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H M Mehendale

Publications and source records attributed to H M Mehendale.

At least 109 records · Page 6Linked to original sources
PubMed1989

Mechanism of the lethal interaction of chlordecone and CCl4 at non-toxic doses.

There is significant interest in the possibility of unusual toxicity due to interaction of toxic chemicals upon environmental or occupational exposures even though such exposures may involve levels ordinarily considered harmless individually. While many laboratory and experimental models exist for such interactions, progress in this area of toxicology has suffered for want of a model where the interactants are individually non-toxic. We developed such a model where prior exposure to non-toxic levels of the pesticide Kepone (chlordecone) results in a 67-fold amplification of CCl4 lethality in experimental animals. The mechanism(s) by which chlordecone amplifies the hepatotoxicity of halomethanes such as CCl4, CHCl3, and BrCCl3 has been a subject of intense study. The biological effects of this interaction include extensive hepatotoxicity characterized by histopathological alterations, hepatic dysfunction, and perturbation of related biochemical parameters. Close structural analogs of chlordecone such as mirex and photomirex do not share the propensity of chlordecone to potentiate halomethane toxicity. Mechanisms such as induction of microsomal cytochrome P-450 by chlordecone and greater lipid peroxidation are inadequate to explain the remarkably powerful potentiation of toxicity and lethality. Time-course studies in which liver tissue was examined 1-36 h after CCl4 administration were conducted. While animals receiving a normally nontoxic dose of CCl4 alone show limited hepatocellular necrosis by 6 h, proceeding to greater injury after 12 h, recovery phase ensues as revealed by greatly increased number of mitotic figures. Such regeneration and hepatic tissue repair processes are totally suppressed in animals exposed to chlordecone prior to CCl4. Thus, the arrested hepatocellular repair and renovation play a key role in the potentiation of CCl4 liver injury by chlordecone. These findings have allowed us to propose a novel hypothesis for the mechanism of chlordecone amplification of halomethane toxicity and lethality. While limited injury is initiated by the low dose of CCl4 by bioactivation followed by lipid peroxidation, this normally recoverable injury permissively progresses due to arrested hepatocellular regeneration and tissue repair processes. Recent studies designed to test this hypothesis have provided additional supporting evidence. Hepatocellular regeneration stimulated by partial hepatectomy was unaffected by 10 ppm dietary chlordecone, while these animals were protected from the hepatotoxic and lethal actions of CCl4 if administered at the time of maximal hepatocellular regeneration. The protection was abolished when CCl4 was administered upon cessation of hepatocellular regeneration.

Animals↗
PubMed1989

Effects of drug-induced pulmonary phospholipidosis on lung mechanics in rats.

Chronic administration of amphiphilic drugs to rats induces pulmonary phospholipidosis (P), a disease characterized by accumulation of phospholipids and large foamy macrophages in alveolar spaces. We investigated whether P induced by chlorphentermine (CPH) causes changes in lung volumes and mechanics in this species. Groups of rats were fed CPH (50 mg.kg-1.day-1) for 1, 2, 3, 5, 9, and 14 wk. After each treatment period, lung volumes and mechanics were studied in the anesthetized, paralyzed, supine rat. Partial pressure-volume (PV) curves were developed at 3 and 6 ml above functional residual capacity (FRC; PV3, PV6), followed by maximal [up to total lung capacity (TLC)] PV curves. FRC was determined by saline displacement. Lungs were then fixed for histopathological examination. A subgroup of animals was allowed a recovery period of 6 wk, after the 9 wk of CPH administration. Pair-fed rats served as controls (CTR) at each time point. Lung weight increased in CPH-treated (CPH-T) rats from 1.5 +/- 0.2 (SD) g at week 1 to 5.8 +/- 1.4 g at week 14, reflecting the development of P. TLC, FRC, transpulmonary pressure at FRC, the shape of maximal PV curves, and static expiratory lung compliance computed from maximal PV data points did not change in CPH-T rats. However, partial PV curves of CPH-T lungs (particularly PV3) were shifted downward and to the right of those of CTR at 2, 3, 5, and 9 wk, indicating increased recoil pressure in phospholipidotic lungs at these time points.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Protection of hepatotoxic and lethal effects of CCl4 by partial hepatectomy.

