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Biomedical subjects

H M Mehendale

Publications and source records attributed to H M Mehendale.

At least 127 records · Page 7Linked to original sources
PubMed1986

Effect of chlordecone on carbon tetrachloride-induced increase in calcium uptake in isolated perfused rat liver.

Intracellular accumulation of Ca2+ can occur in the livers of animals poisoned with a toxic dose of CCl4. We have reported even greater accumulation of cytosolic Ca2+ in animals treated with an ordinarily nontoxic dose of CCl4 in combination with prior exposure to chlordecone (CD). Present studies were designed to examine if intact perfused livers obtained from animals receiving either CCl4 (100 microliter/kg, ip) alone or in combination with prior dietary exposure to 10 ppm CD for 15 days accumulated 45Ca from the perfusate. Livers obtained at 0, 1, 4, 6, 12, 24, and 36 hr after a single CCl4 injection were perfused with Krebs-Ringer bicarbonate buffer containing erythrocytes, bovine serum albumin, and dextrose. After a 15-min equilibration, 45Ca was added to the perfusate, and the perfusion was continued for 30 min. Hepatic 45Ca accumulation in CCl4-treated animals in the whole liver or in the subcellular organelles obtained from perfused liver was not significantly different from corn oil controls. In the CD + CCl4 combination treatment, 45Ca accumulation followed a biphasic pattern with the first increase at 1 hr and then a progressive rise starting at 12 hr after CCl4 administration. Mitochondrial, microsomal, and cytosolic fractions from perfused liver showed a progressive rise in 45Ca at late time periods, which is indicative of unregulated and irreversible influx of extracellular Ca2+ into these livers. These studies demonstrate that cytosolic Ca2+ progressively increases as a result of the unregulated entry of extracellular Ca2+.

Administration, Oral↗
PubMed1986

Effect of endrin and endrin derivatives on hepatobiliary function and carbon tetrachloride-induced hepatotoxicity in male and female rats.

The effects of the cyclodiene pesticide, endrin, and its aldehyde and ketone metabolites on hepatobiliary function and CCl4-induced hepatotoxicity were investigated in Sprague-Dawley rats. The rats were given control diet or diets containing 5 or 10 ppm endrin, 10 ppm endrin aldehyde or 5 ppm endrin ketone for 15 days. Three to six rats from each treatment group were given a single ip dose (100 microliter/kg body weight) of CCl4 in corn oil (1 ml/kg) on day 15. Levels of serum glutamic-oxalacetic transaminase (SGOT), glutamic-pyruvic transaminase (SGPT), isocitrate dehydrogenase and ornithine-carbamyl transferase, bile flow and biliary excretion of an anionic model compound, phenolphthalein glucuronide (PG), were measured on day 16. Dietary treatment with endrin at either dose level did not significantly elevate serum enzyme levels, while endrin aldehyde produced a slight increase in SGOT and SGPT and endrin ketone produced a small elevation in SGPT levels. Treatment with endrin aldehyde or endrin ketone did not result in significant alterations of bile flow or biliary PG excretion. Treatment with 5 ppm endrin produced a significant reduction in bile flow and a corresponding reduction in PG excretion by male rats, whereas treatment with 10 ppm endrin reduced only the PG excretion by male rats. Female rats treated with 5 or 10 ppm endrin showed a dose-dependent choleretic effect with a commensurate increase in PG excretion. With the exception of a further slight reduction in PG excretion by male rats, treatment with the endrin or endrin derivative did not potentiate CCl4-induced alterations in hepatobiliary functions. Although the levels of some serum enzymes of rats given endrin or endrin derivatives plus CCl4 were elevated over those of rats given CCl4 alone, the increases were not of the magnitude of those that have been reported previously for chlordecone. Generally, female rats challenged with CCl4 or endrin/CCl4 exhibited greater increases in serum enzyme levels than did male rats given corresponding treatments.

Alanine Transaminase↗
PubMed1986

Pulmonary synthesis of 5-hydroxytryptamine in isolated perfused rabbit and rat lung preparations.

