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1.
The effects of Cd2+, Mn2+ and Al3+ on rat brain synaptosomal sodium-potassium-activated and magnesium-activated adenosine triphosphatase (Na-K-ATPase and Mg-ATPase) activity and choline uptake were studied. All three types of metal ions inhibited Na-K-ATPase activity more markedly than Mg-ATPase activity. The rank order of inhibition of Na-K-ATPase was: ). The rank order of inhibition of Mg- was: was most potent in inhibiting synaptosomal choline uptake ( in the absence of Ca2+ and 123 μ.M in the presence of 1 mM Ca2+). was a more effective inhibitor of choline uptake than . The presence of 1 mM Ca2+ did not alter choline uptake, nor did it antagonize the inhibitory actions of the three metals. Our observations that Cd2+ and Al3+ inhibited synaptosomal choline uptake, but did not show parallel inhibitory effects on Na-K-ATPase activity directly contradicts the ionic gradient hypothesis. These results are also discussed in relation to the in vivo neurotoxicity of cadmium, manganese and aluminium. 相似文献
2.
A new method of determining the extraction constant (Ke, the true partition coefficient (TPC) and the formation constant (Kf) of ion-pairs, was developed by the solvent extraction technique. Ke and TPC were estimated from the reciprocals of the intercept and the slope of the regression line obtained by plotting in the following equation. where [ATW] and [BTW] are the total concentrations of the cationic compound A and that of the anionic compound B in the aqueous phase respectively, APC is the apparent partition coefficient of A, dA is the partition coefficient of cation A+. Kf, which is expressed by Ke/TPC, was then calculated. These constants were determined for the ion-pair extraction of tetrabutylammonium bromide and isopropamide iodide with 4 organic anions, i.e. benzoic acid, p-toluenesulfonic acid, salicylic acid and taurodeoxycholic acid. This new method might be applicable to other ion-pairs without further assumptions except that the molar ratio of the ion-pair formation be 1 : 1. 相似文献
3.
Effect of polychlorinated biphenyls on the immune responses of rhesus monkeys and mice. 总被引:2,自引:0,他引:2
The relationship between lipid peroxidation, glutathione (GSH) content, and CCl4-induced toxicity was investigated in rat hepatocytes isolated by a collagenase-perfusion technique. Two chemical initiators of lipid peroxidation, ferric ions complexed with adenosine diphosphate () and diethyl maleate, were studied for comparison. CCl4 caused a reduction of intracellular K+ and release of alanine aminotransferase (ALT) into the medium, but no evidence of lipid peroxidation, as measured by the absorbance of thiobarbituric acid (TBA)-reacting materials and lipid-extract diene conjugation. caused lipid peroxidation, but only a small loss of K+. Diethyl maleate caused a greater amount of lipid peroxidation and cell damage than did . Neither response appeared to be related to the GSH content, which was reduced by diethyl maleate, but not by , and by CCl4 only at the highest dose. The results suggest that lipid peroxidation is not a requisite step in CCl4-induced toxicity in isolated hepatocytes. 相似文献
4.
Displacement of [3H]vinblastine binding to tubulin by other Vinca alkaloid derivatives has been demonstrated to be a competitive process, allowing for determination of the association constant of each drug. Correlation of LD50 data and anti-P-388 activity was found with log P and log Ka, according to the equations: . Vincristine and desacetylvinblastine were the two most active agents in this series. That the latter drug had significant biologic activity was of considerable interest, since it is known to be a human metabolite. 相似文献
5.
Richard C. Dirks Morris D. Faiman Earl S. Huyser 《Toxicology and applied pharmacology》1982,63(1):21-28
The relationship between the concentration of unsaturated lipid, free radical initiator, and oxygen concentration on the kinetics of lipid peroxidation was determined. The rate of lipid peroxidation was studied with the thiobarbituric acid (TBA), diene conjugation (DC), and ferrithiocyanate (Fe-SCN) methods. The rate of peroxidation was half-order with respect to unsaturated lipid, initiator, and oxygen. The half-order relationship could be expressed as: . The half-order relationship was found with linoleic (18:2), linolenic (18:3), and arachidonic (20:4) acids. A linear relationship existed between the logarithm of unsaturation and the rate of peroxidation. No peroxidation of linolenic acid was indicated when the DC method was employed, but was when the TBA and Fe-SCN methods were used. 相似文献
6.
