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At least 1,711 records · Page 95Linked to original sources
PubMed1985

Rapid, substrate-specific, and dose-dependent deactivation of liver cytosolic glutathione S-transferases in vivo by 1,1-dichloroethylene.

Administration of 200 mg 1,1-dichloroethylene (1,1-DCE)/kg to fasted male rats rapidly decreased liver cytosolic glutathione (GSH) S-transferase activities by half within 1 hr. This early decrease was not associated with increased serum activities of this soluble enzyme and is considered due to enzyme deactivation. The early decrease in enzyme activities was concomitant with a three-fourths depletion of cytosolic GSH and preceded changes in cytochrome P-450 and the onset of liver cytotoxicity, both of which occurred abruptly between 2 and 3 hr. Substantial changes in GSH S-transferase activities at 4 hr were produced only by severely hepatotoxic doses of 1,1-DCE. The early decrease in hepatic GSH S-transferase activities was selective for substrates dichloronitrobenzene, chlorodinitrobenzene and 1,2-epoxy-3-(p-nitrophenoxy)-propane with apparent sparing of activity towards ethacrynic acid. The rapid, selective and dose-dependent deactivation of the hepatic GSH S-transferases could be relevant to the catastrophic hepatotoxicity of 1,1-DCE.

Alanine Transaminase↗
PubMed1977

Ethanol effects on active and passive Na+ flux in toad bladder.

Ethanol, like other anesthetics, has been reported to interfere with active Na+ transport in living membranes. In an attempt to elucidate the mechanism by which ethanol exerts this action, we tested in the toad bladder membrane: 1) the effect of ethanol on active Na+ transport, 2) the interaction of ethanol with vasopressin on Na+ transport, and 3) the effect of ethanol on passive Na+ flux. We found that, a) 1-500 microgram/ml of ethanol stimulated, and 10,000 microgram/ml depressed active Na+ transport; b) the combined effect of stimulating concentrations of ethanol and vasopressin, although suggestive of a positive interaction, might have arisen by chance (p = 0.08); c) depressant concentrations of ethanol failed to suppress the stimulation by vasopressin; and d) passive Na+ flux in bladders treated with ouabain and ethacrynic acid was not affected by ethanol (1-100 microgram/ml). These results indicate that ethanol in concentrations ranging from 1 to 10,000 microgram/ml does not block ATP/ATPase Na+ pump but apparently exerts a dose-dependent, stimulant-depressant effect on Na+ channels in the membrane.

Animals↗
PubMed1977

Effect of Etozolin on whole kidney function and fluid and electrolyte reabsorption in rat proximal convoluted tubules and loops of Henle.

The effects of ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (etozolin, Elkapin) on whole kidney function and on fluid, sodium and potassium reabsorption in proximal convoluted tubules and loops of Henle of superficial nephrons were studied in rats using clearance and micropuncture techniques. Etozolin (50 mg/kg i.v. initial dose; 50 mg/kg per hour i.v.) markedly increased urinary fluid and sodium excretion and decreased glomerular filtration rate. Fractional tubular sodium reabsorption fell by 8.7%. Fluid and electrolyte reabsorption in the proximal convolution was not significantly influenced by etozolin. The substance significantly increased flow rate, sodium and potassium concentration and decreased tubular fluid/plasma inulin ratio of the early distal tubular, indicating an inhibitory effect on fluid and electrolyte reabsorption in the loop of Henle. Although etozolin is chemically different its site of diuretic action is the same as that of furosemide and ethacrynic acid.

Animals↗
PubMed1984

Induction of cystine and glutamate transport activity in human fibroblasts by diethyl maleate and other electrophilic agents.

