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Biomedical subjects

H M Mehendale

Publications and source records attributed to H M Mehendale.

At least 199 records · Page 11Linked to original sources
PubMedDate not supplied

Effect of chlorphentermine pretreatment on 5-hydroxytryptamine disposition in the isolated perfused rat lung.

Chlorphentermine (CP) is known to be highly accumulated by the lung, to cause pulmonary phospholipidosis and has been suspect in causing pulmonary hypertension possibly by inhibiting the clearance of 5-hydroxytryptamine (5-HT). It was of interest to determine if subacute CP treatment might inhibit 5-HT clearance by the lung. Animals were treated with CP (50 mg/kg/day po in saline) for 7 days while controls received the vehicle only. Artificially ventilated isolated rat lungs were perfused with a constituted medium. In recirculation perfusion experiments, lungs from CP treated animals exhibited both decreased uptake and metabolism of 14C-5-HT (0.02 microM). In order to distinguish between CP-induced morphological effects and the effect of CP itself, CP was added at an initial perfusate concentration of 0.5 or 5 mumol to the perfusate of lung from untreated animals. A dose-dependent inhibition of 5-HT uptake and metabolism was observed, such that lungs receiving 5 mumol of CP inhibited 5-HT metabolism similarly to that observed in treated lungs. In order to distinguish the effect of CP on 5-HT uptake from its effect on metabolism, pulmonary disposition of 5-HT was studied in the presence of pargyline, a monoamine oxidase (MAO) inhibitor known to block the metabolism of 5-HT. In the presence of 1 mM pargyline, CP (5 mumol) significantly decreased 5-HT uptake by the lung. CP was also noted to inhibit the metabolism of 14C-5-HT by in vitro incubations of 700 g lung supernatent fractions. In conclusion, subacute treatment with CP results in obtunded clearance of 5-HT by the rat lung, supporting the proposal that CP-induced pulmonary hypertension may be mediated by decreased pulmonary clearance of 5-HT.

Animals↗
PubMedDate not supplied

Potentiation of bromotrichloromethane hepatotoxicity and lethality by chlordecone preexposure in the rat.

These studies were designed to provide dose-response relationships for chlordecone (CD) potentiation of BrCCl3 hepatotoxicity in male rats using biochemical, functional and histopathological parameters. The influence of this interaction on BrCCl3 lethality was also examined. Male Sprague-Dawley rats (175-200 g) received a single ip dose of 1, 5, 10, 15 or 25 microL BrCCl3/kg following a 15 day dietary pretreatment of 0 or 10 ppm CD. Twenty four hrs after BrCCl3 challenge, biliary excretion of phenolphthalein glucuronide (PG), bile flow, serum transaminases (SGOT and SGPT), serum ICD and OCT were examined as functional and biochemical indices of hepatic injury. Effect of CD on 48 hr LD50 of BrCCl3 was also examined using the method of moving averages. With the exception of 1 microL BrCCl3/kg dose which had no effect, CD-BrCCl3 combination resulted in potentiation of hepatotoxicity by all parameters examined. Activity of all the serum enzymes was elevated in a dose related manner. A dose related decrease in the biliary excretion of PG and bile flow was observed. These effects were more pronounced at the higher doses of BrCCl3. Extensive centrilobular necrosis was observed in the animals given CD-BrCCl3 combination and the necrogenic effect was more severe at the doses of 15 microL and 25 microL BrCCl3/kg. BrCCl3-lethality was increased 5-fold by CD as indicated by the decreased LD50. The results suggest that CD-induced BrCCl3 toxicity is manifested both in the form of hepatotoxicity and lethality and since the hepatic functional status is greatly compromised, the CD potentiated hepatic failure is related to lethality.

Animals↗
PubMedDate not supplied

Effect of adrenalectomy on chlordecone potentiation of carbontetrachloride hepatotoxicity.