7.
Generation of hydrogen peroxide in adipocyte plasma membrane and its intracellular metabolism and regulatory role have been shown by Mukherjee and co-workers to be a major effector system for insulin [Fedn Proc.35, 1694 (1976); Archs Biochem. Biophys.184, 69 (1977); Biochem. Pharmac.27, 2589 (1978); Fedn Proc.37, 1689 (1978); and Biochem. Pharmac.29, 1239 (1980)]. The possible involvement of this mechanism in the action of structurally similar polypeptides having some insulin-like metabolic effects was investigated. The β-subunit of nerve growth factor (2.5 S NGF, mol. wt 13,500) which has a striking structural homology with proinsulin and has been reported to exert certain insulin-like metabolic effects in its own target tissues (e.g. growing neurites and sympathetic ganglia), and the insulin-derived polypeptides, desalanine-insulin and desoctapeptide-insulin, as well as proinsulin, were examined for their effects on rat adipocytes, employing the technique of formate oxidation. Both NGF and proinsulin caused increased [14C]formate oxidation, showing similar intrinsic activities, up to a maximum of 140–160% of the basal rate; insulin increased the rate to 190–210% of the basal rate. The relative potencies of the hormones toward H2O2 formation and stimulation of the pentose phosphate pathway activity were: insulin , desalanine-insulin , proinsulin , and NGF . The biologically inactive derivative, desoctapeptide-insulin, did not stimulate glucose oxidation, although it caused a small increase in formate oxidation, with an , indicating a suboptimal level of H2O2 formation in the elevation of the hexose monophosphate shunt activity. 3-Amino-1,2,4,-triazole (50 mM), which irreversibly decomposes the peroxidatic compound II of the catalase: H2O2 complex, inhibited formate oxidation to a greater extent in the hormone-treated cells than in the control cells, whereas sodium azide, an inhibitor of the hemoprotein, catalase, completely inhibited it. The abilities of the polypeptides to stimulate H2O2 formation correlated with their abilities to promote lipogenesis from [U-14C]-D-glucose, as expected of insulin. The cellular GSH/GSSG ratio increased concomitantly with the stimulation of glucose oxidation via the shunt, indicating a tight coupling between these processes. The results confirm that the hydrogen peroxide production is a common basis of the metabolic actions of growth-promoting polypeptide hormones or mitogens beyond their respective receptors. 相似文献
8.
Quipazine (2-[1-piperazinyl] quinoline maleate) was shown to increase serotonin and decrease 5-hydroxyindoleacetic acid concentrations in whole brain, several brain regions, and the spinal cord of rats 1 hr after its administration (10 mg/kg, i.p.). In animals with transected spinal cords, quipazine induced stronger activation of extensor reflexes than 5-hydroxytryptophan, chlorimipramine, or Lilly 110140. This response could be blocked by methiothepin. In slices of rat cerebral cortex, quipazine inhibited the uptakes of [3H]-serotonin (EC50 = 10?6 M) and [3H]-norepinephrine (); it was equipotent with Lilly 110140 in inhibiting serotonin uptake, but less potent than chlorimipramine (). Quipazine administration to rats did not inhibit monoamine oxidase activity, and actually elevated brain tryptophan levels. These observations suggest that the effects of quipazine on brain serotonin and 5-hydroxyindoleacetic acid concentrations could have been caused by direct activation of central serotonin receptors (which would secondarily decrease impulse flow along serotonergic neurones), or by the inhibition of serotonin reuptake, or by both mechanisms. 相似文献
9.
