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Biomedical subjects

H M Mehendale

Publications and source records attributed to H M Mehendale.

At least 163 records · Page 9Linked to original sources
PubMed1981

Pulmonary metabolism of imipramine in the rat and rabbit. Comparison with hepatic metabolism.

The pulmonary metabolism of imipramine (IMP) was studied, using lung tissue preparations of rats and rabbits, and compared with the metabolism by liver tissue. The postmitochondrial (9,000 g) supernatant fraction was used as the enzyme source, and the differential extraction method was employed to separate and quantitate the metabolites of IMP. The IMP-metabolizing activity of rat lung was found to be significantly higher than that of rabbit lung. The major metabolite produced by rat lung was identified as IMP-N-oxide (IMP-NO). Inclusion of beta-dimethylaminoethyl-diphenyl valerate (SKF-525A; l mM) and depletion of Mg2+ did not inhibit, but slightly increased the N-oxidation of IMP by the lung preparations, whereas piperonyl butoxide (l mM) and Hg2+ (0.1 mM) had little or no effect. The liver/lung ratio of the IMP-metabolizing activity was found to be variable depending on the substrate concentrations used, indicating the unreliability of such ratios as indices of the relative contribution of the lung to the metabolism of a drug. These results suggest that a marked species variation exists with respect to the pulmonary of IMP, that the principal product in rat lung is IMP-NO, and that this biotransformation is catalyzed by a noncytochrome P-450 pathway.

Animals↗
PubMed1981

Effect of chlorphentermine on the pulmonary disposition of norepinephrine in the isolated perfused rabbit lung.

Chlorphentermine (CP) has been noted to cause primary pulmonary hypertension both clinically and experimentally. It was postulated that CP might affect the pulmonary clearance of endogenous vasoactive substances such as norepinephrine (NE). The uptake and metabolism of 14C-NE were followed in artificially ventilated isolated perfused rabbit lung preparations using a constituted perfusate with initial NE concentration of 5 micrograms/100 ml. Perfusate samples were analyzed for total radioactivity, metabolites, and parent compound. Preloading the lungs with 0.25 mM CP significantly increased the concentrations of total radioactivity, deaminated products, and decreased the concentration of normetanephrine in the perfusate. In addition, the accumulation of total radioactivity in the lung tissue after 60 min of perfusion was significantly decreased in CP-treated lungs. The proportion of deaminated metabolites in the lung tissue was slightly decreased while the percent of normetanephrine, and parent compound were significantly increased by the CP treatment. CP (0.1 mM) also inhibited the in vitro metabolism of NE by 79%. These results provide experimental evidence in support of a hindered pulmonary clearance of circulating NE by CP.

Animals↗
PubMed1981

Assessment of neurotoxicity induced by oral administration of chlordecone (Kepone) in the mouse.

Neurotoxicity in the mouse was produced following oral administration of chlordecone at 10, 25 and 50 mg/kg/day in corn oil vehicle. Hyperexcitability and tremors were observed on the 1st, 4th and 9th day after the administration of chlordecone at 50, 25 and 10 mg/kg/day, respectively, and mortality occurred on the 5th, 7th and 13th day after daily administration of the respective doses. In all cases, the cumulative LD 50 for chlordecone was estimated between 180 and 200 mg/kg. Daily oral administration of chlordecone caused loss of body weight, and the loss of body weight was greatest at the onset of tremor. The effect of chlordecone on food and water consumption varied depending on the dose. A recovery in body weight, and food and water consumption were observed upon the termination of chlordecone treatment. In terms of neurotoxic responses, the effect of chlordecone on motor coordination in the mouse was dose-dependent, both during treatment and during recovery after terminating treatment. The threshold for pentylenetetrazol-induced seizures was significantly reduced in chlordecone treated animals. This study may provide essential basic information for studying the biochemical mechanisms of chlordecone-induced neurotoxicity in the mouse.

Animals↗
PubMed1981

Correlation between neurotoxicity and chlordecone (Kepone) levels in brain and plasma in the mouse.