The propensity of chlordecone (CD) to potentiate CCl4 hepatotoxicity in rats of either sex has been well documented. The objective of the present study was to investigate the hepatotoxic effects of CD-CCl4 interaction in adrenalectomized rats. Adrenalectomized rats were maintained on 0 or 10 ppm CD and on day 15 they received a single ip injection of 25 microL CCl4/kg. Hepatotoxicity was assessed by hepatofunctional, biochemical and histopathological parameters, 24 hrs after CCl4 challenge. CCl4-induced hepatobiliary dysfunction and elevation of serum enzymes (GPT, GOT, ICD and OCT) were evident. Hepatic dysfunction was most severe in adrenalectomized rats receiving CD-CCl4 combination treatment. Histopathology of liver exhibited extensive fatty infiltration in the entire lobular structure accompanied by some necrosis. These data indicate that the capacity of CD to potentiate CCl4 hepatotoxicity is unaffected in adrenalectomized rats.

Adrenalectomy↗
PubMedDate not supplied

Chlordecone-induced hepatic dysfunction.

Chlordecone (Kepone) is a decachloroketone analog of the dodecachlorohydrocarbon mirex and is used as a stomach poison insecticide. Despite the structural similarity to mirex, chlordecone is unlike mirex in general organ-specific toxic properties. Chlordecone is primarily accumulated in the liver, where it causes a variety of morphological and biochemical alterations. Although less effective than mirex as a hepatotoxin, it causes liver enlargement, focal necrosis, mitochondrial changes, fatty infiltration of hepatocytes, and proliferation of endoplasmic reticulum. Chlordecone accumulation and morphological alterations in the liver were also observed in occupationally exposed human patients. Induction of hepatic microsomal mixed-function oxidases (MFOs) and impaired production and utilization of hepatocellular energy are the principal biochemical aberrations produced by chlordecone. Chronic exposure causes carcinogenesis in mice and rats. Hyperplastic nodules, which progress to hepatocellular carcinomas, are the principal pathological lesions. Acute and chronic exposures to chlordecone result in hepatobiliary dysfunction manifested as impaired excretion of anionic compounds accompanied by choleresis. Exposure to chlordecone results of greatly potentiated haloalkane hepatotoxicity, representing a most potent toxic interaction at otherwise individually nontoxic levels. In view of the demonstrated carcinogenic effect of chlordecone, such interactions at very low levels assume extraordinary significance in terms of chronic toxicological and pathological manifestations induced by combinations of toxic chemicals.

Adenosine Triphosphatases↗
PubMedDate not supplied

Effect of phenobarbital and mirex pretreatments on CCl4 autoprotection.

Male Sprague-Dawley rats maintained on either normal diet (N) or on a diet containing phenobarbital (PB; 225 ppm) or mirex (M; 10 ppm) for 15 days received either corn oil or 1 single administration of a protective dose of CCl4 (0.3 ml/kg, po) on day 16. At 24, 48, 72, 96, or 144 hr after the protective dose, a high dose of CCl4 (5 ml/kg, po) was administered to rats of all the groups, and they were observed for 14-day lethality. In a second experiment, in rats maintained on N, PB, or M diet, liver microsomal cytochromes P-450, aminopyrine demethylase, and aniline hydroxylase were measured at various time points after the administration of the protective dose of CCl4. Serum aspartate transaminase, alanine transaminase, and sorbitol dehydrogenase elevations and histopathological changes observed under a light microscope were used as toxic end points to assess hepatotoxicity. Autoprotection was 100% when the high dose was given at 24 hr after the protective dose in N rats, whereas it was only 55% in PB- or M-pretreated rats. For later time points of 48, 72, and 96 hr, autoprotection was only around 50% in N rats, whereas it was almost 100% in PB- and M-pretreated rats. When the high dose was administered at 144 hr after the protective dose, autoprotection further declined to 25% in N rats and to 75% in M-treated rats, but it remained at 100% in PB-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Uptake and disposition of aldrin and dieldrin by isolated perfused rabbit lung.