The transport activity for cystine and glutamate in cultured human diploid fibroblasts is enhanced in response to diethyl maleate treatment. The enhancement is time- and dose-related, with a lag of about 3 h, and maximum enhancement (approximately 3-fold increase in the rate of uptake) is attained after 1 to 2 days of incubation of the cells with 0.1 mM diethyl maleate. The enhancement of the transport activity is accompanied by an increase in the Vmax and little change in the Km, and it requires RNA and protein synthesis. Other electrophilic agents, such as cyclohex-2-en-1-one, ethacrynic acid, 1,2-epoxy-3-(p-nitro-phenoxy)propane, and sulfobromophthalein, similarly enhance the transport activity. These electrophiles are known as agents that interact with glutathione. For example, diethyl maleate at high concentrations, i.e. 1 mM, depletes intracellular glutathione and injures the cells. However, at relatively low concentrations diethyl maleate and other electrophilic compounds do cause increases in the intracellular levels of glutathione which we attribute to the enhanced uptake of cystine. It is suggested that the transport system for cystine and glutamate is involved in a protective mechanism of cells against an electrophilic attack.

Biological Transport↗
PubMed1981

[Treatment of hypercalcemias].

Apart from the search for specific oncological treatments, interesting investigations are currently in progress into methods designed to increase bone resistance against tumoral aggression. Several substances are under study. Here the discussion will chiefly centre on the diphosphonates, their mechanism of action and indication in bone oncology. It has been seen that tumoral hypercalcemias (with or without bone metastases) essentially derive from disturbance of the balance between the huge mineral stores of the bone and the small extracellular space. It has also been learned that osteolysis inhibition is the major step in their treatment, while therapies designed to eliminate the calcium excess through the kidney (saline solutions, furosemide, ethacrinic acid, dialysis) or bind it with chelators (EDTA) can have only transitory effects. Tumoral osteolysis may be inhibited by drugs acting on bone and/or tumoral cells (mithramycin, calcitonin, corticosteroids etc.) or by the diphosphonates. At present the latter are the treatment of choice for tumoral hypercalcemias.

Adrenal Cortex Hormones↗
PubMed1982

Calcium-dependent stimulation of renal medullary prostaglandin synthesis by furosemide.

The present study examined the actions of furosemide and other "loop" diuretics on immunoreactive prostaglandin E (iPGE) and [14C]arachidonate (AA) release in vitro in incubates of slices from rat and dog outer or inner medulla. The loop diuretics furosemide, ethacrynic acid, bumetanide and 3-benzylamino-4-phenylthio-5-sulfamoylbenzoic acid all significantly increased [14C]AA and iPGE release (1.5- to 4-fold) into the media of rat outer and inner medulla and dog outer medullary slice incubates. By contrast, equimolar concentrations of chlorothiazide and hydrochlorothiazide were without effects on these parameters. Stimulation of [14C]AA or iPGE by furosemide was abolished by exclusion of Ca++ from the incubation media or by addition of verapamil to complete media, but was not altered by exclusion of Na+. Ca++-free media or verapamil also abolished the increases in [14C]AA and iPGE induced by ionophore A23187. By contrast, these incubation conditions did not influence the iPGE responses to hypertonic mannitol or exogenous AA. The presence of Ca++-responsive acyl hydrolase activity was demonstrated in the microsomal fraction from rat outer medulla. However, this activity was not altered by addition of furosemide to the subcellular fraction in the presence or absence of Ca++. Thus, furosemide and other loop diuretics stimulate renal medullary iPGE synthesis in vitro, and may do so through Ca++-mediated or dependent enhancement of the release of AA.

Amidohydrolases↗
PubMed1980

Effect of metabolic inhibitors on 45Ca fluxes and ATP content of myelinated nerve.