The effect of diphenylhydantoin on the accumulation of [3H]norepinephrine in vitro was examined in brain slices prepared from rat cerebral cortex. High concentrations of diphenylhydantoin (10?3 M) caused a significant reduction in the 5-min accumulation of [3H]norepinephrine. On the other hand, 10?5–10?4 M diphenylhydantoin facilitated the 20-min accumulation of [3H]norepinephrine. This facilitative action of diphenylhydantoin was (1) associated with a reduction in oxidative catabolism of [3H]norepinephrine and (2) abolished by the 2-hr pretreatment of rats with 100 mg/kg of nialamide (i.p.). The inhibitory action of diphenylhydantoin on the oxidative catabolism of [3H]norepinephrine was observed in both whole and lyzed crude synaptosomal preparations. When diphenylhydantoin and pargyline were compared, it was found that pargyline was 37 times more effective than diphenylhydantoin in inhibiting the oxidative deamination of [3H]norepinephrine. These results suggest that diphenylhydantoin alters norepinephrine metabolism in cerebral cortex slices by an inhibitory action on (1) monoamine oxidase activity and (2) the neuronal uptake system. 相似文献
10.
The actions of Ni2+, Co2+ and Mn2+ on the rabbit heart sarcolemmal ATPases, calcium binding, and adenylate cyclase activities were studied. The ability of sarcolemma to hydrolyze ATP was stimulated by 0.1–4 mM concentrations of Ca2+, Mg2+, Co2+, Ni2+ and Mn2+. The sarcolemmal Ca2+ ATPase (22.8 if of ) and Mg2+ ATPase (21.6 of were depressed by 0.25–4 mM-Co2+, Ni2+ and Mn2+, and the order of their potency was Ni2+ > Co2+ > Mn2+. The sarcolemmal Na+-K + ATPase activity (9.4 of ) was decreased by 0.10–4 mM concentrations of Co2+, Ni2+ and Mn2+. The sarcolemmal calcium binding in the presence of 0.1 mM Ca2+ (98 of ) was depressed by 0.25 mM or higher concentrations of Co2+, Ni2+ and Mn2+, whereas that in the presence of 1.25 mM-Ca2+ (772 of ) was decreased by 2–4 mM-Co2+, Ni2+ and Mn2+. The sarcolemmal adenylate cyclase activities in the absence (124 pmoles cyclic of ) and presence of 2 mM-NaFI517 pmoles cyclic of ) were decreased by 0.1–4 mM-Co2+ or Ni2+ and stimulated by 0.1–4 mM-Mn2+. The contractile force of the isolated rabbit heart was decreased by varying degrees by 0.1–1 mM of divalent cations (Ni2+ > Co2+ > Mn2+). These results indicate sarcolemma is one of the sites involved in the cardiodepressant actions of Ni2+, Co2+ and Mn2+. 相似文献
11.
The effects of the inhalation anaesthetic agent, halothane (CF3CHBrCl), on the stability of the calcium transport system of isolated rabbit white skeletal muscle sarcoplasmic reticulum have been studied. Calcium transport activity was unaffected when suspensions of sarcoplasmic reticulum vesicles were preincubated at 37° and pH 6.8 at concentrations of halothane below 5 mM, but was progressively inactivated at higher concentrations. (Ca2+,Mg2+)-ATPase activity was enhanced during inactivation of calcium transport. At pH 6.3 and 5.8, halothane increased the first order rate constants of inactivation and effects were noted in the anaesthetic range of concentration (1–2 mM). The inulin inaccessible space of membrane vesicles did not change appreciably during the period of treatment with halothane, excluding increased permeability as an explanation of the inhibition of calcium accumulation. Inactivation was irreversible and highly temperature dependent, with an activation energy of 52.7 kcal/mol. Calcium ions had a protective effect against inactivation (K0.5 (Ca2+) = 1.5 × 10?6M), as did ATP (). It is concluded that mild acid conditions and halothane act synergistically during inactivation of the calcium transport system of sarcoplasmic reticulum membranes. These studies suggest that halothane interacts with the (Ca2+, Mg2+)-ATPase protein at the ATP-specific binding site or that it disrupts protein-lipid associations in the membrane. In either case the destabilizing effect of halothane may be modified by the conformational state of the protein. 相似文献
12.