CCl4 is a hepatotoxic haloalkane, capable of producing hepatocellular fatty degeneration and centrilobular necrosis. Previous reports indicate induction of liver regeneration after 36-48 hr of CCl4 treatment, which is considered as a secondary effect. The present investigation was undertaken to evaluate the primary effects of CCl4 on hepatic DNA synthesis and to correlate liver regeneration with CCl4 toxicity. These studies were conducted in normal and actively regenerating livers using male Sprague-Dawley rats undergoing sham operation (SH), or partial (70%) hepatectomy (PH). Incorporation of 3H-thymidine (3H-T) in hepatocellular nuclear DNA and autoradiographic analyses of liver sections served as indices for hepatocellular regeneration. Initial experiments established that peak regeneration occurs at 2 days post-PH (PH2) and liver regeneration phases out by 7 days post-PH (PH7). SH and PH rats were challenged with a single ip dose of either corn oil vehicle or CCl4 at either 0.1 ml/kg (to represent subtoxic dose) or 2.5 ml/kg (to represent toxic dose). The low dose of CCl4 was not toxic and did not alter 3H-T incorporation and percentage labelled cells at 6 or 24 hours after administration to SH, PH2 or PH7 groups, indicating that there was no interference with PH-stimulated hepatocellular regeneration. The high dose of CCl4 was significantly hepatotoxic and lethal in SH rats, while in PH2 rats both hepatotoxic and lethal effects were significantly decreased. 3H-T incorporation as well as percentage labelled cells, highly stimulated by PH, were significantly decreased by high dose of CCl4. However, hepatocellular regeneration in PH2 rats treated with high dose of CCl4 was still significantly higher than SH or PH7 groups by virtue of the stronger stimulatory effect of PH. In PH7 rats, where hepatocellular regeneration had returned to the SH level, the hepatotoxic and lethal effects of the large dose of CCl4 were also restored. These findings show that the progressive phase of a single high dose of CCl4 injury which normally culminates in hepatotoxic and lethal effects is significantly mitigated by previously stimulated hepatocellular regeneration. High dose of CCl4 suppresses hepatocellular regeneration at early time points after administration in contrast to the smaller subtoxic dose of CCl4. By virtue of the much stronger stimulatory effect, PH results in the protection against the hepatotoxic and lethal effects of CCl4 despite the obtunding effects of the high dose on hepatocellular regeneration.

Alanine Transaminase↗
PubMed1988

Passive sequestration of putrescine, spermidine and spermine by rat lungs.

The pulmonary uptake and accumulation of the three polyamines putrescine, spermidine and spermine by isolated ventilated and perfused rat lungs was investigated using 0.1, 1 or 5 mM concentrations of these compounds. The lung uptake of putrescine for all concentrations was greater than that of spermidine and spermine, but all three showed concentration-dependent linear uptake. A significant uptake of all three polyamines was also observed when incubated separately with rat lung slices for 60 min. Harmaline (0.4 mM), ouabain (0.2 mM) and perfusate with decreased Na+ (50 mEq/l) did not affect the uptake of any of the three polyamines by isolated perfused rat lungs or rat lung slice incubations. HPLC analysis of the whole lung or slices and media after perfusion or incubation studies, respectively, with polyamines did not reveal the presence of any metabolites. Likewise, the analysis of the lung homogenate incubated at 37 degrees C for 60 min with polyamines did not show any metabolites, confirming the absence of detectable pulmonary metabolism. These findings indicate a significant accumulation of polyamines in the rat lungs, accumulation predominantly occurring via simple diffusion, at variance with the reported active polyamine uptake process in the lung.

Animals↗
PubMed1988

Protection of chlordecone-potentiated carbon tetrachloride hepatotoxicity and lethality by partial hepatectomy.