The brain and plasma levels of chlordecone were monitored after daily oral administration of chlordecone at 10 to 50 mg/kg/day. At a low dose, the plasma level of chlordecone increased steadily and the brain level showed a steady increase and then a plateau. However, at the higher dose the brain and plasma concentrations of chlordecone decayed biphasically. The data also revealed that chlordecone-induced neurotoxicity correlated closely with both brain and plasma concentration of chlordecone. Brain and plasma concentrations required for low and high dose for induction of the loss of motor coordination were estimated to be 10 to 65 ug/g and 10 to 25 microgram/ml, respectively. In addition, the chlordecone levels in the brain at time of death were 0.10 and 0.41 mg/g in groups receiving 10 and 50 mg/kg/day, respectively. However, the cumulative lethal dose of chlordecone in animals treated with different doses was about the same. This study established the threshold levels of chlordecone in plasma and brain for motor incoordination and mortality in the mouse.

Animals↗
PubMed1980

Functional and biochemical correlates of chlordecone exposure and its enhancement of CCl4 hepatotoxicity.

Animals pretreated with chlordecone exhibit a greatly increased hepatotoxic response to CCl4 challenge. Possible mechanisms underlying this interaction were examined. A single p.o. administration of chlordecone (5 mg/kg) was followed by CCl4 (200 microliter/kg) administered i.p. 48 h later. Twenty-four hours later, animals treated with chlordecone mccl4 had decreased hepatic excretory function (20% of controls) and elevated plasma transaminase activities and bilirubin. Hepatic mixed function oxidase activity was assessed as pentobarbital sleeping time and was not affected by chlordecone pretreatment. Irreversible binding of label from 14CCl4 to hepatic protein or lipid was not different in the chlordecone group compared to vehicle controls. Hepatic and renal glutathione concentrations were not affected by chlordecone alone (at 6 h, 1, 2, 3, 5 and 7 days) or by a combination of chlordecone (48 h) and CCl4 (24 h). CCl4-induced lipid peroxidation of liver tissue, measured in vitro or in vivo, was not increased by chlordecone treatment. Thus, while the mechanism for the enhanced toxicity remains to be elucidated, these results suggest that the interaction between chlordecone and CCl4 is a subtle one, not causally involving increased covalent binding of the toxin, increased susceptibility of tissue lipids to peroxidative damage or decreased hepatic GSH.

Animals↗
PubMed1980

Chlorphentermine uptake by rabbit lung slices.

Slices of rabbit lung tissue (approximately 150 mg; 0.5 mm) were incubated in 5 ml of Krebs-Ringer phosphate buffer, in the presence of 0.25 mM [14C]chlorphentermine (CP) with shaking at 37 degrees C and under an atmosphere of an O2/CO2 mixture (95 : 5). Incubation medium (M) and tissue (T) were analyzed for radioactivity. Uptake of CP reached a plateau after 30 min at a T/M ratio of 20. Upon varying the concentration of [14C]CP from 0.125 mM to 2 mM, the concentration-response curve was seen to saturate and the T/M ratio decreased with increasing concentration. Substituting LiCl for NaCl or increasing the K+ content in the medium decreased CP uptake. Incubation of slices with Na+-pump inhibitors, harmaline and iodoacetate, significantly decreased CP uptake. Chloroamphetamine, desimipramine, imipramine, morphine, chlorpromazine, dieldrin, methadone, amphetamine (each at 1 mM) and incubation at 10 degrees C inhibited CP uptake. Imipramine and amphetamine were both effective in displacing previously accumulated CP from the tissue slices. Efflux of CP from the lung slices was biphasic and was not affected by removal of Na+ from the medium. Binding of CP to lung homogenate was unaffected by substituting LiCl for NaCl or by the presence of 1 mM iodoacetate. However, 1 mM harmaline or 1 mM imipramine decreased CP binding. These studies offer evidence for a partially Na+-dependent, active uptake process for pulmonary sequestration of CP compatible with earlier findings obtained with perfused intact lung preparations.