The present investigation was designed to determine the pulmonary biosynthesis of 5-hydroxytryptamine (5-HT) from L-tryptophan. Artificially ventilated, isolated rabbit and rat lungs were perfused with a constituted medium. Tryptophan and its metabolites were detected by high pressure liquid chromatography using an electrochemical detector. 14C-tryptophan uptake by the rabbit lung was 5.6% and 3.9% in the rat lung after 1 hr of perfusion. The perfusate (100 ml) concentrations of 5-hydroxytryptophan and 5-hydroxytryptamine increased significantly (1.1 to 1.8 micrograms 5-HT and 4.4 to 6.5 micrograms 5-HTP) during rabbit lung perfusion. However, no metabolites were detected in the perfusate during rat lung perfusion. 5-Hydroxytryptamine and 5-hydroxyindoleacetic acid levels were greater in both rabbit and rat lungs when they were perfused with 0.4 mM tryptophan, compared to their levels in lungs perfused without tryptophan. The increase of 5-HT content in rat lung alone was statistically significant. 5-Hydroxytryptophan was not detected in the rabbit or rat lungs. These results suggest the presence of a mechanism for tryptophan metabolism in lung, similar to that in brain and gastrointestinal tract. However, since the rate of pulmonary metabolism of tryptophan is very low, pulmonary synthesis of 5-HT from tryptophan and its contribution to the circulating 5-HT pool is unlikely to be of significance.

5-Hydroxytryptophan↗
PubMed1986

Pulmonary sequestration of amiodarone and desethylamiodarone.

We hypothesized that one of the reasons for the particular susceptibility of the lung toward the adverse effects from the antiarrhythmic agent amiodarone (A) could be a high pulmonary accumulation of this drug. This hypothesis was tested using the isolated perfused lungs of Fischer 344 and Sprague-Dawley rats and New Zealand White rabbits. Uptake of a 3 microM starting concentration of a mixture of A and [14C]A by the lung occurred rapidly in each species, and only 25.6, 19 and 16.4% of the initial concentration remained in the perfusate at the end (60 min) of the experiment in Fischer 344, Sprague-Dawley rats and rabbits, respectively. No metabolism of A was detected by the high-performance liquid chromatography technique. Raising the initial concentration of A from 0.3 to 120 microM (n = 26) in the Fischer 344 rats apparently did not saturate the uptake process, and the tissue/medium ratio averaged 122.5. The uptake of desethylamiodarone (DEA), the main metabolite of A in vivo, was more extensive (tissue/medium ratio = 506) than that of the parent compound. DEA also was not metabolized by the isolated perfused lungs. Lung homogenate incubations fortified with cofactors did not metabolize A or DEA. We conclude that in the isolated perfused lungs: A is extensively taken up by the lungs of rats and rabbits; the uptake is not saturated by raising the concentrations over a 400-fold range; DEA is taken up more readily than A; and metabolism of neither compound is observed.

Amiodarone↗
PubMed1986

Neurotoxicity in rats following subchronic amiodarone treatment.

Rats were treated with amiodarone (20 mg/kg/day) up to 6 weeks and the neurotoxicity was assessed by determining changes in motor coordination, pain-threshold and rectal temperature every week during treatment. Body weight gain was decreased during amiodarone treatment and it was significant at and after 5 weeks. Food intake and water consumption were significantly reduced during treatment. After the first week of treatment with amiodarone, rats showed decreased ability to balance on horizontal rods. In the hot plate test (paw-lick), the amiodarone treated rats showed increased pain-thresholds throughout the treatment. Hypothermia was significant only at 6 weeks. These results show that amiodarone causes toxicity in rats and this model might be useful for further studies. Decreased motor-coordination, and increased pain-responding times may indicate development of peripheral neuropathy in addition to muscle weakness.

Amiodarone↗
PubMed1985

Accumulation of Ca2+ induced by cytotoxic levels of menadione in the isolated, perfused rat liver.