Chlordecone (CD) pretreatment is known to markedly potentiate CCl4 hepatotoxicity. Previous studies have shown that prior exposure to CD obtunds the increased hepatocellular regeneration and repair observed in non-treated rats challenged with a single, low dose of CCl4. These observations allowed us to hypothesize that suppression of hepatic regeneration and tissue repair by CD + CCl4 combination treatment might be involved in this interaction. To test this hypothesis, CCl4 hepatotoxicity was evaluated in actively regenerating livers using CD-treated (10 ppm in the diet for 15 days), surgically partially hepatectomized (PH) male Sprague-Dawley rats. Rats undergoing no surgical manipulation (CTRL) and sham operation (SH) were included as appropriate controls. Surgical manipulations were conducted on day 15 of the dietary protocol. Based on liver-to-body weight ratios (LW/BW), mitotic indices, hepatic cytochrome P-450 content, and hepatic glutathione (GSH and GSSG) levels, PH-induced hepatocellular regeneration was not affected by pretreatment with CD. Thus, the PH model was considered valid for assessing the effects of CD + CCl4 combination treatment. CCl4 (100 microliter/kg; i.p.) was administered 1, 2, 4 or 7 days after the surgical manipulations. Hepatotoxicity was assessed 24 h later by measuring LW/BW and serum enzymes (SGPT, SGOT and ICD) in all four groups. Hepatic histopathological, histomorphometric and lethal effects were assessed in animals receiving CCl4 1 or 7 days after the surgical manipulations. CCl4-induced increases in LW/BW were observed in CD + PH rats receiving CCl4 4 or 7 days post-PH, but not in the 1 or 2 day post-PH groups in which the hepatocellular regeneration was maximal. CCl4-induced serum enzyme elevations were significantly less in the CD + PH rats as compared to CD + SH. This decrease in the serum enzyme elevations was most prominent in the 1 day post-PH group, where the hepatocellular mitotic activity was most pronounced. CCl4 lethality, assessed in the 1 day post-surgical manipulation group, was also decreased in the CD + PH rats in comparison to CD + SH rats. Such a protection was not observed in rats receiving CCl4 7 days post-PH. These data are consistent with and are supportive of the hypothesis that a suppression of otherwise normally stimulated hepatocellular regeneration following low-dose CCl4 administration is involved in the marked amplification of CCl4 toxicity by CD.

Animals↗
PubMed1988

Glutathione metabolism and utilization of external thiols by cigarette smoke-challenged, isolated rat and rabbit lungs.

The purpose of the present investigation was to understand the acute effects of cigarette smoke on glutathione (GSH) metabolism and on utilization of external thiols by cigarette smoke-exposed, perfused rat and rabbit lungs. Most of the experiments were carried out using freshly drawn cigarette smoke. However, cigarette smoke condensate was used in some perfusions for the comparison of the effects between the types of exposures on utilization of external thiols. Cigarette smoke decreased GSH levels significantly (50%) without any increase in glutathione disulfide (GSSG) in both rabbit and rat lungs. In smoke-exposed rabbit lungs, protein thiol groups (protein-SH) decreased significantly (17%) without a significant change in protein-GSH mixed disulfides. However, in the rat lungs, cigarette smoke did not decrease protein-SH and protein-GSH mixed disulfides, indicating species variation in the effect of cigarette smoke. Cigarette smoke inhibited selenium-dependent and -independent GSH peroxidase activities in the rat lung (33%), but not in the rabbit lung. GSH S-transferase and GSSG reductase activities were not altered in cigarette smoke-challenged rabbit and rat lungs. gamma-Glutamylcysteine synthetase and glucose-6-phosphate dehydrogenase activities were significantly lower in smoke-exposed rat lungs as against control lungs, indicating that rat lung enzymes were more susceptible to the effects of cigarette smoke when compared to those of rabbits. N-Acetylcysteine, but not GSH, added to the perfusate significantly protected rabbit lung from smoke-induced GSH depletion. Smoke condensate added to the perfusate also caused GSH depletion in rabbit lung, and GSH or N-acetylcysteine added to the perfusion medium protected the lung indicating that GSH in the media directly interacts with condensate in the media before coming in contact with cellular GSH. These results indicate that acute smoke inhalation decreases pulmonary GSH and that the decreased GSH was not related to disulfide formation. Inhibited GSH synthesis in rat lung could account for the loss of GSH in part after exposure to cigarette smoke. The alternative pathway of GSH utilization could be conjugation with electrophilic smoke components. Thiols, like N-acetylcysteine, were protective against cigarette smoke-induced damage to the rabbit lung. The mechanism could be either by the increased GSH synthesis or by the direct delivery of sulfhydryls from N-acetylcysteine.