Jiunn Huei Lin Yuichi Sugiyama Shoji Awazu Manabu Hanano 《Biochemical pharmacology》1980,29(20):2825-2830
Kinetic parameters (Km and Vmax) of ethoxybenzamide deethylation in isolated rat hepatocytes and liver microsomes were compared. Adjustment of cofactors in microsomal deethylation, such as NADPH and Mg2+, to give optimum conditions, and appropriate correction of the apparent kinetic parameters for nonspecific binding and microsomal yield resulted in good agreement among the kinetic parameters of isolated hepatocytes [ and Km = 0.459 mM] and microsomes [Vmax = 0.124 μmoles · min?1 · (gliver)?1 and Km = 0.378 mM]. 相似文献
13.
Philip R. Miles Jo Rae Wright Linda Bowman Howard D. Colby 《Biochemical pharmacology》1980,29(4):565-570
Experiments were performed to study the mechanism of action of drug substrates on lipid peroxidation in rat hepatic microsomes. Addition of the drug substrates, aniline, β-diethylaminoethyl diphenylpropylacetate (SKF-525A), aminopyrine, benzo[a]pyrene or ethylmorphine, to hepatic microsomes causes almost complete inhibition of NADPH-induced (enzymatic) lipid peroxidation. These substrates also produce similar inhibition of ascorbate-induced (non-enzymatic) lipid peroxidation in microsomes in which drug-metabolizing enzymes were inactivated by heat treatment. The substrate concentrations producing half-maximal inhibition ( are also similar for NADPH- and ascorbate-induced lipid peroxidation. Addition of metyrapone, an inhibitor of drug metabolism, has no effect on either the values or on the maximal substrate inhibition of NADPH-induced lipid peroxidation. All five drug substrates also inhibit Fe2+-stimulated oxidation of linoleic acid. These results demonstrate that inhibition of lipid peroxidation in hepatic microsomes by drug substrates is independent of drug metabolism and is probably due to the antioxidant properties of the substrates. 相似文献
14.
Our experiments were designed to localize the inhibitory influence of bencyclane2 on the process of oxidative phosphorylation in isolated heart and liver mitochondria. The following results were obtained: (1) The state-3-respiration of rat liver and rabbit heart mitochondria was inhibited by bencyclane. This inhibition was dependent on the substrate used as energy donator, being much more pronounced with glutamate of protein, respectively) than with succinate of protein, respectively). Since the 2,4-dinitrophenol stimulated respiration was equally inhibited, and glutamate transfer through the mitochondrial membrane not influenced, we assume the NADH-coenzyme-Q-reductase to be the site of interaction at the molecular level. (2) Bencyclane stimulates the state-4-respiration of isolated mitochondria with . This effect depends on the molar bencyclane concentration of the incubation medium, and is not abolished by the addition of atractyloside, oligomycin or ruthenium red. Therefore, it is suggested that uncoupling of oxidative phosphorylation is the reason for this bencyclane effect. Theoretically, both of the described effects result in a reduction of the amount of ATP in the living cell. Possible consequences on myocardial function and the cardiovascular system are discussed in terms of previously published data in this field. 相似文献
15.
A low molecular weight cadmium-binding protein has been isolated from Syrian hamster lung. The protein elutes from a Sephadex G-75 column with (1.64 – 1.98) characteristic of metallothionein-like proteins and has an estimated molecular weight of 15,000. The Cd-binding protein does not appear to bind Cr3+, Ni2+, or Se4+. A low molecular weight Cd-binding protein in lungs of this species may be responsible for the prolonged retention of Cd in lung following pulmonary exposure of hamsters to CdCl2. 相似文献
16.