The effects of metabolic inhibitors on ATP levels and on 45Ca fluxes were studied in desheathed tibial nerves of Rana pipiens. ATP levels were significantly reduced and Ca influx and efflux increased following exposure to cyanide, mersalyl, azide, dinitrophenol, iodoacetate or ethacrynic acid. The efflux changes were relatively small compared to squid axons but are not attributable to depolarization of the cell or to changes in the transmembrane Na gradient. The magnitude of the effluxes are consistent with ideas about the amount of labile Ca sequestered in energy-dependent Ca pools. The efflux stimulated by metabolic inhibitors is reduced by removing extracellular Na or Ca, indicating that a large portion of Ca efflux in the poisoned state is mediated by Na-Ca countertransport. In the nominal absence of both these cations Ca efflux can be stimulated by metabolic inhibitors, suggesting that mechanisms in addition to countertransport participate in Ca efflux.

Adenosine Triphosphate↗
PubMed1981

Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase.

A nonspecific NADPH-dependent carbonyl reductase from human brain (formerly designated as aldehyde reductase 1; Ris, M. M., and von Wartburg, J. P. (1973) Eur. J. Biochem. 37, 69-77) has been purified to homogeneity. The enzyme reduces a number of biologically and pharmacologically active carbonyl compounds. Quinones, e.g. menadione, ubiquinone, and tocopherolquinone are the best substrates, followed by aldehydes containing an activated carbonyl moiety, e.g. 4-nitrobenzaldehyde or methylglyoxal. The enzyme also reduces ketones, e.g. prostaglandins of the E and A class, the anthracycline antibiotic daunorubicin and 3-ketosteroids. During catalysis the pro 4S hydrogen atom of the nicotinamide ring of NADPH is transferred to the substrate. Flavonoids, e.g. quercetin and rutin, indomethacin, ethacrynic acid, and dicoumarol inhibit the enzyme activity. 4-Hydroxymercuribenzoate and iodoacetate inactivate the enzyme. NADPH and substrate do not protect against the loss of activity. Carbonyl reductase consists of a single polypeptide chain with a molecular weight of 30,000. The native enzyme occurs in three molecular forms with similar substrate specificity and inhibitor sensitivity. The isoelectric points of the three enzyme species are 6.95, 7.85, and 8.5. In the presence of coenzyme the isoelectric points are shifted to 5.2 to 5.9. The comparison of structural and enzymic features of carbonyl reductase with other monomeric oxidoreductases suggests a close relationship of carbonyl reductase with prostaglandin 9-keto-reductase and xenobiotic ketone reductase.

Alcohol Oxidoreductases↗
PubMed1981

[Therapy of coronary insufficiency with diuretics].

Saluretic drugs like thiazide and benzothiadiazine (chloruretic sulfonamides), potassium-sparing diuretics (amiloride, triamterene and spironolactone) and diuretics with an effect on the loop of Henle (furosemide, ethacrynic acid, bumetadine and etozoline) support the efficiency of digitalis preparations in such cases, in which the load of the heart may be diminished by hemodynamic disburdening of the myocardium through reduction of preload. Here, reduced venous filling pressure is the result of increased elimination of sodium and of dehydration. These drugs are efficacious, but can endanger the patient even if prescribed under right indication and by right dosage. Therefore they should be taken only if necessary and only under continuous medical supervision. The therapeutic breadth of the different diuretics is more favourable than that of the digitalis glycosides. Thus the careful prescription of diuretic drugs can enhance digitalization significantly, especially for patients of higher age with increased sensitiveness on heart glycosides or with supposedly "refractory" heart failure. A rapid intravenous injection of furosemide is the best method for the emergency treatment of an acute pulmonary edema in consequence of left heart failure. This is efficacious in a shorter time and in a better manner than an initial injection of heart glycosides. The favourable effect of diuretic drugs in myocardial failure may be explained by improving the force-velocity curve of the heart with reduction of preload of the myocardium and with diminished venous congestion.

Diuretics↗
PubMed1981

[Application of a shuttle avoidance schedule in rats to evaluate a drug-induced auditory impairment (author's transl)].