Acetylcysteine↗
PubMed1988

In vivo metabolism of CCl4 by rats pretreated with chlordecone, mirex, or phenobarbital.

The propensity of chlordecone (CD) to potentiate hepatotoxic and lethal effects of CCl4 is well established. Mirex (M), a close structural analogue of CD, or phenobarbital (PB), powerful inducers of hepatic microsomal drug metabolizing enzymes, are much weaker potentiators of CCl4 toxicity. The purpose of this study was to test the possibility that CD potentiates the toxicity of CCl4 by increasing the metabolism of CCl4 to a greater degree than either PB or M. We compared the in vivo metabolism of CCl4 in rats pretreated with CD, M, or PB, by measuring the hepatic content of 14CCl4, the expiration of 14CCl4, expiration of 14CCl4-derived 14CO2, and lipid peroxidation. Male Sprague-Dawley rats (250-270 g) were pretreated with a single oral dose of CD (10 mg/kg), M (10 mg/kg), or corn oil vehicle (1 ml/kg). PB pretreatment consisted of an ip injection of sodium PB (80 mg/kg) in saline (0.9%) for 2 successive days. Twenty-four hours later, 14CCl4 (0.1 ml/kg; sp act: 0.04 mCi/mmol) was administered ip in corn oil and the radioactivity present in the expired air was collected for 6 hr. Excretion of the parent compound as represented by the 14C label in the toluene trap was unchanged by any of the pretreatments. Expiration of 14CO2 measured during the 6 hr after CCl4 administration was increased in animals pretreated with PB or CD. In vivo lipid peroxidation measured as diene conjugation in lipids extracted from the livers was increased to a similar extent in animals pretreated with PB and CD, whereas the serum transaminases (ALT, AST) were significantly elevated only in animals pretreated with CD.M did not affect 14CO2 production and was without a significant effect on the lipid peroxidation. The radiolabel present in the liver at 6 hr showed no difference in hepatic content of free 14CCl4 among the groups, but the covalently bound label present in the lipid fractions of the livers pretreated with PB was elevated in comparison to CD and M treatments. These data indicate that a single oral administration of CD (10 mg/kg) 24 hr prior to CCl4 administration (100 microliter/kg) enhances the oxidative metabolism of CCl4 but to a lesser extent than PB (80 mg/kg, ip, twice), which is in inverse relationship to the potentiation of the hepatotoxic and lethal effects of CCl4 associated with these pretreatments.

Animals↗
PubMed1988

Amplification of chloroform hepatotoxicity and lethality by dietary chlordecone (kepone) in mice.

Male Swiss Webster mice (25-30 g) maintained on powdered control diet, or on diets containing chlordecone (CD, 10 ppm), mirex (M, 10 ppm), or phenobarbital (PB, 225 ppm) were used in this study. At these low levels, chlorinated hydrocarbon pesticides are not toxic, they neither affect food or water consumption, nor the body weight of mice. After a 15-day dietary protocol, a single challenge dose of CHCl3 (0.1 ml/kg) was administered intraperitoneally in corn oil vehicle. Liver damage was assessed 24 hours later using serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, histopathology, and lethality. For comparison, serum enzymes were measured in a separate group of mice receiving a high dose of CHCl3 (1.0 ml/kg) alone. None of the dietary treatments alone affected any of the serum transaminases. The serum enzymes were remarkably elevated in the mice treated with CD and CHCl3. A high dose of CHCl3 (1.0 ml/kg) elevated the serum enzymes more than 10-fold over those in the mice fed normal diet receiving only the corn oil vehicle. The histopathology of the liver indicated midzonal necrosis typical of liver injury from CHCl3 and depletion of PAS positive glycogen deposits. These effects were not evident in mice treated with 0.1 ml/kg CHCl3 alone. Additional histological alterations in the livers of the CD + CHCl3 group include the degenerated cells, loss of basophilic staining characteristics, and an increased degree of cytoplasmic vacuolation. The amplification of CHCl3 hepatotoxicity by CD was also reflected by a 4.2-fold increase in lethality determined by 48-hour LD50.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1988

Types of interaction of amphiphilic drugs with phospholipid vesicles.