Stephen Brimijoin Keith P. Mintz Franklyn G. Prendergast 《Biochemical pharmacology》1983,32(4):699-706
Interactions between dansylarginine N-(3-ethyl-1,5-pentanediyl)amide (DAPA) and the cholinesterases were examined by the techniques of enzyme kinetics and fluorescence spectroscopy. When tested with partially purified enzyme preparations, DAPA was a potent inhibitor of butyrylcholinesterase but not of acetylcholinesterase . For a detailed study of the effects of DAPA on butyrylcholinesterase (BuChE), the enzyme was purified to homogeneity from horse serum, with the aid of affinity chromatography on N-methyl acridinium. The kinetics of the inhibition of purified BuChE by DAPA were complex, having both competitive and non-competitive features, and it was not possible to estimate Ki unambiguously. Spectroscopic measurements showed that the fluorescence of the dansyl moiety was strongly affected by the binding to BuChE. With excitation at 330 nm, total fluorescence emission from bound DAPA (at 450 nm and above) was 21-fold greater than from free DAPA. In a titration experiment, this enhancement of fluorescence intensity was used to calculate that each monomer of BuChE has two apparently independent DAPA-binding sites with a Kd of 4.5 × 10?7 M. Further measurements showed that the fluorescence emission of bound DAPA was markedly blue-shifted (to 502 nm from 570 nm in free solution) and that the fluorescence lifetime of this form was greatly prolonged (to 24 nsec from 2.7 nsec). These observations indicate that the high affinity binding sites on BuChE lock DAPA in a highly non-polar environment. 相似文献
17.
Hepatocytes of adult rats were isolated by infusion of a hyaluronidase collagenase mixture. High yields of cells excluding trypan blue were obtained. These cells, in Hank's buffer containing rat serum and 0.1% glucose, ethylmorphine. The formaldehyde initially formed is further metabolized to tritiated water. Fifteen per cent of the original metabolic activity was observed after 21 hr at 37° in 5% CO2-air, and cumulative metabolism is linear for up to 90 min under these conditions. The Km for the N-demethylation of [3H-CH3-N]ethylmorphine is 50 μM, 20 per cent of the value observed for this reaction by musomal preparations. An active transport of the substrate into the cell is postulated to account for this difference. 相似文献
18.
A method suitable for the analysis of nitrate in human urine was developed. Normal urinary concentrations of nitrate in urine of human volunteers in Dade County, Florida, where the drinking water contains negligible amounts of nitrate, averaged 47.6 ppm of (SD = 17.3). On a vegetable and preserved-meat-free diet, the nitrate concentration was reduced (10 to 30 ppm of ), but, on nitrate-supplemented drinking water, the urinary concentration rose to a range of 34–87 ppm of . A high vegetable diet resulted in peak urinary nitrate concentrations of 270–425 ppm. These results indicated that nitrate in drinking water is a factor in determining urinary nitrate concentration, but that vegetable ingestion is of greater significance. 相似文献
19.
Using a double-label procedure, the incorporation of endogenously-derived 35SO4 into phenylethylene glycol sulfates (PGS) was estimated. When [3H]norepinephrine and [35S]cysteine were injected concomitantly into the brain, about 30–80 percent of the tritium and about 4 percent of the 35S retained in the brain 1 hr later were in PGS. In B6-deficient rats, the proportion of 35S was increased as was the ratio. Probenecid caused a significant increase in the amount of PGS found in the brain, but a minimal enrichment of 35S was observed, suggesting that there was little or no effect on sulfotransferases. Cysteine in high concentrations inhibits the incorporation of tritium into PGS. 相似文献
20.
J C Gage 《Toxicology and applied pharmacology》1975,32(2):225-238
Organic mercury compounds are to varying extents degraded by ascorbate and by soluble proteins. Phenyl-, methyl-, and methoxyethyl mercury are attacked by ascorbate, provided that the solution has been exposed to air in the presence of Cu2+, although the reaction can subsequently proceed in the absence of air. Mercury vapour (Hg0) and inorganic mercury (Hg2+) are released, and the ratio varies with the three compounds, being high with methoxyethyl-mercury and very low with methylmercury. The ratio is much reduced in the presence of cysteine. It is suggested that the ascorbate free radical is responsible for the reaction. γ-Globulin can degrade phenyl-mercury, but not methyl- and methoxyethylmercury, to yield Hg2+. The action is much stimulated by glutathione and dithiothreitol, and the evidence suggests that these act by reducing protein disulphide groups, and that the Hg2+ released remains attached to reactive protein thiol groups. Serum albumin appears to have a similar action. Most of the activity of the soluble fraction of a rat liver homogenate can be accounted for by the presence of thiol-activated proteins. 相似文献