Previous studies have indicated that the presence of cytotoxic levels of menadione (2-methyl-1,4-naphthoquinone) causes rapid changes in intracellular thiol and Ca2+ homeostasis in isolated rat hepatocytes. The present investigation was undertaken to examine these effects in the intact liver. Rat livers were therefore perfused with Krebs-Henseleit buffer containing 1.3 mM Ca2+ using a single-pass mode, and the perfusate Ca2+ level was monitored with an on-line Ca2+-selective electrode. Infusion of menadione elicited an increased O2 uptake by the liver, followed by a dose-dependent decrease in the perfusate level of Ca2+. Hepatic accumulation of Ca2+ was accompanied by stimulation of cytosolic phosphorylase a activity. Cessation of menadione infusion resulted in gradual recovery of perfusate Ca2+ to base levels. Ca2+ uptake was not accompanied by decreases in reduced pyridine nucleotide or ATP levels in the liver as evidenced by measurements either during maximal Ca2+ uptake or after recovery. However, Ca2+ uptake was correlated with decreased glutathione and increased glutathione disulfide levels in the liver, both of which reversed during recovery from Ca2+ uptake. Moreover, depletion of hepatic glutathione by pretreatment with diethylmaleate resulted in increased Ca2+ uptake during menadione infusion. The amount of protein-bound mixed disulfides showed a particularly striking relationship to Ca2+ uptake, reaching a maximal level during Ca2+ uptake and reversing toward normal value during recovery from Ca2+ accumulation. The present findings suggest that menadione-induced Ca2+ uptake is due to plasma membrane dysfunction as a result of loss of protein thiol groups critical for maintaining the plasma membrane Ca2+ extrusion mechanism. Our model offers a particularly useful opportunity to study mechanisms underlying toxic disturbances in Ca2+ homeostasis in the intact liver, since Ca2+ fluxes can be monitored under conditions in which cellular control mechanisms are not obliterated by excessive toxicity.

Animals↗
PubMed1985

The effect of dietary exposure to a mirex plus chlordecone combination on CCl4 hepatotoxicity.

The purpose of these studies was to investigate the effect of a mirex plus chlordecone combination on CCl4-induced hepatotoxicity. Male Sprague-Dawley rats were maintained on control diet or on diets containing 10 ppm chlordecone (CD), 10 ppm mirex (M), or M plus CD (10 ppm each; MCD) for 15 days. On Day 15 the rats received a single ip injection of CCl4 (100 microliters/kg) and hepatotoxicity was assessed 24 hr later. Animals in the control group receiving CCl4 alone were unaffected. Significant increases in liver-to-body weight ratios were observed in all three pretreatment groups following CCl4 challenge. Increases in serum enzymes (SGPT, SGOT, and ICD) occurred in all three pretreatment groups with CD = MCD greater than M greater than control. While MCD and CD pretreatment led to significant cholestasis and decreases in PG excretion, no such effect was observed with M. Light microscopic examination of tissues revealed swollen hepatocytes (balloon cells), hepatocellular necrosis, and lipid accumulation in the MCD, CD, and M groups following CCl4 challenge. In summary, as assessed by serum enzyme elevation, biliary flow and hepatic excretory function, M pretreatment led to only a slight increase in CCl4 hepatotoxicity. The MCD combination pretreatment did not potentiate hepatotoxicity above that seen with CD alone. These results provide additional evidence that CD pretreatment results in a rather specific sensitization of animals to CCl4 toxicity in ways independent of the actions of M.

Alanine Transaminase↗
PubMed1984

Excessive hepatic accumulation of intracellular Ca2+ in chlordecone potentiated CCl4 toxicity.

