hours, which accordingly postpones the optimal autoprotection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Adenosine triphosphate protection of chlordecone-amplified CCl4 hepatotoxicity and lethality.

Dietary exposure to a nontoxic level of chlordecone (10 ppm for 15 days) followed by a single exposure to a subtoxic dose of CCl4 (100 microliters/kg, ip) is known to result in a 67-fold amplification of CCl4 toxicity. The hypothesis that the underlying mechanism is due to incapacitation of hepatocytes leading to an ablation of the early-phase hormetic response of tissue repair as a consequence of precipitous decline in hepatic glycogen and ATP, received experimental support from Mehendale in 1990. The present study was designed to investigate if direct administration of ATP to rats maintained on the chlordecone diet would result in protection from the hepatotoxic and lethal effects of the chlordecone+CCl4 combination. Male Sprague-Dawley rats (125-150 g) were maintained either on a diet containing no added contaminants (control) or on a diet containing 10 ppm chlordecone for 15 days, and were challenged with CCl4 (100 microliters/kg, ip) on day 16. Without ATP administration all rats died within 72 h, while administration of ATP (100 mg/rat, sc) to chlordecone-pretreated rats at -1, +1, 3, 5, 12, 24 and 36 h of CCl4 injection resulted in 100% survival. Injection of ATP, at -1, +1, 3 and 5 h of CCl4 administration to chlordecone pretreated rats decreased plasma enzyme elevations (alanine and aspartate aminotransferase, sorbitol dehydrogenase) as well as substantially preventing elevation of plasma bilirubin levels at 6, 12 and 24 h. Hepatic ATP levels were also elevated at 6 and 12 h, but not at 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1994

Novel mechanisms in chemically induced hepatotoxicity.

This review focuses on cellular events that modulate hepatotoxicity subsequent to initial liver insult. Cellular events that determine the nature and extent of hepatotoxic injury and the ultimate outcome of that injury are also discussed. The roles of cell types other than hepatocytes, hepatocyte organelle-specific processes, and regeneration in progression or recovery from liver injury are emphasized. Leukocyte activities are key events in two distinct hepatotoxicities. Neutrophil-mediated, periportal inflammation appears to play a primary role in progression of alpha-naphthylisothiocyanate-induced cholangiolitic hepatitis. However, a humorally mediated autoimmune response to protein adducts that occurs after anesthesia is critical in onset of halothane-induced hepatitis. New insights into specific events at the hepatocyte level are also emerging. Although reducing gap junctional communication between hepatocytes can protect against progression of liver injury, down-regulation of the subunit proteins (connexins) can isolate neoplastic cells from growth regulation. Acidic intracellular pH characteristic of hypoxia is protective against both hypoxic and toxicant-induced cell injury. In oxidative injury, a pH-mediated mitochondrial permeability transition causes mitochondrial uncoupling and ATP loss and leads to cell death. The ultimate outcome of hepatotoxic injury depends on the extent of tissue repair. Stimulation of tissue repair after a sublethal dose of CCl4 appears to be the central mechanism in protection against death from a subsequent large dose. Taken together, these examples illustrate the importance of events subsequent to initial liver injury as determinants of extent of liver damage.

1-Naphthylisothiocyanate↗
PubMed1994

Amplified interactive toxicity of chemicals at nontoxic levels: mechanistic considerations and implications to public health.

