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Biomedical subjects

H M Mehendale

Publications and source records attributed to H M Mehendale.

At least 145 records · Page 8Linked to original sources
PubMed1983

N-oxidation of N,N-dimethylaniline in the rabbit and rat lung.

We have reported previously that chlorpromazine (CPZ) and imipramine (IMP) are metabolized via N-oxidation by the rat lung, while they are not appreciably metabolized by the rabbit lung. Indeed, marked species differences exist in the pulmonary N-oxidation of these pneumophilic drugs. In the present studies, the isolated, ventilated and perfused lung (IPL) preparations as well as in vitro preparations of the rabbit and rat lungs were used to examine the pulmonary disposition of [14C]-N,N-dimethylaniline (DMA) which has been used frequently as a substrate for N-oxidation. Although the IPLs of both species were active in DMA N-oxidation, the rabbit lung was more active in DMA N-oxidation than the rat lung on the basis of per g lung. The gradual decline in radiolabel concentration in the perfusate was more marked in the rat than in the rabbit IPL. This decline was not due to the drug accumulation in the lung, but to its volatility. There was no dose dependency in the tissue/medium DMA concentration ratios (approximately 1.60), indicating uptake by simple diffusion and low affinity for the lung tissue. In vitro lung preparations showed higher DMA N-oxidase activity in the rabbit than in the rat, regardless of whether whole homogenate, post-mitochondrial supernatant fraction or microsomal fraction was used, or how the activities were expressed (per mg protein or per g tissue). These results suggest that, although DMA is not highly concentrated in the lung, it is N-oxidized by the lung and that DMA N-oxidase is different from CPZ or IMP N-oxidase reported previously.

Aniline Compounds↗
PubMed1983

Acute hepatotoxicity and lethality of CCl4 in chlordecone-pretreated rats.

In a subchronic dietary pretreatment protocol chlordecone (CD) is a powerful potentiator of CCl4 hepatotoxicity, as indicated by biochemical, hepatofunctional, histopathological, and lethality parameters. The purpose of this investigation is to further explore the CD + CCl4 interaction in an acute CD pretreatment protocol and to compare the two pretreatment protocols in terms of their effect upon quantitative histopathology, serum enzymes, and lethality. Groups of four male rats received one of the following four pretreatments: chlordecone (10 mg/kg; single po), mirex (10 mg/kg; single po), phenobarbital (PB) (80 mg/kg/day for 2 successive days; ip in 0.9% saline), or corn oil vehicle (1 ml/kg; single po). Twenty-four hours later, the rats were given a single ip injection of CCl4 (0.1 ml/kg). Twenty-four hours after CCl4 administration, serum enzymes (SGPT, SGOT, and ICD) were measured and the livers removed and fixed in 10% buffered formalin for histological evaluation. The LD50 were determined by the method of moving averages. CD + CCl4 was the most hepatotoxic combination, in terms of serum enzyme elevations and lethality followed by PB + CCl4. The PB + CCl4 combination caused a greater degree of hepatocyte necrosis. These findings indicate that the acute pretreatment with CD enhances hepatotoxicity and the lethality of CCl4 in a fashion qualitatively similar to the subchronic pretreatment protocol.

Acute Disease↗
PubMed1983

Chlordecone-induced potentiation of carbon tetrachloride hepatotoxicity: a light and electron microscopic study.