The possible role of Ca2+ in chlordecone potentiation of CCl4 hepatotoxicity was examined in male Sprague-Dawley rats. The rats were maintained on a diet containing either 0, 10, 25, 50 or 100 ppm chlordecone for 15 days. On day 15, they received a single i.p. injection of corn oil (1 ml/kg) or CCl4 (100 microliter/kg) in corn oil vehicle. The animals were killed at 1, 6, or 12 h after the oil or CCl4 challenge for hepatic Ca2+ determinations. Ca2+ in whole liver, mitochondria, microsomes or in cytosolic fraction was unaltered in any group of animals receiving chlordecone + oil treatments, indicating that chlordecone alone does not alter whole liver content or hepatic subcellular distribution of Ca2+, even after exposure to toxic levels (50 or 100 ppm). Administration of CCl4 at an otherwise non-toxic dose to chlordecone treated animals resulted in significant increases of whole liver and subcellular Ca2+ as compared to chlordecone alone and CCl4 alone with a characteristic biphasic response. These increases were significant at all 3 time points in whole liver, cytosolic and mitochondrial fractions. Microsomal Ca2+ increased only at 12 h after CCl4. The increases were all progressive with increases in dietary levels of chlordecone, indicating that chlordecone-induced sensitivity is responsible for CCl4 elicited perturbations in whole liver and intracellular Ca2+ levels. This study suggests that chlordecone modifies the liver plasma membrane to amplify the CCl4 elicited perturbations in hepatocellular Ca2+ homeostasis especially during 6-12 h after CCl4 administration. This perturbation of Ca2+ homeostasis may be related to the arrested repair and regeneration of damaged liver tissue leading to progressive deterioration observed in previous histomorphometric studies.

Animals↗
PubMed1984

CCl4-induced alterations in Ca++ homeostasis in chlordecone and phenobarbital pretreated animals.

Male S-D rats were maintained on normal powdered diet or on the same diet containing 10 ppm chlordecone or 225 ppm phenobarbital for 15 days. On day 15, all the animals received a single ip injection of either corn oil or a subtoxic dose of CCl4 (25-200 microliter/kg) in corn oil vehicle (1 ml/kg). The animals were sacrificed 12 hrs later. Liver microsomal cytochrome P-450 and Ca++ levels in whole liver, mitochondria, microsomes and cytosol were determined. Cytochrome P-450 induction was greater with phenobarbital pretreatment than with chlordecone but the CCl4 induced destruction of cytochrome P-450 was almost similar in both groups and progressive with the dose of CCl4. CCl4 given to animals on normal diet in a dose range of 25-200 microliter/kg did not significantly alter the cytochrome P-450 levels. These findings are consistent with greater bioactivation of CCl4 after the above two pretreatments. There was a massive accumulation of Ca++ in chlordecone and phenobarbital pretreated animals after CCl4 administration. Cytosolic Ca++ levels remained high despite the mitochondrial and microsomal sequestration. This perturbation of hepatocellular Ca++ homeostasis might lead to hepatic lesion and hepatic failure. Chlordecone or phenobarbital alone do not alter hepatic Ca++ levels. These findings suggest that excessive accumulation of Ca++ may be causally related to the progression of hepatotoxic response due to CCl4 in chlordecone treated animals.

Animals↗
PubMed1984

Effect of chlorphentermine pretreatment on the distribution of chlorphentermine in isolated perfused rat lungs.

Previous studies have shown that a 7-day treatment of rats with chlorphentermine (CP) enhances total pulmonary phospholipids and significantly enhances the accumulation of CP in perfused lungs. This study was conducted to determine if the accumulation of CP was associated with a particular fraction of the lung, and if the enhanced uptake correlated with the increased phospholipids. Rats were treated daily for 7 days with 50 mg/kg CP dissolved in saline and pair-fed controls received the vehicle only. On Day 8, the rats were sacrificed, and the lungs were removed, ventilated, and perfused. [14C]Chlorphentermine (5 mumol) was added to the perfusate of control and CP-pretreated lungs. After perfusion, the lung was homogenized and subjected to standard fractionation procedures. Some lungs were examined by light and electron microscopy. After 60 min of perfusion, CP uptake by lungs obtained from CP-treated rats was enhanced in comparison to uptake by lungs from control rats. However, CP was distributed uniformly among subcellular fractions, and CP pretreatment did not alter this pattern. Pulmonary macrophages obtained from CP-treated animals contained 8 times more CP than controls. Increased CP uptake following pretreatment can be accounted for by increased CP in the macrophages of treated rats. Macrophages in the lung tissue and in the lavage fluid from rats treated with CP were more numerous and larger than in controls lungs. This suggests that a close association may be found between accumulated CP and macrophage uptake.