It is widely recognized that exposure to combinations or mixtures of chemicals may result in highly exaggerated toxicity even though the individual chemicals might not be toxic. Assessment of risk from exposure to combinations of chemicals requires the knowledge of the underlying mechanism(s). Dietary exposure to a nontoxic dose of chlordecone (CD; 10 ppm, 15 days) results in a 67-fold increase in lethality of an ordinarily inconsequential dose of CCl4 (100 microliters/kg, ip). Toxicity of closely related CHCl3 and BrCCl3 is also enhanced. Phenobarbital (PB, 225 ppm, 15 days) and mirex (10 ppm, 15 days) do not share the propensity of CD in this regard. Exposure to PB + CCl4 results in enhanced liver injury similar to that observed with CD, but the animals recover and survive in contrast to the greatly amplified lethality of CD + CCl4. Investigations have revealed that neither enhanced bioactivation of CCl4 nor increased lipid peroxidation offers a satisfactory explanation of these findings. Additional studies indicate that exposure to a low dose of CCl4 (100 microliters/kg, ip) results in limited injury, which is accompanied by a biphasic response of hepatocellular regeneration (6 and 36 hr) and tissue repair, which enables the animals to recover from injury. Exposure to CD + CCl4 results in suppressed tissue repair owing to an energy deficit in hepatocytes as a consequence of excessive intracellular influx of Ca2+ leading initially to a precipitous decline in glycogen and ultimately to hypoglycemia. Supplementation of cellular energy results in restoration of the tissue repair and complete recovery from the toxicity of CD + CCl4 combination. In contrast, only the early-phase hepatic tissue repair (6 hr) is affected in PB + CCl4 treatment, but this is adequately compensated for by a greater stimulation of tissue repair at 24 and 48 hr resulting in recovery from liver injury and animal survival. 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 CCl4. For instance, a 35-fold greater CCl4 sensitivity of gerbils compared to rats is correlated with the very sluggish tissue repair in gerbils. These findings are consistent with a two-stage model of toxicity, where tissue injury is inflicted by the well described "mechanisms of toxicity," but the outcome of this injury is determined by whether or not sustainable tissue repair response accompanies this injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Hepatic failure leads to lethality of chlordecone-amplified hepatotoxicity of carbon tetrachloride.

Chlordecone (Kepone) amplification of CCl4 toxicity occurs at small, nontoxic levels of chlordecone and CCl4 and results in highly increased irreversible hepatotoxicity culminating in lethality. Although it is generally assumed that CCl4 lethality is due to hepatic failure, no definitive studies are available in the literature bridging massive liver failure and death. The present studies were designed to evaluate whether hepatic failure is the cause of the lethality during chlordecone-amplified CCl4 toxicity. Male Sprague-Dawley rats were maintained on control or a chlordecone (10 ppm) diet for 15 days and injected with CCl4 (100 microliters/kg, ip) on Day 16. Rats were killed at 0, 6, 12, 24, 36, and 48 hr after CCl4 challenge. Hepatic failure was evaluated by measuring plasma glucose, ammonia, bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), sorbitol dehydrogenase (SDH), hepatic ATP, glycogen, and by histological and histomorphometric analyses. Plasma creatinine, urea, and kidney histopathology were also assessed for possible renal injury. As expected CCl4 administration to chlordecone-pretreated rats resulted in 20% lethality by 36 hr, which progressed with time, and all rats died within 72 hr. A significant and progressive hypoglycemia was observed with a 60% reduction in plasma glucose at 48 hr. Hepatic glycogen content dropped precipitously. Similarly, hepatic ATP levels remained suppressed (80% of control) at all the time points studied. Plasma ammonia levels were significantly elevated, and by 48 hr, a threefold increase was observed. Plasma ALT, AST, SDH, and bilirubin increased progressively until the death of rats receiving the chlordecone + CCl4 combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

G2 subpopulation in rat liver induced into mitosis by low-level exposure to carbon tetrachloride: an adaptive response.

Recent findings by Mehendale (Med. Hypoth. 33, 289-299, 1990) indicate that prior exposure to chlordecone markedly enhances CCl4-induced lethality. It was established that chlordecone suppressed the capacity of CCl4-induced toxicity to cause an early (i.e., 6 hr after exposure) hepatocellular division which is believed to be a critical tissue response reducing subsequent CCl4-induced hepatotoxicity. Despite the strong evidence presented by Mehendale, occurrence of such an early cellular division has been considered unlikely since most studies indicate that cellular replacement requires from 30-60 hr depending on the agent, dose, and animal species. This paper presents evidence that supports the observations of Mehendale and indicates that the early mitoses were most likely caused by the activation of hepatocytes arrested in the G2 phase of the cell cycle that became activated by CCl4 treatment, induced injury, or both. The concept being put forward here requires additional experimental verification and validation.

Animals↗
PubMed1993

Loss of calcium homeostasis leads to progressive phase of chlordecone-potentiated carbon tetrachloride hepatotoxicity.