Previous studies have shown that a chlorinated pesticide, chlordecone (Kepone), greatly potentiates carbon tetrachloride (CCl4) hepatotoxicity and lethality (Curtis, L.R., Williams, W.L., and Mehendale, H.M. (1979). Toxicol. Appl. Pharmacol. 51, 283-293; Curtis, L.R., and Mehendale, H.M. (1980). Drug Metab. Dispos. 8, 23-27). The present study describes sequential morphologic changes which occurred in livers of rats given a "nontoxic" level of chlordecone (10 ppm for 15 days) followed by a single injection of CCl4 (0.1 ml/kg). The hepatic alterations were examined 1 to 36 hr after exposure of the rats to CCl4. Those changes were compared to hepatic alterations which occurred in rats that received the same dose of chlordecone (10 ppm for 15 days) or a single injection of CClr (0.1 ml/kg) alone. The only change noted in livers from rats that received chlordecone alone was focal increase in smooth endoplasmic reticulum (SER) of hepatocytes at 24 hr and continuing throughout the time course of the experiment. Livers from animals that received CCl4 alone showed morphologic changes at 6 hr consisting of glycogen loss, increase in SER, and dilatation of rough endoplasmic reticulum (RER) in pericentral hepatocytes. Accumulation of small lipid droplets was also noted in midzonal hepatocytes. After 6 hr, there was no further increase in severity of injury. At 12 hr recovery was noticeable and, by 36 hr, livers from the CCl4 group appeared normal. Prior administration of chlordecone greatly potentiated pathologic changes in livers of animals that received CCl4. By 4 hr, there was total loss of glycogen in hepatocytes throughout the entire lobule. Small lipid droplets were present in pericentral, midzonal and periportal hepatocytes. Hepatocytes with extremely dilated RER were randomly scattered throughout the entire lobule. At 6 hr, there was further accumulation of lipid in the form of large droplets in hepatocytes. Focal, necrotic cells surrounded by polymorphonuclear leukocytes were randomly distributed throughout the lobule. The number of necrotic foci had progressively increased at the 12- and 24-hr intervals. By 36 hr, confluent areas of necrosis in pericentral and midzonal areas were observed in livers of some animals. This study indicates that although the combination of chlordecone and CCl4 produces much greater hepatic injury resembling damage due to a massive dose of CCl4, histologically, some differences in the progression and distribution of hepatocellular damage within the lobular architecture of the liver are evident.

Animals↗
PubMed1983

Chlordecone-induced potentiation of carbon tetrachloride hepatotoxicity: a morphometric and biochemical study.

The present study, conducted over a time course of 36 hr after CCl4 administration, describes sequential morphometric and biochemical changes which occur in livers of rats exposed to a combination of low levels of chlordecone (10 ppm for 15 days) and a single ip injection of CCl4 (0.1 ml/kg). Those changes were compared to hepatic alterations which occur in rats that received the same dose of chlordecone or CCl4 alone. Biochemical studies showed only trivial increases in levels of glutamic-pyruvic transaminase (GPT), glutamic-oxalacetic transaminase (GOT), and moderate but temporary increases in isocitrate dehydrogenase (ICD) after CCl4 alone. The combination of chlordecone and CCl4 resulted in significantly greater elevations of all three serum enzymes at all time intervals examined. Morphometric data showed no difference between normal diet controls and animals exposed to chlordecone alone as far as numerical density of hepatocytes or volume densities of hepatocytes with glycogen, lipid, dilated rough endoplasmic reticulum (RER), pyknosis, or mitoses. Morphometric analysis of livers from animals that received CCl4 alone showed decreases in numerical density, temporary decrease in percentage of hepatocytes containing glycogen, an increase in hepatocytes containing lipid, temporary increase in hepatocytes with dilated RER, and temporary increases in pyknotic nuclei. Soon after the initial hepatic injury was histologically evident between 4 and 6 hr, the number of mitoses increased dramatically and this progressed until complete recovery from CCl4 damage. From all indices of damage, complete recovery was evident by 36 hr after CCl4 administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1983

Possible nephrotoxic effect of carbon tetrabromide and its interaction with chlordecone.

The hepatotoxic and nephrotoxic effects of CBr4 were studied in male Sprague-Dawley rats following a single i.p. administration in a dose range of 25 to 125 microliter/kg to animals maintained for 15 days either on normal diet or a diet containing 10 ppm chlordecone (CD). At these doses, CBr4 did not cause hepatotoxic effects when given alone or in combination with prior exposure to CD. CBr4 caused renal dysfunction characterized by oliguria, aciduria and hypo-osmolality, and these effects were abolished by dietary CD pretreatment. In vitro incubation of renal cortical slices obtained from CBr4-treated animals revealed a significant depression of organic anion transport, i.e., decreased transport of p-aminohippurate (PAH). Organic cation transport was unaffected as judged by accumulation of tetraethylammonium (TEA). CBr4-induced renal dysfunction appeared unrelated to depressed PAH transport since CD pretreatment which abolished renal dysfunction failed to restore PAH transport. These results show that CD does not potentiate CBr4 hepatotoxicity and the nephrotoxic effects of this halomethane are abolished by prior exposure to CD.

