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J J Kocsis

Publications and source records attributed to J J Kocsis.

At least 19 recordsLinked to original sources
PubMed1995

Dexamethasone induces resistance to the lethal consequences of electron transport inhibition in cultured hepatocytes.

Pretreatment of cultured rat hepatocytes with 1 microM dexamethasone protected against cell killing by 5 microM rotenone and 1 mM cyanide. Simultaneous treatment (no pretreatment) was ineffective, as was pretreatment with 10 microM of sex hormones or the mineralocorticoid aldosterone. Protection by dexamethasone was blocked by 10 microM of glucocorticoid receptor antagonist, RU486, and by 1 microM of the inhibitor of protein synthesis, cycloheximide. Cells pretreated with dexamethasone for 6, 12, and 18 h showed increasing degrees of protection. Pretreatment with dexamethasone had no effect on either the decline of cellular ATP or the loss of the mitochondrial membrane potential. In addition, dexamethasone did not prevent the mitochondrial permeability transition. By contrast, dexamethasone prevented the increased release of [3H]arachidonic acid from phospholipids produced by cyanide. These data describe an inductive effect of dexamethasone in protecting cultured hepatocytes against inhibition of electron transport by rotenone and cyanide. It is concluded that pretreatment with dexamethasone prevents cell killing by inhibiting a mechanism that couples the mitochondrial permeability transition to the accelerated degradation of plasma membrane phospholipids.

Adenosine Triphosphate↗
PubMed1990

Aspirin acetylates the tricyclic antidepressant amoxapine spontaneously to N-acetylamoxapine in vitro and in vivo.

1. N-Acetylamoxapine is formed nonenzymically in vitro, and in mice, from amoxapine, a tricyclic antidepressant, and aspirin. 2. Formation of acetylamoxapine from amoxapine and aspirin in vitro was maximal at pH 5.0 since this pH optimized reactant solubilities as well as decreasing aspirin hydrolysis. 3. Formation of aceylamoxapine from amoxapine and aspirin in mouse stomachs was rapid, and the pH study indicates that the intestinal pH would favour formation even more. 4. Acetylamoxapine administered to mice produced the same CNS-related signs, leading to death, as with amoxapine, but much larger doses and longer time periods were required to elicit these effects. As brain and liver levels of amoxapine in animals dying from acetylamoxapine administration were less than half those found in animals given lethal doses of amoxapine, the toxicity in mice of acetylamoxapine may not be due solely to deacetylation of acetylamoxapine to the parent compound.

Acetylation↗
PubMed1989

Acute toxicity and urinary excretion of diphenyldiselenide.

The acute toxicity of diphenyldiselenide (DPDS) in the male Swiss mouse was found to be enhanced by pretreatment with phenobarbital of SKF-525A. DPDS decreased hepatic glutathione content by 50% at 1 h after administration. Following administration of 14C-DPDS, labelled metabolites were found in urine but not in bile or feces. Analysis of the urinary metabolites of 14C-DPDS showed that selenium-containing metabolites elute from a DEAE-Sephadex column in two fractions: the first has not been chemically characterized, while the second peak contained the glucuronide conjugates of C6H4(OH)SeH and C6H5SeH. Virtually all of the administered selenium is excreted within 5 days, while only about 36% of the 14C is excreted in the same time period. This discrepancy indicates metabolic scission of the carbon-selenium bond.

Animals↗
PubMed1988

An improved method for isolating Ca2+-resistant myocytes from the adult rat heart.

Maintaining viability in cardiac myocytes isolated from adult rats using collagenase is difficult in Ca-containing media due to cell damage that occurs on reintroduction of Ca after perfusing the heart with the Ca-free medium needed to isolate myocytes with collagenase. Recently it has been proposed that Ca-free perfusion of isolated rabbit interventricular septa leads to cellular Na overload which, on reintroducing Ca, produces influx of toxic concentrations of Ca due to the Na/Ca exchange mechanism in the sarcolemma. We have found that replacing a portion of the 118 mM NaCl in the Ca-free perfusion medium with 69 mM LiCl dramatically increased the proportion of Ca-tolerant cardiac myocytes isolated from adult male rats with collagenase. Myocyte viability was maintained over a four hour period of incubation at 37 degrees C in 1 mM Ca.