Earlier work has shown increased hepatocellular free Ca2+ levels in rats receiving a single subtoxic dose of CCl4 after dietary pretreatment with nontoxic (10 ppm, 15 days) levels of chlordecone (CD), indicating a significant perturbation of Ca2+ homeostasis in the interactive toxicity of CD + CCl4 combination treatment. In the present study, the mitochondrial and microsomal ability to sequester Ca2+ as well as plasma membrane translocase activity was investigated, since it is known that cells maintain normal Ca2+ homeostasis by these mechanisms. Hepatic plasma membrane Ca(2+)-ATPase (high and low affinity components) as well as 45Ca uptake by mitochondria and microsomes was measured using a range of calcium concentrations in Ca(2+)-EGTA-buffered medium at different time points after a single ip administration of CCl4 (100 microliters/kg). Male Sprague-Dawley rats were maintained for 15 days either on a normal diet or on a diet containing 10 ppm CD prior to CCl4 injection. Hepatic plasma membranes, devoid of microsomal and mitochondrial contamination, were prepared using polyethyleneimine-coated beads. CD treatment alone did not significantly decrease the plasma membrane Ca(2+)-ATPase activity. Similarly, CCl4 treatment alone did not alter Ca(2+)-ATPase in hepatic plasma membranes at any concentration of free Ca2+ in assay medium employed in this study. The interactive combination treatment, however, resulted in significant, irreversible, and specific inhibition of the high affinity component of the hepatic plasma membrane Ca(2+)-ATPase at early time points. Low affinity Ca(2+)-ATPase was not affected with any treatment protocol. CD pretreatment alone significantly inhibited 45Ca uptake by mitochondria and microsomes when incubated at 10 microM and higher, concentrations much higher than normal cytosolic levels, but not at lower concentrations of Ca2+. CCl4 administration to both normal and CD-pretreated rats resulted in significant inhibition of microsomal and mitochondrial 45Ca uptake as early as 1 hr at all concentrations of free calcium. While the extent of inhibition was greater and irreversible after CD + CCl4 treatment, it was reversible after normal diet + CCl4 treatment. Phosphorylation of proteins was determined in order to investigate if the inhibition of microsomal 45Ca uptake during CD + CCl4 toxicity might be correlated to decreased phosphorylation of any particular protein involved in Ca2+ transport. SDS-polyacrylamide gel electrophoresis of microsomal protein revealed at least 30 Coomassie blue stainable bands. Of these, 6 bands were phosphorylated when microsomes were incubated with [32P]ATP.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Effect of antimitotic agent colchicine on carbon tetrachloride toxicity.

A single administration of a subtoxic dose of CCl4 (100 microliters/kg, i.p.) is known to induce hepatocellular regeneration and tissue repair at 6 and 48 h in rats, permitting prompt recovery from the limited liver injury associated with that dose of CCl4. Substantial evidence has accumulated to indicate that the early-phase hepatocellular regeneration and tissue repair are critical for recovery from halomethane hepatotoxicity. The objective of these studies was to test this concept in an experimental framework, wherein a selective ablation of the early-phase cell division should result in prolongation of liver injury followed by recovery. The studies were designed to evaluate the influence of the antimitotic agent colchicine (1 mg/kg, i.p. in saline) on CCl4 toxicity. Colchicine was administered 2 h prior to CCl4 or corn oil injection. Toxicological end points and markers of hepatocellular regeneration were assessed at various time points (2, 6, 12, 24, 48 and 72 h) after the injection of CCl4 to male Sprague-Dawley rats. Hepatocellular injury was assessed through elevations of serum alanine and aspartate aminotransferase and by histopathological examination of the liver. Incorporation of 3H-thymidine in hepatocellular nuclear DNA and mitotic index were used as indices of hepatocellular regeneration. Hepatocellular regeneration stimulated by CCl4 at 2-6 h was blocked by colchicine as evidenced by the decreased 3H-thymidine incorporation and mitotic index,without any significant effect on the second phase of cell division at 48 h. Ablation of this early phase of tissue repair resulted in prolongation of CCl4 hepatoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1993

Resiliency to amplification of carbon tetrachloride hepatotoxicity by chlordecone during postnatal development in rats.

The interactive hepatotoxicity of CCl4 and chlordecone, at an individually nontoxic dosage, was studied in neonatal and young developing rats. The well-documented amplification of CCl4 (100 microL/kg) hepatotoxicity and lethality by prior dietary exposure to chlordecone (10 ppm, for 15 d) was absent in neonatal and developing rats through 35 d of age. The chlordecone-potentiated hepatotoxicity and lethality of CCl4 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 chlordecone-treated 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 3H-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 CCl4, in terms of 14CO2 production derived from 14CCl4 and 14CCl4 metabolites bound to hepatic tissue, was not significantly different between 35-, 45-, and 60-d-old chlordecone-treated rats, whereas CCl4-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 CCl4 toxicity by chlordecone in postnatally developing rats is well correlated with the presence of ongoing and stimulatable hepatocellular regenerative activity.