Alanine Transaminase↗
PubMed1983

Absence of potentiation of bromoform hepatotoxicity and lethality by chlordecone.

Our previous studies indicated that the toxicity of chloro- or bromo-methanes is potentiated by chlordecone (CD). The present work was conducted to study the effect of prior dietary exposure to CD on toxicity of bromoform. Male S-D rats (175-200 g) were fed 0 or 10 ppm CD in the powdered ration for 15 days. Bromoform (25 to 300 microliters/kg) was given i.p. on day 15. 24 h later, hepatotoxicity was assessed by functional, biochemical and histopathological parameters. Excretion of phenolphthalein glucuronide in bile and the rate of bile flow were unaltered by either bromoform or CD-bromoform combination. Serum enzymes (GPT, GOT and isocitric dehydrogenase (ICD) were also not significantly elevated by any treatment. The results suggest that, unlike chloroform, CHBr3 does not act as a potent hepatotoxin and that its effects are not potentiated by CD to any significant extent.

Animals↗
PubMed1983

Effect of chlorphentermine on the pulmonary clearance of 5-hydroxytryptamine in rabbits in vivo.

Previous studies from this laboratory demonstrated that the pulmonary clearance of 5-hydroxytryptamine (5-HT) is perturbed by pulmonary accumulation of chlorphentermine (CP) by isolated perfused lung preparations. This observation raises the possibility that depressed 5-HT clearance may be one factor contributing to CP-induced pulmonary hypertension. The primary objective of the present studies was to determine if the effect of CP could be demonstrated in vivo during single-pass circulation through the lungs. Pulmonary extraction and metabolism of [14C]-5-HT during single pulmonary passage were examined using the reference indicator radioisotope dilution technique in male New Zealand albino rabbits. In control or saline vehicle injected animals, it was established that 81% of administered [14C]-5-HT was extracted by the lung and 25% of total radioactivity in the blood stream was recovered as 5-hydroxyindoleacetic acid (5-HIAA) during single passage through the lungs. Appropriate control incubations of 5-HT with blood and simulated pulmonary circulation through the extracorporeal circulation system yielded only 2 and 5% metabolism, respectively. These results indicate that significant pulmonary metabolism of 5-HT followed by efflux of 5-HIAA into venous output occurs during single-pass circulation. Preadministration of CP (0.5, 1 and 3 mg/kg single dose, i.v.) caused a dose-related inhibition of pulmonary extraction of 5-HT. This effect was also accompanied by a dose-related suppression of the appearance of the metabolite of 5-HT. These results provide in vivo evidence for impairment of pulmonary extraction and deactivation of 5-HT as a result of prior pulmonary accumulation of CP.

Animals↗
PubMed1983

Drug-specificity in the perturbation of pulmonary disposition of serotonin in rabbit in vivo.

Previous work indicates that one consequence of the accumulation of several xenobiotics in the lung is compromised pulmonary disposition of 5-hydroxytryptamine (5-HT). In the present studies, we examined whether pulmonary accumulation of chlorpromazine (CPZ), propranolol (P), imipramine (IMP), and clomipramine (Cl-IMP) affected 5-HT disposition in rabbit lungs. Pulmonary extraction and metabolism of [14C]-5-HT during single pulmonary passage were examined using the reference indicator radioisotope dilution technique in male New Zealand albino rabbits. After control experiment, animals received CPZ or P (2.5, 5, or 10 mg/kg), IMP or Cl-IMP (0.25, 0.5 or 1.0 mg/kg) via the jugular vein. Pulmonary clearance was 83% of administered 5-HT. A significant proportion (28%) of total radioactivity in the bloodstream after single passage was recovered as 5-HIAA in control experiments. These values were reduced significantly to 70 and 20%, respectively upon prior administration of IMP (0.25 mg/kg). Cl-IMP was more effective in reducing these values further. CPZ and P were marginally effective at the highest dose. While prior administration of IMP and Cl-IMP resulted in pulmonary accumulation of both drugs, the latter accumulated to a significantly greater extent. These results suggest that Cl-IMP has higher affinity to the rabbit lung than IMP and may inhibit pulmonary uptake of 5-HT by competition for uptake and binding sites more than IMP.