Binding characteristics of nine amphiphilic drugs, which induce pulmonary phospholipidosis, to L-alpha-dipalmitoyl phosphatidylcholine (DPPC) vesicles were studied using fluorescence probes, 1,6-diphenyl-1,3,5-hexatriene and 1-anilino-8-naphthalene sulfonate (ANS) for hydrophobic and hydrophilic interactions, respectively. Drug binding to DPPC was quantitated using Scatchard analysis. The tested drugs bound to DPPC with different capacities. The order of binding capacity to hydrophobic site of DPPC using 1,6-diphenyl-1,3,5-hexatriene as fluorescence probe was promethazine greater than amiodarone greater than chlorpromazine greater than chloramphenicol greater than imipramine greater than trimipramine greater than propranolol much greater than chloroquine and chlorphentermine. Two binding affinities were evident for amiodarone, chlorpromazine, imipramine, trimipramine and promethazine. The order of binding strength at high affinity site was amiodarone greater than trimipramine greater than chlorpromazine greater than promethazine greater than imipramine. The order of drug binding capacity using ANS as fluorescence probe was chlorphentermine greater than trimipramine greater than propranolol much greater than amiodarone, chloroquine and chloramphenicol. Each of these drugs displayed a single binding affinity. Imipramine and chlorpromazine at 1 mM and higher concentrations showed intense fluorescence with ANS (5-20 microM) in the absence of DPPC indicating an interaction of these drugs with ANS. Chloroquine did not bind to either sites on DPPC. The binding of these drugs and their interactions with hydrophobic or hydrophilic sites of DPPC were correlated with their capacity to induce pulmonary phospholipidosis. These results indicate that not all the drugs which bind to DPPC in vitro induce phospholipidosis in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1987

Glutathione status in constituted physiological fluids containing albumin.

1. Glutathione (GSH) and cysteine, added to the constituted incubation medium, rapidly disappeared from the medium in the presence of bovine serum albumin (BSA). The major portions of added GSH and cysteine were oxidized. Only a fraction was recovered as cysteine-GSH mixed disulfide in case of GSH. About 15-30% cysteine or GSH were not recovered in the media. 2. The rate of GSH oxidation was linear with time, however, GSH disappearance was not linear with GSH concentrations. 3. Oxidation of GSH to GSSG in the albumin supplemented media was greater under O2 atmosphere, but was significantly decreased under N2 atmosphere. 4. Catalase, a peroxy radical scavenger, but not dimethyl pyroline N-oxide (DMPO), N-tertbutyl-2(-2 sulfophenyl)-nitrone (NTBSPN), mannitol or superoxide dismutase (SOD), decreased BSA mediated GSH oxidation. 5. GSH oxidation was abolished when mono- or divalent metal ions were absent in the BSA supplemented media. 6. Alkaline pH favored and acidic pH inhibited GSH oxidation. GSH oxidation was maximum above pH 7.4. GSH oxidation was minimal in the media containing boiled BSA. 7. A reaction mechanism involving the mixed GSH-BSA disulfide formation, followed by the reduction of these disulfides by GSH and subsequent release of GSSG is proposed.

Animals↗
PubMed1987

Comparative changes in hepatic DNA, RNA, protein, lipid, and glycogen induced by a subtoxic dose of CCl4 in chlordecone, mirex, and phenobarbital pretreated rats.