In attempts to study drug-induced auditory impairment we measured the auditory threshold in rats, using the shuttle box method. The auditory threshold with physical impairment of ears was also measured. The sensitivity of the rats to the auditory response was decreased to about 15dB in cotton-stuffed ears and to about 20dB in pierced eardrums. In this experiment, we used drugs known to be ototoxic; dihydrostreptomycin sulfate, kanamycin sulfate, neomycin sulfate and ethacrynic acid. With successive administration of each drug, the auditory sensitivity in rats decreased. This shuttle box method is easily facilitated and the auditory threshold of many rats can be measured over a short period. This approach may be a useful method for screening ototoxic drugs.

Aminoglycosides↗
PubMed1995

Role of oxidative stress generated from the mitochondrial electron transport chain and mitochondrial glutathione status in loss of mitochondrial function and activation of transcription factor nuclear factor-kappa B: studies with isolated mitochondria and rat hepatocytes.

Mitochondria are an important source of reactive oxygen intermediates because they are the major consumers of molecular oxygen in cells. Respiration is associated with toxicity, which is related to the activation of oxygen to reactive intermediates. The purpose of the present study was to examine the role of reduced glutathione (GSH) in the maintenance of mitochondrial functions during oxidative stress induced through selective inhibition of the complex III segment of the electron transport chain. Hydrogen peroxide monitored by the fluorescence of dichlorofluorescein increased in a time- and dose-dependent manner on incubation of mitochondria with antimycin A (AA), an inhibitor of complex III. However, blockade of complex I or II with rotenone or thenoyltrifluoroacetone, respectively, did not result in accumulation of hydrogen peroxide. Depletion of mitochondrial GSH to 10-20% of control by preincubation with diethylmaleate (0.8 mM) or ethacrynic acid (250 microM) also increased dichlorofluorescein and malondialdehyde levels and resulted in an additional (2-3-fold) increase after AA. Similar results were obtained when mitochondrial GSH depletion was produced by treatment with buthionine L-sulfoximine before mirochondria isolation. The endogenous oxidative stress induced by AA was accompanied by a moderate loss of activity of ATPase complex (77% of control) and complex IV of respiration (75% of control), which was accentuated after depletion of mitochondrial GSH (51% and 45% of control, respectively). Similar results were observed in isolated hepatocytes in which depletion of mitochondrial GSH and AA led to peroxidation and mitochondrial dysfunction. In addition, with electrophoretic mobility shift assay of the transcription factor nuclear factor-kappa B (NF-kappa B), we detected its activation in response to AA (2-3-fold). Depletion of mitochondrial GSH in hepatocytes (20% of control) led to further enhancement of NF-kappa B activation (2-4-fold), which correlated with generation of hydrogen peroxide. Thus, our results suggest that GSH protects mitochondria against the endogenous oxidative stress produced at the ubiquinone site of the electron transport chain. Mitochondrial GSH depletion potentiates oxidant-induced loss of mitochondrial functions. Oxidant stress in mitochondria can promote extramitochondrial activation of NF-kappa B and therefore may affect nuclear gene expression.

Animals↗
PubMed1995

[Diuretics in the neonatal period].

Careful management of fluid and electrolytes may require the rational use of diuretic agents in some neonatal pathological conditions. High efficacy diuretics include "loop" diuretics--furosemide, bumetanide and ethacrynic acid. The elimination half-life and renal effects of furosemide are prolonged in newborn infants as compared with adults. In congestive heart failure, the mean net losses associated with a 1 mg i.v. dose of furosemide, are 28 ml/kg, 3.6 mmol/kg and 0.3 mmol/kg respectively for water, sodium and potassium. The furosemide--dopamine (2 micrograms/kg/min) combination may improve renal insufficiency in the course of respiratory distress syndrome (RDS). Furosemide also decreases the deleterious renal effects of indomethacin. Beneficial effect of furosemide has not been clearly demonstrated in RDS and bronchopulmonary dysplasia (BPD). Metabolic alkalosis, hypokalemia, renal calcifications, cholelithiasis and worsening in BPD outcome have been related to long-term administrations of furosemide. The risk of furosemide induced-ototoxicity has not been clearly assessed in newborn infants. Medium efficacy diuretics (thiazides) act primarily in the early distal tubule. Chlorothiazide may reduce calcium urinary excretion in neonates receiving long-term furosemide therapy. Weak diuretics (potassium-sparing diuretics and carbonic anhydrase inhibitors) cause excretion of less than 5% of the filtered sodium. Potassium-sparing diuretics are usually reserved for neonates with congestive heart failure and are always used in combination.