Animals↗
PubMed1980

Disposition and nephrotoxicity of hexachloro-1,3-butadiene.

Hexachloro-1,3-butadiene (HCBD) administration to rats results in impaired kidney function. The time course of nephrotoxicity and disposition of HCBD were examined. Within 4 h after HCBD (300 mg/kg, i.p.) compromised kidney function was found as decreased urine osmolality, glomerular filtration rate (GFR) and drug excretion. At 24 h elevated blood urea nitrogen (BUN) was found. However, no definitive signs of hepatotoxicity were observed up to 48 h after HCBD. Control ralts excreted 40% of tracer dose (0.1 mg/kg, i.p.) of [14C]HCBD in feces and 30% in urine in 48 h. Rats with HCBD-induced nephrotoxicity excreted much less, 7% in feces and 6% in urine. Aliquots of these samples were extracted with hexane. All of 14C in bile and 87% of that in urine was water soluble, indicating that HCBD was biotransformed into polar metabolites.

Animals↗
PubMed1980

Inhibition of mouse brain synaptosomal ATPases and ouabain binding by chlordecone.

The effect of chlordecone on the mouse brain synaptosomal Na+-K+ ATPase, Mg2+ ATPase and p-nitrophenyl phosphatase (PNPPase) activities was determined. In addition, the effect of chlordecone on [3H] ouabain binding to synaptosomes was also investigated. The in vitro data show that chlordecone inhibits PNPPase, Na+-K+ ATPase, and Mg2+ ATPase activities with ID50 values of 4, 5 and 7 micrograms respectively. Treatment of mice with symptomatogenic doses of chlordecone resulted in a decreased synaptosomal Na+-K+ and oligomycin-sensitive (mitochondrial) Mg2+ ATPases. The decrease was dose-dependent. The oligomycin-insensitive Mg2+ ATPase activity was unaffected either in vitro or in vivo. The binding of [3H] ouabain to synaptosomal membranes was inhibited by chlordecone in a dose-dependent manner in both in vitro and in vivo experiments. The binding of [14C] chlordecone to synaptosomes occurs even at nanomolar concentrations. The marked inhibition of brain synaptosomal ATPases and ouabain binding by chlordecone suggests that chlordecone may impair active transport mechanisms in synaptosomal membranes.

4-Nitrophenylphosphatase↗
PubMed1980

Alterations of xenobiotic excretory function induced by potassium dichromate or carbon tetrachloride pretreatment.

Biliary and urinary excretory functions were determined in animals pretreated with a hepatotoxin (CCl4) or a nephrotoxin (K2Cr2O7), using polar metabolites of imipramine (PMIMP) and digoxin as models for anionic and neutral transport systems. Biliary excretion of PMIMP was decreased in CCl4-treated rats; urinary excretion was increased. Urinary and biliary excretion of digoxin were both unaffected by CCl4 treatment, but accumulation of digoxin by liver was impaired. K2Cr2O7 treatment resulted in severe nephrotoxicity accompanied by decreased urinary excretion of both model compounds. Hepatic excretion of digoxin, but not PMIMP, was increased in these animals. With minimal nephrotoxicity, urinary excretion of both compounds was unaffected. Thus the effect of toxicity on hepatic or renal excretion depends on the properties of the compounds used for excretion studies. In addition, for compounds excreted by both routes, impaired excretion by one route may be accompanied by increased excretion by the other. The extent of this compensatory mechanism may depend on several factors including the physiochemical properties of the compounds and the degree to which they are excreted by each route normally. In addition, specific cellular transport mechanisms may be important factors if involved in the excretory events.

Animals↗
PubMed1980

Assessment of photomirex toxicity in the mouse.