The uptake, metabolism, and release of aldrin and dieldrin by the lungs were studied by use of isolated perfused rabbit lungs that were artificially ventilated and perfused through the pulmonary artery. Both recirculating and single-pass experiments were conducted using an artificial medium as perfusate. Aldrin accumulated in the lung from the perfusate through two distinct phases of uptake: a rapid phase involving simple diffusion and nonspecific binding and a slower phase representing its metabolic turnover as dieldrin. Dieldrin was not metabolized but accumulated in the lungs by a saturable and a nonsaturable process. Single-pass experiments with aldrin indicated that the initial velocity of uptake could be fitted to one component and a constant representing the rate of metabolism. Uptake of dieldrin was biphasic: one phase independent of the perfusate concentration and the other saturable with respect to the perfusate concentration. By the application of Michaelis-Menten kinetics, the maximum amount of dieldrin accumulation attributable to the saturable component was calculated to be 0.64 mumol/lung. Our results indicate that the accumulation of these chlorinated xenobiotics takes place through the processes of simple diffusion followed by nonspecific tissue binding. There was no evidence for irreversible binding of aldrin or dieldrin, its epoxide, in the lung. While the lung plays a role in metabolizing aldrin to dieldrin followed by a transient storage, neither substrate has the potential for long-term storage in the lung.

Aldrin↗
PubMedDate not supplied

Mirex-induced impairment of hepatobiliary function. Suppressed biliary excretion of imipramine and sulfobromophthalein.

Effect of pre-exposure to the pesticide mirex on hepatic uptake, metabolism, and biliary excretion of the tricyclic antidepressant, imipramine (IMP), was studied by using isolated perfused rat liver preparations obtained from control and treated animals. Pretreatment of male rats with mirex (50 mg/kg/day, po, for 3 days) resulted in a marked suppression (91%) of biliary excretion of endogenously formed polar metabolites of IMP. This impairment of biliary excretory function is related neither to the bile flow nor to the rate of metabolism of IMP. These conclusions are supported by the following observations: 1) pre-exposure to mirex results in a significant increase in bile secretion; 2) endogenously formed metabolites of IMP accumulate in increasing concentrations in the perfusate of liver preparations from mirex-treated rats; 3) over 98% of the IMP was metabolized by livers of both control and mirex-treated rats. Furthermore, biliary excretion of exogenously provided polar metabolites of IMP was also suppressed by 88% of that of control livers. Addition of mirex (5 X 10(-5) M) to the perfusate of control liver preparations was without effect on biliary excretion of IMP metabolites. Biliary excretion of sulfobromophthalein was also markedly suppressed (90%) by preexposure to mirex. These results suggest that mirex-induced impairment of hepatobiliary function is not specific to substrates. The mechanism of mirex-induced impairment is located at the site of transfer of otherwise readily excretable substances such as metabolites of IMP and sulfobromophthalein.

Animals↗
PubMedDate not supplied

In vitro metabolism of amiodarone by rabbit and rat liver and small intestine.

The present studies were designed to investigate whether amiodarone (Am) is metabolized in the major organs and tissues of the rat and rabbit. Incubations using Am and tissue homogenates (600 g supernatant) of rabbit and rat lung, liver, kidney, and gut revealed formation of desethylamiodarone (DEA) by the liver and gut. Subsequent experiments using the post-mitochondrial, cytosolic, and microsomal fractions of these tissues indicated that metabolism of Am was greatest in the microsomal fractions. In both species, greater DEA formation was detected for microsomes of hepatic origin. The hepatic microsomal mediated production of DEA was altered by protein concentration in both the rabbit and rat preparations with protein concentrations of 5 mg providing the greatest DEA production. DEA formation by gut microsomes was greatest at 3 mg of protein for the rabbit but exhibited no significant change from 1 mg to 10 mg of protein for the rat. In vitro metabolism of Am by rabbit and rat hepatic microsomal preparations was significantly reduced by 1 mM piperonyl butoxide, SKF 525-A, n-octylamine, and carbon monoxide. Effects of these inhibitors on rabbit and rat gut microsomal incubations were inconclusive. HPLC analysis of incubation samples revealed a species difference in the metabolism of Am as demonstrated by the detection of three metabolites in addition to DEA. The unidentified metabolites (I, II, III) were detected in rabbit hepatic microsomal incubations. Metabolite II was also detected in incubations using rabbit duodenal tissue microsomes. No metabolites other than DEA were found in incubations using rat tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMedDate not supplied

Uptake and disposition of putrescine, spermidine, and spermine by rabbit lungs.