Benzothiadiazines↗
PubMed1995

Transduction of NIH 3T3 cells with a retrovirus carrying both human MDR1 and glutathione S-transferase pi produces broad-range multidrug resistance.

In the experiments, we examined the ability of a retroviral vector, pHaMASV, to encode two potential chemoprotective genes on separate transcription units. We previously described the pHaMSV vector, which includes the human MDR1 gene as a selectable marker and chemoprotective gene, plus an internal SV40 promoter for expressing a second heterologous gene along with MDR1 [M. E. Metz, D. M. Best, and S. E. Kane. Virology, 208: 634-643, 1995]. To test the ability of this vector to deliver two therapeutic genes simultaneously, the cDNA for human glutathione S-transferase pi (GST pi, the most abundant member of the glutathione S-transferase family in human tumor cells) was inserted into pHaMASV, and this plasmid was transfected into ecotropic packaging cells. The resulting pHaMASV.GST pi ecotropic retrovirus, which was produced at a titer of 2 x 10(6) colony-forming units/ml, was used to transduce NIH 3T3 cells. After initial selection in 60 ng/ml colchicine, a population of transduced cells was exposed to stepwise increasing colchicine concentrations to select for amplified expression of MDR1. As MDR1 expression increased, the expression of GST pi increased in concert, as demonstrated by Northern analysis, Western analysis, and measurement of glutathione S-transferase activity. Transduced cells growing in 1280 ng/ml colchicine had about 3-fold higher total glutathione S-transferase activity than nontransduced cells and 2.5-fold higher activity than transduced cells growing in 60 ng/ml colchicine. Northern hybridizations demonstrated a 3-5-fold increase in both the full-length retroviral message encoding MDR1 and the subgenomic mRNA encoding GST pi after amplification of resistance from 60 to 1280 ng/ml colchicine. The cytotoxic effects of several xenobiotics were evaluated in NIH 3T3 cells transfected with MDR1 (3T3.MDR) or transduced with the MDR1-GST pi retrovirus (3T3.GST640 or 3T3.GST1280) to evaluate the ability of our vector to produce a spectrum of drug resistances specific for the genes expressed. 3T3.MDR and 3T3.GST1280 cells expressing equivalent levels of MDR1 had identical levels of resistance to doxorubicin or colchicine. These results suggest that GST pi expression did not contribute to doxorubicin resistance in this model system. However, 3T3.GST640 cells were about 4-fold resistant to ethacrynic acid and 1-chloro-2,4-dinitrobenzene compared to cells expressing MDR1 alone, consistent with the ability of GST pi to conjugate both of these cytotoxins. Increases in drug resistance paralleled increases in gene-specific mRNA and recombinant protein levels in all cases.4+ chemotherapy.

3T3 Cells↗
PubMedDate not supplied

Insights into mechanisms of cisplatin resistance and potential for its clinical reversal.