Animals↗
PubMed1983

Effects of chlorphentermine and phentermine on the pulmonary disposition of 5-hydroxytryptamine in the rat in vivo.

This study was designed to examine whether chlorphentermine (CP) affects pulmonary disposition of 5-hydroxytryptamine (5-HT) in rat in vivo. Further, the effects of CP were compared with those of phentermine (P), the nonchlorinated congener. The right jugular vein and left carotid artery of male Sprague-Dawley rats were cannulated to the level of the superior caval vein and ascending aorta, respectively. After 10 min of stabilization, 0.3 ml fresh saline solution containing 150 micrograms indocyanine green and a mixture of labeled and unlabeled 5-HT was injected into the jugular vein, and arterial blood samples were collected for 20 s. Pulmonary extraction of 5-HT during a single pass was inversely proportional to the injected dose, ranging from 67% cf injected dose for a 2.6 nmol dose to 30% for a 130 nmol dose, indicating a saturable pulmonary uptake for 5-HT. In order to compare the effect of CP and P on pulmonary disposition of 5-HT, 2.6 nmol [14C]-5-HT was employed for in vivo single-pass experiments. Each animal was used for 2 in vivo single-pass experiments. After the first experiment, which served as a control, animals received an indicated dose of CP or P, to commence the second "drug-treated" in vivo experiment. Pulmonary clearance of 5-HT was inhibited by prior administration of CP (1 mg/kg) by 42%, whereas at the highest dose (20 mg/kg) P inhibited 5-HT clearance by only 25%. Pulmonary accumulation of CP was greater than P at higher doses, and the inhibition of 5-HT clearance correlated with the pulmonary accumulation of these drugs. In addition to the in vivo demonstration of the CP inhibition of pulmonary clearance of 5-HT in the rat, these studies also demonstrate a higher affinity of the lung tissue for CP than for P and a greater propensity for the impairment of pulmonary 5-HT clearance.

Animals↗
PubMed1982

Potentiation of CCl4 lethality by chlordecone.

Previous studies have dealt with the propensity of chlordecone (CD) to potentiate the hepatotoxicity of CCl4. The effect of this interaction upon CCl4 lethality has never been reported. The objective of the present study was to evaluate the effect of CD on CCl4 lethality and several parameters associated with cytochrome P-450 activity. Male Sprague-Dawley rats (150-200 g) were fed powdered diets containing 0 to 10 ppm CD or 225 ppm phenobarbital (PB) for 15 days. On day 15, rats from each group received an i.p. injection of CCl4 in corn oil and the 48-h LD50 determined. Additional animals were used to measure hepatic microsomal levels cytochrome P-450 and aminopyrine demethylase. CD decrease the LD50 of CCl4 from 2.8 ml/kg to 0.042 ml/kg, representing a 67-fold increase in toxicity, as assessed by lethality. PB in this protocol decreased the LD50 to 1.7 ml/kg, representing a 1.6-fold increase in lethality. However, the induction of cytochrome P-450 and associated parameters of mixed-function oxidase (MFO) activity did not correlate with the lethality data. Hepatic microsomal P-450 was increased over controls by 40% and 76% in CD and PB rats respectively. PB also stimulated aminopyrine demethylase activity to a much greater extent (190%) than CD (49%) relative to controls. These findings provide evidence that the CD-CCl4 interaction results in a marked increase in CCl4 lethality, in addition to the previously reported marked increase in hepatotoxicity. These results remain consistent with the proposal that bioactivation is the mechanisms underlying enhanced CCl4 toxicity, but suggest that specific effects of CD upon CCl4 metabolism may be the pivotal mechanism underlying potentiation.

Animals↗
PubMed1982

Chlordecone-induced fat depletion in the male rat.