Male Sprague-Dawley rats (200-250 g) were maintained on a normal powdered diet or on a similar diet containing 10 ppm chlordecone (CD), 10 ppm mirex (M) or 225 ppm phenobarbital (PB) for 15 days. On day 15, the animals received a single i.p. administration of CCl4 (100 microliters/kg). Hepatic DNA, RNA, protein, lipid and glycogen were determined 1, 4, 6, 12, 24 and 36 h after CCl4 administration. A significant decrease (18%) in hepatic protein was observed 24 h after CCl4 challenge in the CD-pretreated rats; significant changes were not observed in the other treatment groups. Hepatic RNA was decreased (37%) in CD-pretreated rats at 36 h; no changes were observed in the DNA content. Hepatic RNA and DNA were increased (20% and 16%, respectively) 6 h after exposure to CCl4 alone. Lipid content was increased at all time points starting at 4 h in response to CCl4 challenge in the CD-pretreated rats. In the M- and PB-pretreated rats increases in hepatic lipid (22 and 28%, respectively) were observed only at the 6-h time point. Only a transient increase occurred after CCl4 alone at 4 h. While depletion of hepatic glycogen was manifested in all groups at all time points following CCl4, that in the CD + CCl4 group was the greatest. A recovery of glycogen beginning at 12 h was observed in the rats receiving CCl4 alone and in the M and PB pretreated animals. No such recovery was evident in CD + CCl4 group. These studies indicate that biochemical changes compatible with cellular death are more pronounced in the CD-pretreated rats than in those receiving CCl4 alone, suggesting that the metabolic and supportive biochemical mechanisms for hepatocellular repair are suppressed in rats receiving CD + CCl4.

Animals↗
PubMed1987

Precursor utilization of 5-hydroxytryptophan for 5-hydroxytryptamine biosynthesis in isolated and perfused rabbit and rat lungs.

The present study was designed to investigate whether lungs can utilize 5-hydroxytryptophan (5-HTP), formed elsewhere and transported, for the synthesis of 5-hydroxytryptamine (5-HT). [14C]5-HTP uptake was 7.7 +/- 1.1 and 3.9 +/- 0.2% by rabbit and rat lungs, respectively, after 1 h of perfusion with 10 microM [14C]5-HTP. There was an increase in the lung uptake of [14C]5-HTP when the lungs were preperfused with 0.5 mM chlorphentermine (CP) and the uptake was low when the lungs were preperfused with 0.1 mM hydroxybenzylhydrazine dihydrochloride (HBH). The perfusate concentration of 5-hydroxyindole acetic acid (5-HIAA) increased significantly (3-4 micrograms/100 mL) during rabbit lung perfusion with 10 microM [14C]5-HTP and this did not change significantly when the lungs were preperfused with 0.5 mM CP. However, 5-HT increased with time in the perfusate. 5-HT, but not 5-HIAA, was detected in the perfusate and increased with time of perfusion when the rat lungs were perfused either with 10 microM 5-HTP or with 0.5 mM CP and 10 microM 5-HTP. However, no metabolites were detected in either the rabbit lung or rat lung perfusates when they were preperfused with 0.1 mM HBH. Lung contents of 5-HT and 5-HIAA were significantly higher in the rat lungs and only 5-HIAA increased in rabbit lungs after 1 h of perfusion with 10 microM 5-HTP. Preperfusion with 0.5 mM CP resulted in a greater increase in the 5-HT content of both rabbit and rat lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Hydroxytryptophan↗
PubMed1986

Absence of diamine oxidase activity from rabbit and rat lungs.

To study the presence of diamine oxidase (DAO) activity in any tissue with putrescine as the substrate, it is necessary to use inhibitors to block all pathways that could further metabolize gamma-aminobutyraldehyde, which is the product of enzyme reaction. It is also necessary to inhibit any enzyme that may convert putrescine into higher polyamines. By this approach it was observed that lung tissue of both rat and rabbit exhibited no DAO activity. DAO activity was observed in the rat and rabbit intestine, the former showing 3 times as much activity as the latter. The other potential pathways of putrescine metabolism are of no consequence in the rat and rabbit intestine and lungs.

Amine Oxidase (Copper-Containing)↗
PubMed1986

Effect of amiodarone on Na+-, K+-ATPase and Mg2+-ATPase activities in rat brain synaptosomes.