Animals↗
PubMed1984

Potentiation of halomethane hepatotoxicity: chlordecone and carbon tetrachloride.

The propensity for chlordecone to potentiate hepatotoxicity of CCl4 and some related analogs (CHCl3 and CBrCl3) has been well established. The interaction results in potentiation of halomethane hepatotoxicity at incredibly small, nontoxic levels of chlordecone and these halomethanes. Biological effects of such interactions include extensive hepatotoxicity characterized by total hepatic failure as determined by histopathological alterations, hepatic dysfunction, elevation of serum enzymes, and perturbation of related biochemical parameters. The chlordecone + CCl4 interaction occurs in animals of both sexes and is characterized by profoundly potentiated lethality. Close structural analogs of chlordecone such as mirex and photomirex do not share the propensity of chlordecone to potentiate halomethane toxicity. The mechanism of this potentiation of halomethane hepatotoxicity has eluded several investigations. Induction of microsomal P-450 by chlordecone and greater lipid peroxidation appear inadequate to explain the powerful potentiation of toxicity. Time-course studies in which liver tissue was examined 1 to 36 hr after CCl4 administration to chlordecone treated animals revealed possible mechanisms. It appears that a greater bioactivation of CCl4 in chlordecone treated animals resulted in an initial potentiation of toxic events in the liver cells. While animals receiving a normally nontoxic dose of CCl4 alone demonstrate repair and renovation of liver tissue as revealed by greatly increased mitotic index after 12 hours, such a renovation process is totally suppressed in animals exposed to chlordecone. Thus, a combination of initial greater injury along with prevention of hepatocellular repair and renovation appears to play a key role in the potentiation of liver injury. The greater initial liver injury is consistent with enhanced metabolism and bioactivation of CCl4 in chlordecone exposed animals. The mechanism of suppressed cellular mitosis is less clearly understood. Recent studies have revealed a greater perturbation of intracellular Ca2+ homeostasis in chlordecone treated animals and this observation is consistent with continued destruction and cellular damage. These observations point to more than a single factor involved as underlying mechanisms and two such mechanisms are consistent with the available information. First, chlordecone induction of a specific form of P-450 capable of greater bioactivation of CCl4. Second, chlordecone sensitization of hepatocellular plasma membrane for excessive accumulation of intracellular Ca2+.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Chlordecone potentiation of CCl4 hepatotoxicity in ovariectomized rats.

Previous reports from this laboratory have established the propensity of chlordecone to potentiate the hepatotoxicity and lethality in male and female rats. The present study was designed to investigate the hepatotoxicity of CCl4 in chlordecone (CD) pretreated, ovariectomized rats. Ten days after bilateral ovariectomy, the rats were maintained on a dietary protocol of either 0 or 10 ppm chlordecone and on the day 15, they received a single i.p. injection of either corn oil (1 ml/kg) or 25 microliter CCl4/kg in corn oil. Hepatic function, serum enzyme levels and histopathological changes were assessed 24 h after CCl4 challenge as functional biochemical, and morphological parameters of hepatotoxicity. Hepatobiliary function was markedly impaired and serum enzyme levels were elevated in ovariectomized rats receiving the same treatment but not significantly different from normal females receiving the chlordecone and CCl4 combination. Histological findings indicated a greater degree of centrilobular hepatic necrosis accompanied by extensive fatty infiltration. This study suggests that chlordecone sensitizes the liver in ovariectomized rats as well to amplify the toxic effects of CCl4.

Animals↗
PubMed1984

Species differences in pulmonary N-oxidation of chlorpromazine and imipramine.