Age Factors↗
PubMed1993

Halomethane-chlordecone (CD) interactive hepatotoxicity--current concepts on the mechanism.

Why is a low dose of toxic chemical nontoxic? What makes a larger dose of the same chemical toxic? Extensive work done to understand the mechanism of halomethane hepatotoxicity and its potentiation by chlorinated insecticide, chlordecone has resulted in the understanding of these basic tenets of toxicology. Studies suggest that ordinarily a small dose of halomethane causes limited liver injury which is accompanied by stimulated tissue repair enabling complete recovery from injury before manifestation. A large dose of halomethane becomes toxic due to suppressed tissue repair, which permits injury to progress in an unchecked fashion. Exposure to very low levels of chlordecone results in highly exaggerated toxicity of ordinarily nontoxic doses of halomethane because of suppressed hepatocellular regeneration and restoration, permitting the progression of liver injury ultimately resulting in liver failure and animal mortality. This concept is further supported by the observation that, while exposure to even high levels of phenobarbital and subsequent low nontoxic doses of halomethane results in greater level of initial liver injury, tissue repair is not completely suppressed; it is slightly postponed by 24 hr, but then much higher rate of tissue repair ensures and consequently enables the animals to completely recover from liver injury and survive. Thus, whether initiation of tissue repair processes occurs or not is the critical determinant in the ultimate manifestation of hepatotoxicity and its end result of either animal death or recovery and survival. Currently understood 'Mechanisms of toxicity' adequately explain only how toxic injury begins. These mechanisms do not permit us to predict the ultimate outcome of toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Ongoing hepatocellular regeneration and resiliency toward galactosamine hepatotoxicity.

In previous studies, we reported that the age-dependent hepatotoxicity of galactosamine (GalN) was evident in hepatocytes maintained in primary cultures. Cellular proliferation and tissue repair are not manifested in response to injury in this in vitro system. Neonatal (5-day) rats have ongoing hepatocellular proliferation in contrast to adult (5-month) rats, and should be therefore resilient to GalN toxicity. Liver injury was assessed by serum transaminases (ALT, AST), 3H-thymidine (3H-T) incorporation into nuclear DNA, and content of hepatocellular nuclear DNA. While the dose of 400 mg/kg did not cause any significant liver injury in the neonates, it did produce significant liver injury in adult rats. At a dose of 800 mg/kg, GalN produced significant injury in the neonates. Because 400 mg/kg causes clearly demonstrable liver injury in the adult and no injury in the neonates, this dose was used for further studies. In addition to the above measures of injury, uracil nucleotides (UTP, UDP, and UMP), glycogen, histopathology, and autoradiographic examination of liver sections were used to assess the liver injury in neonatal and adult rats. In a time-course study, all of the above were measured at 0, 12, 24, 36, 48 and 72 h after GalN administration. Serum enzyme elevations as well as the appearance of necrotic and swollen hepatocytes were maximal at 24 h in the adults rats. In contrast to these observations in the adult rats, none of these measurements indicated significant liver injury in the neonates. 3H-T incorporation into nuclear DNA was much higher in the neonatal liver in comparison to the adults reflecting the difference in regeneration. Hepatocellular nuclear DNA was also higher in the neonate and was significantly decreased due to GalN treatment. In the adult rats, the quiescent normal level of 3H-T incorporation and nuclear DNA content were further decreased at 12 h, increased at 48 h and returned to normal low, quiescent levels at 72 h. In the neonates mitotic activity of hepatocytes was higher than in the adult rats. In the adult rats, mitotic activity was increased at 48 h after GalN administration and returned to normal at 72 h. In the neonates GalN did not alter the mitotic activity significantly. These findings demonstrate that in the presence of hepatocellular regeneration, galactosamine toxicity is minimal while in the absence of it, clear toxicity is manifested. In conclusion, while perturbation in uracil nucleotides and related biochemical events may explain the infliction of liver injury by GalN in an age-dependent fashion, the extent of tissue repair impacts decisively on the final outcome of injury.

Aging↗