The pulmonary uptake and accumulation of the three polyamines in intact, ventilated, and perfused rabbit lungs was investigated. Lungs were perfused using Krebs-Ringer bicarbonate buffer with albumin in which putrescine, spermidine, or spermine were included at an initial concentration of 10(-3), 10(-2), 10(-1), 5, 10, or 20 mM. At a 5 mM concentration of spermidine and spermine, the uptake by isolated lungs reached a steady state equilibrium in 20-30 min of perfusion. This did not occur for putrescine, which showed linear uptake throughout the entire period of the 60-min perfusion. The lung uptake of putrescine for all perfusate concentrations was greater than that of spermidine or spermine, but all three showed concentration-dependent linear uptake. In the presence of harmaline (1 mM) and ouabain (1 mM), isolated perfused rabbit lungs showed a decrease in uptake of putrescine although no effect was seen for spermidine and spermine. Perfusate containing decreased sodium showed no effect on putrescine uptake by isolated rabbit lungs, but there was a significant increase in the uptake of spermidine and spermine. Significant uptake of all three polyamines was also observed when incubated separately with rabbit lung slices for 60 min. HPLC analysis of lung, the perfusate samples, lung slices, and the incubation medium after a 60-min incubation did not indicate the presence of metabolites of these polyamines. Likewise, the analysis of the lung homogenate incubated with polyamines did not show any metabolites confirming the absence of detectable pulmonary metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Effect of cytochrome P-450 and flavin-containing monooxygenase modifying factors on the in vitro metabolism of amiodarone by rat and rabbit.

Experiments were conducted to affirm hepatic cytochrome P-450 involvement in the biotransformation of the class III antiarrhythmic agent, amiodarone (Am; Cordarone X) to its major metabolite, desethylamiodarone (DEA). Male Sprague-Dawley rats and male New Zealand white rabbits were treated with phenobarbital (PB) or 3-methylcholanthrene (3-MC) (to induce cytochrome P-450 (PB-inducible cytochrome(s) P-450) or P-448 (MC-inducible cytochrome P-450). In vivo decreases in rat hepatic microsomal cytochrome P-450 were achieved either by a single ip dose of CCl4 or by a 2-day treatment with CoCl2. In vitro biotransformation of Am by hepatic microsomes from PB-induced and 3-MC-induced rats and PB-induced rabbits was significantly greater than that from noninduced animals. Conversely, in vitro DEA production was significantly decreased with hepatic microsomes from CCl4- and CoCl2-pretreated rats. The classic P-450 inhibitors, piperonyl butoxide, SKF 525A, n-octylamine, and CO provided a significant reduction in the in vitro formation of DEA by microsomes from induced animals. In vitro DEA formation by hepatic microsomes from PB- and 3-MC-induced rats was significantly decreased by 0.5 mM chloroquine (specific inhibitors of PB-inducible cytochrome(s) P-450) and 0.3 mM quinacrine (specific inhibitor of MC-inducible cytochrome(s) P-450), respectively. Further evidence for involvement of gut microsomal flavin-containing monooxygenase was provided by the inhibition of gut microsomal-mediated in vitro DEA formation in the presence of methimazole. Methimazole had no effect on hepatic microsomal DEA production in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMedDate not supplied

Possible molecular mechanism of mirex-induced hepatobiliary dysfunction.

Male Sprague-Dawley rats were treated with mirex, po, at 0, 5, 10, and 50 mg/kg/day in 0.4 ml of corn oil for 3 days. Forty-eight hours after the last treatment, the biliary excretion of exogenously provided polar metabolites of 14C-imipramine was suppressed at all levels of mirex in a dose-dependent manner. Biliary excretion of phenolphthalein glucuronide was suppressed at high doses of mirex. These effects of impaired biliary excretion were accompanied by increased bile flow. Persistence of the mirex-induced biliary excretory dysfunction toward otherwise readily excretable, preformed metabolites suggests aberration of transport of these substances from the liver to bile. Whereas mitochondrial Mg++-ATPase and microsomal Na+-K+-ATPase activities were both inhibited by exposure to mirex in a dose-dependent manner, the latter activity was consistently inhibited to a higher degree. These results are suggestive of mirex-induced interference with energy production and utilization in the manifestation of hepatobiliary dysfunction.

Adenosine Triphosphatases↗