Our previous studies have demonstrated that chlorpromazine (CPZ) and imipramine (IMP) are metabolized appreciably via N-oxidation catalyzed by pulmonary microsomal flavin monooxygenase in the rat but not in the rabbit. The present work deals with the species differences in N-oxidase of pulmonary microsomes from male cat, dog, goat, guinea pig, hamster, mouse, pig, rabbit and rat. Although CPZ-N-oxidizing activities were generally higher than IMP-N-oxidizing activities, the CPZ-/IMP-oxidizing activity ratios were not constant among the species tested. Little or no activity was detected in the guinea pig and rabbit lung. The following ranking was assigned: mouse less than hamster less than pig less than rat less than dog less than cat less than guinea pig less than goat less than rabbit for CPZ, and pig less than rat less than mouse less than dog less than hamster less than cat less than guinea pig less than goat less than rabbit for IMP. Nitrosobenzene, a known inhibitor of N-oxidase reductase, inhibited rather than increasing the N-oxidation of both substrates. Therefore, it is unlikely that the marked species differences in pulmonary N-oxidase activities are due to differences in N-oxide reductase. Optimum pH for CPZ-N-oxidase was relatively broad over a range of 7.4-8.5 for rat and 8-9.5 for other species. The pH optima for IMP-N-oxidase ranged from 8.5 to 9.5. n-Octylamine accelerated CPZ-N-oxidation in most species. IMP-N-oxidation was affected to a lesser extent by this primary amine. DPEA (2,4-dichloro-6-phenyl- phenoxyethylamine ) also stimulated the CPZ-N-oxidation in rat, pig and cat but inhibited IMP-N-oxidation in these species.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Perturbation of calcium homeostasis by CCl4 in rats pretreated with chlordecone and phenobarbital.

Male Sprague-Dawley rats were maintained on normal powdered diet or on the same diet containing 10 ppm chlordecone (CD) or 225 ppm phenobarbital (PB) for 15 days. On day 15, they received a single IP injection of a subtoxic dose of CCl4. Induction of cytochrome P-450 was greater with phenobarbital treatment than with chlordecone, but the CCl4-induced destruction of P-450 was similar in both groups and was progressive with the dose of CCl4 and with time after CCl4 administration. CCl4 given to animals on normal diet in a dose range of 25 to 200 microL/kg did not significantly alter the P-450 levels. These findings are consistent with greater bioactivation of CCl4 after the above two pretreatments There was a massive accumulation of Ca2+ in CD- and PB-pretreated animals after CCl4 administration, CD being more effective in this regard. Elevation of cytosolic Ca2+ was progressive despite the mitochondrial and microsomal sequestration of cytosolic Ca2+ at elevated levels. This perturbation of hepatocellular Ca2+ homeostasis which occurs 3 to 6 hr after CCl4 may prevent hepatocellular repair and renovation in CD-treated animals, leading to progressive hepatic lesion, hepatic failure and animal death by 36 to 48 hr at nontoxic doses of CCl4. Neither CD nor PB nor CCl4 alone affected hepatic Ca2+. These findings suggest that excessive Ca2+ accumulation may be related to the progression of hepatotoxic response to CCl4 in CD-treated animals.

Animals↗
PubMed1984

Pulmonary disposition and effects of drugs on pulmonary removal of endogenous substances.

Pulmonary sequestration of drugs and other xenobiotics is known to affect respiratory and nonrespiratory functions of the lung and may be causally related to drug-induced pulmonary disease. We employed chlorphentermine (CP), an anorexic drug of amphiphilic physicochemical properties, to unravel possible mechanisms underlying drug-induced pulmonary hypertension associated with this class of drugs. In isolated perfused lungs, CP interferes with pulmonary clearance of 5-hydroxy tryptamine (5-HT) and norepinephrine. Pulmonary uptake and metabolism of 5-HT are inhibited by CP in rabbit and rat lungs. In in vitro incubations, CP is a powerful inhibitor of pulmonary monoamine oxidase activity. When pulmonary metabolism of 5-HT was blocked by pargyline, CP also inhibited pulmonary uptake of 5-HT. These effects of CP can be demonstrated in vivo in rabbits and rats during a single pulmonary passage of radio-labeled 5-HT. Not all pneumophilic drugs interfere with pulmonary clearance of 5-HT, as illustrated by the lack of effects by chlorpromazine and propranolol despite their pulmonary accumulation to a significant extent. Pulmonary accumulation of the chlorinated analogs such as chlomipramine and CP is greater than their nonchlorinated congenors, and this is in agreement with their ability to impede pulmonary clearance of 5-HT. These studies suggest that the electrophilic chlorine substitution increases the affinity of these chemicals for lung tissue, which increases the likelihood of their interference with the pulmonary disposition of 5-HT.