Animals↗
PubMed1986

Metabolism of salicylate by isolated kidney and liver mitochondria.

Mitochondria are known to contain a P-450 like system similar to that found in microsomes. Since previous in vivo studies from this laboratory have suggested that renal mitochondria may metabolize salicylate (SAL) to a reactive intermediate capable of protein binding, the ability of isolated kidney and liver mitochondria to activate salicylate was investigated. Renal mitochondria were 4 times more active than liver in converting SAL to a reactive intermediate and metabolized approx. 1% of the SAL to 2,3-dihydroxybenzoic acid, the catechol analogue of SAL. The formation of 2,3-dihydroxybenzoate (2,3-DHBA) and the amount of radiolabel bound to mitochondrial protein was decreased in the presence of SKF 525-A; however, excess unlabeled metabolite had no effect on binding. These data indicate that kidney mitochondria activate SAL via a cytochrome P-450 like system, but suggest that the binding species is not 2,3-DHBA itself. Oxidation of SAL and covalent binding of radiolabel, however, were also observed after the addition of ferrous iron and ascorbic acid to a model system containing [14C]SAL and bovine serum albumin. Mannitol decreased SAL oxidation and covalent binding, suggesting radical formation may represent a non-enzymatic mechanism for SAL activation.

Animals↗
PubMed1986

The effect of mixed function oxidase induction and inhibition on salicylate-induced nephrotoxicity in male rats.

A previous study in this laboratory demonstrated that greater nephrotoxicity was induced by 500 mg/kg [14C]salicylate in 12-month-old male Sprague-Dawley rats than in 3-month-old animals, and the increased nephrotoxicity was correlated with greatly increased binding of radioactivity to the renal mitochondria in the older rats. To determine the role of reactive intermediate generation in salicylate-induced nephrotoxicity, male Sprague-Dawley rats were pretreated with piperonyl butoxide, phenobarbital, or Aroclor prior to the administration of 500 mg/kg [14C]salicylate. In the kidneys of rats pretreated with only corn oil, mitochondrial macromolecules contained 57% of the total covalently bound radioactivity while in the livers of these same animals, microsomes contained most (52%) of the bound radioactivity. Pretreatment with piperonyl butoxide, an inhibitor of mixed function oxidase activity, decreased (a) salicylate-induced nephrotoxicity; (b) the covalent binding of [14C]salicylate equivalents to renal mitochondria; and (c) the formation of the 2,3- and 2,5-dihydroxybenoic acid metabolites of salicylate. Pretreatment with phenobarbital and Aroclor, inducers of hepatic P-450, on the other hand, had no effect on salicylate-induced nephrotoxicity nor on the covalent binding of [14C]salicylate equivalents to renal mitochondria. These data are consistent with the hypothesis that salicylate is metabolized to reactive intermediates that irreversibly bind to renal mitochondria and lead to salicylate-induced nephrotoxicity.

Alanine Transaminase↗
PubMed1985

The effect of age on salicylate-induced nephrotoxicity in male rats.

The administration of 500 mg/kg sodium [14C]salicylate to 3- and 12-month-old male rats produced proximal tubular necrosis in the older animals but only mild nonspecific cellular changes in the younger group. The onset of renal damage was similar for both 3- and 12-month-old rats but recovery time was prolonged in the older rats. Covalent binding of salicylate equivalents was present in renal cortices from all rats and was largely confined to the mitochondrial fraction; however, older rats displayed five times more binding to this organelle than younger rats. Also the mitochondrial pathway for salicylurate synthesis was significantly inhibited in the older animals. These results demonstrate the existence of an age-dependent susceptibility to salicylate nephrotoxicity and suggest that mitochondrial injury may play an important role in the development of salicylate-induced proximal tubular necrosis.

Aging↗
PubMed1981

Toxicological and biochemical effects of repeated administration of benzene in mice.