Amiodarone hydrochloride is a diiodinated antiarrhythmic agent widely used in the treatment of cardiac disorders. With the increasing use of amiodarone, several untoward effects have been recognized and neuropathy following amiodarone therapy has recently been reported. The present studies were carried out to study the effect of amiodarone on rat brain synaptosomal ATPases in an effort to understand its mechanism of action. Na+, K+-ATPase and oligomycin sensitive Mg2+ ATPase activities were inhibited by amiodarone in a concentration dependent manner with IC50 values of 50 microM and 10 microM respectively. [3H]ouabain binding was also decreased in a concentration dependent manner with an IC50 value of 12 microM, and 50 microM amiodarone totally inhibited [3H]ouabain binding. Kinetics of [3H]ouabain binding studies revealed that amiodarone inhibition of [3H]ouabain binding is competitive. K+-activated p-nitrophenyl phosphatase activity showed a maximum inhibition of 32 per cent at 200 microM amiodarone. Synaptosomal ATPase activities did not show any change in rats treated with amiodarone (20 mg kg-1 day-1) for 6 weeks, when compared to controls. The treatment period may be short, since the reported neurological abnormalities in patients were observed during 3-5 years of treatment. The present results suggest that amiodarone induced neuropathy may be due to its interference with sodium dependent phosphorylation of Na+, K+-ATPase reaction, thereby affecting active ion transport phenomenon and oxidative phosphorylation resulting in low turnover of ATP in the nervous system.

4-Nitrophenylphosphatase↗
PubMed1986

In vivo and in vitro synthesis, release, and uptake of [3-H]-dopamine in mouse striatal slices after in vivo exposure to chlordecone.

Effects of treatment of mice with chlordecone (25 mg/kg/d) on striatal dopaminergic activities such as synthesis, turnover, uptake, and release were investigated in vivo and in vitro. In mice receiving chlordecone for five days, there were no significant changes in in vivo dopamine (DA) synthesis and turnover in striatum and in vitro [3-H]-dopamine uptake and K+-stimulated [3-H]-dopamine release in striatal slices. In mice receiving chlordecone for eight days, the in vivo synthesis of [3-H]-dopamine from [3-H]-tyrosine in striatum was slightly inhibited and the in vitro [3-H]-dopamine synthesis in striatal slices was significantly decreased. Furthermore, both uptake and K+-stimulated release of [3-H]-dopamine from striatal slices were significantly reduced. The turnover rate of newly synthesized [3-H]-dopamine from [3-H]-tyrosine in striatal slices was unchanged after eight consecutive days of chlordecone administration. These results suggest that chlordecone may cause impairments in pre- and/or postsynaptic membranes of dopaminergic neurons which modulate motor function.

Animals↗
PubMed1986

Effects of cysteine and diethylmaleate pretreatments on renal function and response to a nephrotoxicant.

The effects of treatment with either cysteine (2 X 150 mg/kg) or diethylmaleate (0.7 ml/kg) on renal function and response to the nephrotoxicant hexachloro-1,3-butadiene (HCBD) were examined. Cysteine caused oliguria, blocked the polyuric and glucosuric effects of HCBD and attenuated the reduction of urine osmolality. Diethylmaleate (DEM) decreased urine osmolality; further decreases of urine osmolality were not seen after HCBD. DEM pretreatment increased HCBD-induced proteinuria. HCBD-induced elevation of plasma creatinine concentration was not affected by either of the pretreatments whereas the plasma urea nitrogen concentration was greater in the DEM-pretreated group. The latter may represent an effect of DEM on non-filtration handling of urea. The results suggest that cysteine and diethylmaleate each have effects on kidney function which alter the response of the nephron tubule to a subsequently administered toxic agent.

Animals↗
PubMed1986

Effect of chlorphentermine on incorporation of [14C]choline in the rat lung phospholipids.

The effect of chlorphentermine (CP) treatment (50 mg/kg/day, per os [po]) on the incorporation of [14C]choline into rat lung phospholipid was studied. Total phospholipid content was increased 2.0-fold and 1.7-fold after seven and 14 days, respectively, compared with the pair-fed rats. The incorporation of [14C]choline into phosphatidylcholine (PC) was significantly inhibited by either seven or 14 days of CP treatment. Nevertheless, the PC content was significantly increased by day 7 and stayed elevated at day 14 of CP treatment. Choline and phosphorylcholine contents were significantly decreased by the CP treatment. These results suggest that the higher accumulation of PC is due to inhibition of enzymes involved in the hydrolysis of phospholipids rather than to a stimulation of the phospholipid synthesis.

Animals↗