Animals↗
PubMed1984

Lack of effects of chlordecone on synthesis rates, steady state levels and metabolites of catecholamines in rat brain.

Reports on effects of chlordecone on brain catecholamine concentrations have been inconsistent. Because various studies indicate the potential for toxic effects on neurotransmitter systems, the following study was performed to assess effects of chlordecone on brain adrenergic systems. Male Sprague-Dawley rats dosed once with chlordecone at 100 mg/kg were sacrificed after 24 hr, then brain norepinephrine (NE) and dopamine (DA) levels were assayed. Another group was fed chlordecone at 10 mg/kg for 10 days. Additionally, animals treated with 10 mg/kg/day were injected iv with 3H-tyrosine at two intervals prior to sacrifice in order to estimate NE and DA synthesis rates. Whole brain concentrations of NE, DA, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylglycol sulfate (MOPEG-SO4) were measured. No changes were observed in whole brain catecholamine or metabolite concentrations, nor in NE or DA synthesis rates. In another experiment, administration of chlordecone (10 mg/kg for 10 days) was found not to alter the rate of incorporation of 3H-tyrosine into NE or DA in any brain area tested. Results suggest that the initial functional deficits responsible for neurological symptoms do not result from inhibition of synthesis and transport of brain catecholamines.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Destruction of hepatic mixed-function oxygenase parameters by CCl4 in rats following acute treatment with chlordecone, Mirex, and phenobarbital.

Previous work has established the marked potentiation of CCl4 hepatoxicity by prior exposure to chlordecone (CD). This study was conducted to determine if prior exposure to CD results in enhancement of CCl4-induced destruction of the hepatic microsomal mixed-function oxygenase (MFO) system. Male Sprague-Dawley rats received a single oral dose of CD (10 mg/kg) or corn oil vehicle alone (1 ml/kg) 24 hr prior to a single ip injection of CCl4 (0-100 microliter/kg). Mirex (M; 10 mg/kg) and phenobarbital (PB; 80 mg/kg/day for two days) were used as negative and positive controls respectively for the potentiation of CCl4 hepatotoxicity. Hepatotoxicity was evaluated 24 hrs after CCl4 administration by elevations of three serum enzymes (GPT, GOT, and ICD). The key hepatic microsomal MFO parameters measured were microsomal protein, cytochrome P-450 content, glucose-6-phosphatase (G-6-Pase), and aminopyrine demethylase (APD). As previously demonstrated using a subchronic dietary pretreatment protocol, CD potentiated CCl4 hepatotoxicity over a range of CCl4 doses to a greater extent than PB or M, as judged by elevations in serum enzymes. PB caused the greatest increase in total P-450 content and the greatest increase in CCl4-mediated destruction of microsomal protein and APD activity. M caused the least destruction of total hepatic cytochrome P-450, despite the same level of cytochrome P-450 as in the PB group. CD treatment caused the greatest decrease in G-6-Pase activity in comparison to PB or M pretreatments and a similar degree of P-450 destruction as observed with the PB group. These findings suggest that in general, CCl4-induced destruction of hepatic MFO parameters measured in this study is disproportional to the known degree of potentiated hepatotoxicity by the pretreatments and does not accurately reflect the potentiation of CCl4 hepatotoxicity by CD.

Alanine Transaminase↗