Repeated dosing of mice with benzene led to a dose-related decrease in red cell production as measured by the incorporation of 59Fe into developing erythrocytes. Phenol, catechol, and hydroquinone were observed in the urine, largely conjugated with glucuronic acid and ethereal sulfate. During repeated dosing, toluene-soluble radioactivity derived from labeled benzene was found to accumulate in blood, liver fat, and, most significantly, bone marrow. Greater accumulation was observed when water-soluble metabolites of benzene were examined in these organs. Covalent binding of benzene metabolites was also observed in liver and marrow during repetitive treatment. Both covalently bound and soluble metabolites accumulated in bone marrow, liver, and kidney over a 24-h period after a single administration of benzene. The highest levels of covalent binding were seen in kidney and liver after 3 d of dosing at 880 mg/kg, two doses per day. Studies in vitro demonstrated the necessity for metabolic activation to produce covalent binding from benzene. These studies demonstrate that increasing benzene toxicity during repetitive treatment of mice is accompanied by increases in the levels of both water-soluble and covalently bound benzene metabolites.

Adipose Tissue↗
PubMed1981

The use of ferrokinetics in the study of experimental anemia.

Erythropoietic cells in bone marrow are vulnerable to cytotoxic substances. There are three types of erythroid precursors: cells that can take up Fe but do not proliferate (reticulocytes), those that can take up Fe and proliferate (normoblasts and pronormoblasts), and those cells that do not take up Fe but can proliferate and differentiate into the erythroid cell line (ERC and stem cells). Each of these erythroid precursors requires a certain time before they emerge into the peripheral blood as mature red blood cells. By applying our understanding of ferrokinetics associated with erythropoiesis, it was possible to estimate a cytotoxic effect of chemicals on proliferating erythgroid precursors (pronormoblasts) in mice by measuring 24-hr 59Fe uptake in red blood cells 48 hr after treatment with chemicals. The effect of chemicals on pluripotent hemopoietic stem cells in mice was also estimated by measuring 24-hr 59Fe uptake 72 hr after treatment with chemicals. The validity of experimental schemes was tested using cytarabine, methotrexate, vinblastine, cyclophosphamide, and busulfan, which are known to act against specific cell types. Effects on pluripotent hemopoietic stem cells were tested with or without activation of stem cells in G0 into cell cycle. Applications of the 59Fe uptake method in the study of (1) benzene toxicity and (2) effect of pentobarbital on the toxic action of hydroxyurea and cytarabine are described. Proper application of the ferrokinetic characteristics of erythropoietic cells enables the establishment of a methodology which can be used to evaluate potential toxic effects of chemicals on erythroid precursor cells and pluripotent hemopoietic stem cells.

Anemia↗
PubMed1979

Partial hepatectomy reduces both metabolism and toxicity of benzene.

Removal of 70--80% of the liver reduced both the metabolism and the toxicity of benzene in rats. Metabolism was evaluated by measuring the levels of urinary metabolites in both sham-operated and partially hepatectomized rats given 2200 mg/kg [3H]benzene sc. Toxicity was evaluated by measuring the incorporation of 59Fe into circulating erythrocytes according to the method of Lee et al. The observation that partial hepatectomy decreases benzene metabolism and protects against benzene toxicity indicates that the liver may play a primary role in the development of benzene-induced bone marrow toxicity. The fact that benzene administration also reduces the ability of the liver to regenerate after partial hepatectomy suggests that the regenerating liver may serve as a model system in lieu of the bone marrow for studying the mechanism by which benzene inhibits cell proliferation.

Animals↗
PubMed1978

Fatty acids and the initial events of endothelial damage seen by scanning and transmission electron microscopy.

A method was developed for observing changes in the endothelial cells in rabbit ear veins in vivo by scanning electron microscopy. Injection of fatty acids into the ear vein caused damage to the endothelium. The first signs of damage seen were marked bulges in the nuclei and loss of the rhomboidal shape of the endothelial cells. More severe damage included loss of nuclei, leaving holes in the cytoplasm. Some parts of the damaged endothelium showed complete separation of cells from each other and exposure of sub-endothelial tissue to which platelets with pseudopodia were adhering. Damage to the endothelium was produced by arachidonic, linoleic, gamma-linolenic, 8,11,14-eicosatrienoic, 5,8,11,14,-eicosatetraenoic or 15-hydroperoxy-5,8,11,13-eicosatetraenoic acids. The effect of arachidonic acid was not prevented by pre-treating the animals with aspirin. It appears that damage produced by the fatty acids is non-specific.

Animals↗