The principal objective of this study was to quantitate the anatomical and biochemical parameters associated with the depletion of body fat by the pesticide, chlordecone (CD, or Kepone). Groups of 5 male Sprague-Dawley rats (150-175 g) were fed a control diet or a diet containing 100 ppm CD for 5, 15, or 20 d. After the treatment period, animals were killed by exsanguination. Weight of the period epididymal fat pads was taken as the anatomical marker for the depletion of body fat. Blood levels of acetoacetate, 3-hydroxybutyrate, and nonesterified fatty acids (NEFA) were measured as biochemical as biochemical markers for lipolysis of body fat depots. Serum enzymes (SGPT, ICD) and serum triglycerides were measured to assess liver damage. A consistent and significant difference was observed in the weight of epididymal fat pads between the control and each of the treatment groups. The reduction in epididymal fat reached a maximum of 60% in the CD-fed animals after 20 d. Circulating ketone bodies were not different in any of the treated-animal groups, indicating that CD treatment does not result in metabolic ketosis. Serum triglycerides and NEFA levels were not significantly different in treatment groups versus in controls. Serum transaminases and isocitrate dehydrogenase were not elevated by exposure to CD. These findings indicate that metabolic ketosis is not induced by dietary exposure to CD. Utilization of lipids as energy substrates appears to be the primary underlying mechanism responsible for the loss of body fat observed in CD-treated rats. It appears that CD induces a depletion of body fat stores as a consequence of altered energy balance of the animal.

Adipose Tissue↗
PubMed1982

Comparison of brain discrete area distributions of chlordecone and mirex in the mouse.

Discrete area distributions of chlordecone or mirex in the brain at different times after a single oral administration of the compounds, 50 mg/kg, were investigated. Whole brain and plasma levels of these compounds also were compared. With the same dose of chlordecone or mirex administered to mice, both brain and plasma levels of chlordecone were significantly higher than those of mirex. Chlordecone appeared to distribute to specific discrete areas in the brain--the striatum and medulla/pons areas having higher chlordecone levels and retaining chlordecone longer. Mirex showed less specific distribution in discrete areas. Therefore, it appears that these structurally related analogs exhibited distribution and pharmacokinetic differences.

Animals↗
PubMed1982

Effects of oral administration of chlordecone and mirex on brain biogenic amines in mice.

Levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and the 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA) were determined in brains of mice after daily oral administration of 10, 25 or 50 mg/kg of chlordecone or mirex until mortality occurred. Significant decreases in whole brain and striatal DA levels were observed in chlordecone-treated mice exhibiting tremors. Mirex had no effect at the 3 doses tested. In mice treated with chlordecone or mirex, the 5-HT levels were elevated only in animals exhibiting severe tremors or diarrhea, respectively. NE levels were not altered by chlordecone or mirex. These results suggest that chlordecone-induced neurotoxicity may be due in part to a decrease in the inhibitory state of dopamine neurons.

Administration, Oral↗
PubMed1981

The isolated perfused lung--a critical evaluation.

Recent refinement and application of the technique of perfusing isolated intact lung preparations from suitable experimental animal has enhanced our knowledge of the non-respiratory functions of the lung. The technique consists of perfusion with whole blood or constituted media via pulmonary artery or artificially ventilated lungs. Such preparations have been known to be especially useful for studies of uptake, metabolism and disposition of exogenous and endogenous substances. Recent advances in unilateral, split-lung perfusion in which left and right lungs are unilaterally perfused simultaneously have enabled investigators to maintain paired controls during perfusion. Such techniques are useful in the study of the interactions of endogenous and exogenous chemicals in the lung tissue. Differences between subcellular or lung slice preparations and intact lung perfusion are to be expected on the basis of distorting natural vascular and extra-vascular barriers in the case of in vitro preparations. Areas in which perfused lungs have not been extensively used include uptake and disposition of gases, solvents and vapors, effects of toxic chemicals on respiratory and non-respiratory functions of the lung and alteration of pulmonary mechanisms and hemodynamics in the presence of interacting chemical or physical stimuli. With suitable modifications, application of isolated perfused lung preparations for these investigations should be technically feasible in the future.

Animals↗