Toxicity in the mouse was produced after oral administration of photomirex at 10, 25 and 50 mg/kg.d in corn oil. Mortality began to occur 4, 7, and 16 d after daily administration of photomirex at 50, 25, and 20 mg/kg, respectively. In all cases, the cumulative LD50 for photomirex was estimated as 225-250 mg/kg. The effect of photomirex on food and water consumption varied depending on dose. Daily oral administration of photomirex caused a dose-dependent loss of body weight. No overt behavioral changes were observed during the experiments. Body temperature was unaffected. Biochemical studies also showed that photomirex did not affect plasma glucose and free fatty acid content and brain biogenic amine levels. It appears that photomirex is similar to mirex in terms of peripheral toxicity.

Amines↗
PubMed1980

Effect of chlorphentermine on the pulmonary disposition of 5-hydroxytryptamine in the isolated perfused rabbit lung.

It has been postulated that chlorphentermine (CP), as well as other drugs known to accumulate and to induce morphologic changes in lung tissue, might affect the uptake and metabolism of the endogenous vasopressor amine, 5-hydroxytryptamine (5-HT). The uptake and metabolism of [14C]5-HT was followed in artificially ventilated, isolated perfused rabbit lung preparations using erythrocyte-free perfusate with an initial 5-HT concentration of 5 microgram/100 ml. Samples of the perfusate were analyzed for total radioactivity, metabolites, and the parent compound. Preloading the lungs with 25 or 30 mumoles of CP significantly decreased the formation of 5-hydroxyindolacetic acid (5-HIAA) to 56% and 34% of the control value, respectively. These experiments indicated that decreased pulmonary metabolism of 5-HT by CP might be mediated via a dual effect of hindered uptake and inhibition of metabolism. In experiments designed to examine the effect on uptake by blocking 5-HT metabolism, CP significantly decreased 5-HT uptake by lungs preloaded with pargyline. In other experiments designed to examine the effect of CP on 5-HT metabolism, CP (0.3 mM) significantly inhibited 5-HT metabolism by 60% in in vitro incubations of rabbit lung homogenates. These experiments provided evidence that CP significantly decreases the pulmonary uptake and metabolism of 5-HT. Decreased pulmonary 5-HT clearance may bear a causal relation to the drug-induced pulmonary hypertension observed with chronic CP treatment.

Animals↗
PubMed1980

Aldrin epoxidase activity in developing rabbit lung.

Pulmonary aldrin epoxidase activity was determined in 2-, 4-, 6-, 8-, 12-, and 16-week-old male rabbits using isolated perfused lung preparations and in vitro incubation techniques. In the perfusion experiments, it was determined that aldrin epoxidase activity increased with age up to 12 weeks of age. Although there was an increase in the weight of lungs with age, this did not appear to be related to the increase in aldrin epoxidation. In vitro experiments carried out using the same substrate to tissue ratio failed to exhibit an age-related increase in the aldrin epoxidase activity. Extrapolated values for aldrin epoxidation from in vitro experiments yielded much higher values than realized from perfusion experiments. Accessibility of the substrate to the enzymatic sites, saturation of the accessible enzyme system, and limiting availability of the cofactor necessary for the oxidative reaction remain as the possible mechanisms for the discrepancy between perfusion and in vitro incubation studies.

Age Factors↗
PubMed1979

Effects of hexachlorobutadiene (HCBD) on renal function and renal organic ion transport in the rat.

1,3-Hexachorobutadiene (HCBD) has been suggested to cause nephrotoxicity. In addition, it is eliminated to a large extent in the urine. This study was designed to examine the effects of HCBD on overall renal function and specific renal transport systems in the rat. A single i.p. dose of 100 mg HCBD/kg caused a reduction in urine osmolality and body weight. Urine flow rate increased slightly and marked increases in urinary protein, glucose and ketones were observed. Renal slices after the same dose showed a reduced PAH accumulation. The transport of other organic compounds was affected only slightly. After daily administration on 4 successive days with various doses a graded response was observed on both transport and overall renal function. Glutathione administered in a 2.5-fold molar excess did not obtund the effects of HCBD on renal function or transport

Animals↗