Cisplatin in combination with other cytotoxic agents is the backbone for a potential cure of testicular germ cell neoplasms and is a critical factor in the substantial activity observed in the treatment of small cell lung cancer, bladder cancer, and ovarian germ cell tumors. Resistance to cisplatin at the onset of treatment or at relapse limits its curative potential, however. Laboratory studies using both cells selected for cisplatin resistance by exposure to sublethal concentrations and biopsy specimens from patients' tumors provide insights for the potential mechanisms of resistance. The mechanisms identified in vitro include a complex and wide array of related and unrelated pathways such as alterations in cellular drug transport, enhanced DNA repair dependent and independent of signal transduction pathways, and enhanced intracellular detoxification such as glutathione and metallothionein systems. Studies of these mechanisms have identified a number of agents with known potential for administration to humans and that reverse cisplatin resistance in vitro; for example, reversal of cellular accumulation defects by dipyridamole; inhibition of DNA repair by hydroxyurea, pentoxifylline, and novobiocin; inhibition of the glutathione system by ethacrynic acid and buthionine sulfoximine; and inhibition of signal transduction pathways by cyclosporine, tamoxifen, and calcium channel-blocking agents. Current phase I clinical trials are focusing on the most effective doses and schedules to administer these agents in combination with cisplatin. Initial uncontrolled trials in limited numbers of patients suggest that the addition of modulators of cisplatin has the potential to reverse resistance in patients previously failing therapy. Another promising avenue for circumventing cisplatin resistance is the development of noncross-resistant platinum analogs.

Animals↗
PubMed1996

[Diuretics].

Diuretics have been empirically developed. Inorganic mercury was used as diuretics from 16C. Guy's Hospital Pills (containing the equal part of Hg2Cl2, digitalis, and squill) was well known in the 19 C. Discovery of the diuresis of merbaphen has led to develop many organomercurial diuretics and to give suggestion of the drug design of ethacrynic acid. Diuresis in patients given sulfonamide was discovered in 1938. Inhibition of carbonic anhydrase by sulfonamide was related to its diuresis. Drug design aimed to enhance the inhibition of this enzyme has obtained acetazolamide, then chlorothazide. But, the discovery of remarkably enhanced diuretic activity (decreased inhibition on the enzyme) of hydrochlorothazide changed this drug design to rondom chemical modification of thiazide ring. Then, furosemide and other loop diuretics were obtained. The structure-activity relationship of thiazides using the electronic state and other physico-chemical indices was studied by us. A large hydrophobic center linked to a positive formal charge was assumed to the receptor of thiazide. Binding of thiazide to erythrocyte which gives mild and long acting diuretic property was found by us. Recently, shut down of the tubuloglomerular feedback by loop diuretics was reported. Loop diuretics are metabolized to loss their activity. Therapeutic drug monitoring is necessary to obtain a desirable diuresis. By wide clinical use of thiazides and loop diuretics, patients with hyponatremia with eu-or hypervolemic increased. I have proposed aquaretics since 1976. In 1992, nonpeptide selective vasopressin V2 receptor antagonist (OPC-31260) was first synthesized in Japan. This has been found to cause hypotonic diuresis and elevation of serum Na level in men. The combined use of loop diuretics and aquaretics should be considered.

Animals↗
PubMed1996

Study of oxidative-stress in rotavirus infected infant mice.

Rotavirus induced diarrhoea was investigated in neonatal mice. Assessment of oxidative/antioxidative profile was the mechanistic approach to study the nature of injury. Neonatal mice (NMRI strain) were infected orally with the homologous strain of (EB) rotavirus (serotype 3). The peak severity of rotavirus infection was attained on the third day post infection. The whole small intestine of neonatal mice on day 3 post infection was homogenized and analysed for oxidative/antioxidative profile. Glutathione and related thiols were significantly declined in rotavirus infected group. Superoxide dismutase, glutathione peroxidase and glutathione-S-transferase (1-chloro 2, 4 dinitrobenzene) activities were also decreased in the rotavirus infected group. The activities of glutathione reductase and glutathione-S-transferase (ethacrynic acid) however were elevated with rotavirus infection in comparison to the control group. Similarly, ADP-FeCI3, NADPH induced lipid peroxidation was elevated with rotavirus infection. Thus the altered oxidative/antioxidative profile indicated the presence of oxidative stress in the rotavirus infected group and can be postulated to have a prominent role in the pathogenesis of the disease.

Animals↗