Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The appearance of drug resistant strains of herpes simplex virus type 1 (HSV-1) against 9-beta-D-arabinofuranosyladenine (araA), in comparison with 5-iodo-2'-deoxyuridine (IUdR) and 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine, ACG), has been investigated in green monkey kidney cell cultures (Vero) and human embryo lung cell cultures (HEL). Growth curves of HSV-1 in Vero cells and HEL cells in the presence or absence of 20 micrograms/ml of araA showed that not only the viruses produced by these cells in the presence of araA but also the viruses produced in the absence of araA were resistant to the same concentration of araA. However, both viruses were unable to grow in the presence of a combination of 20 micrograms/ml of araA and 3 micrograms/ml of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) which is an inhibitor of adenosine deaminase. On the other hand, the viruses produced only in the presence of IUdR or ACG were resistant to each drug. All virus clones obtained from five serial clonings in the presence of araA alone or araA and EHNA in combination were not resistant to araA. These results show that the strain of HSV-1 resistant to araA is an apparently resistant strain, and a truly resistant strain to araA may not be established as easily as the truly resistant strains to IUdR and ACG.
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PMID:Study on the apparent resistant strains of herpes simplex virus type 1 against 9-beta-D-arabinofuranosyladenine. 285 80

Zymosan particle-stimulated beta-galactosidase secretion by mouse peritoneal macrophages was found to be inhibited by micromolar concentrations of adenosine, AMP, ADP, and ATP. Inhibition by all four agents was increased to approximately 80% by adding erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA; 10 microM) an adenosine deaminase inhibitor, to the incubation medium. The inhibition of lysosomal enzyme secretion by ATP, ADP, and AMP was reversed by adding alpha, beta -methylene ADP (100 microM), a 5'-nucleotidase inhibitor, to the incubation medium. Inhibition by adenosine, however, was unaffected by alpha, beta -methylene ADP indicating that the inhibition by AMP, ADP, and ATP only occurred after they had been converted to adenosine by cell surface phosphohydrolases, including 5'-nucleotidase. Theophylline, a competitive antagonist of the binding of adenosine to plasma membrane adenosine receptors, failed to reverse the inhibitory effect of adenosine indicating the probable site of adenosine action to be intracellular. Other purine nucleosides, e.g., guanosine, and several purine and ribosemodified structural analogues of adenosine also inhibited zymosan-stimulated beta-galactosidase secretion, while xanthosine and certain pyrimidine nucleosides, e.g., thymidine, were inactive in this respect.
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PMID:Regulation of macrophage lysosomal secretion by adenosine, adenosine phosphate esters, and related structural analogues of adenosine. 298 3

Adenosine deaminase reversibly increased the amplitude and the quantum content of the end-plate potentials (EPPs) recorded from superficial muscle fibers of frog sartorius preparations in which twitches have been prevented with high-magnesium solutions. Adenosine deaminase prevented the inhibitory effect of exogenously applied adenosine but not that of 2-chloroadenosine on the amplitude of EPPs. The effect of adenosine deaminase was abolished by erythro-9(2-hydroxy-3-nonyl)adenine (EHNA). The results suggest that endogenous adenosine exerts an inhibitory 'tone' over neuromuscular transmission.
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PMID:Enhancement of transmission at the frog neuromuscular junction by adenosine deaminase: evidence for an inhibitory role of endogenous adenosine on neuromuscular transmission. 300 27

The loss of the catabolic products of adenosine triphosphate in the form of purine nucleosides and oxypurines during ischemia and subsequent reperfusion may limit adenine nucleotide regeneration. This study compared the effects of infusion of inhibitors of the major reactions involved in the degradation of adenosine triphosphate to inosine on the postischemic recovery of high energy phosphate and myocardial function. Isolated rat hearts were made totally ischemic after a 5-min infusion of p1,p5-diadenosine pentaphosphate, alpha, beta-methylene adenosine diphosphate, nitrobenzyl-6-thioinosine, or erythro-9-(2-hydroxy-3-nonyl) adenine, which are inhibitors of adenylate kinase, 5'-nucleotidase, adenosine translocase, and adenosine deaminase, respectively. Following 30 min of ischemia, only hearts infused with alpha, beta-methylene adenosine diphosphate recovered significantly better ventricular function than did the control (P less than 0.05), but all hearts had increased adenosine triphosphate and creatine phosphate regeneration (P less than 0.05). The formation and washout of greater than 30% of the total adenine pool metabolites were not prevented by any drug. Nevertheless all manipulations of adenine metabolism resulted in recruitment of high energy phosphate during preischemic infusion which may have potential benefits in elective ischemic arrest.
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PMID:Influence of inhibitors of ATP catabolism on myocardial recovery after ischemia. 304 Nov 5

The simultaneous administration of 3'-deoxyadenosine N1-oxide (3'-dANO) and the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) or 2'-deoxycoformycin (2'-dCF) to mice bearing Ehrlich ascites tumor cells resistant to 3'-dANO resulted in 80%-90% inhibition of tumor growth in vivo. 3'-dANO and 2'-dCF increased the survival time of tumor-bearing mice by a factor of 2. In vitro studies showed that the 3'-dANO resistant Ehrlich cells initiate the metabolism of 3'-dANO by a reduction to 3'-deoxyadenosine, which is converted primarily to 3'-deoxyinosine by adenosine deaminase and, to a small extent, phosphorylated to the cell toxic agent 3'-dATP. By the addition of EHNA or 2'-dCF it was possible to block the formation of 3'-deoxyinosine, resulting in a profound stimulation in the accumulation of 3'-dATP. The development of resistance to 3'-dANO was studied in cell cultures and found to be accompanied by changes in the enzyme activities of the reductase, the adenosine kinase, and the adenosine deaminase.
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PMID:Synergistic effect of 3'-deoxyadenosine N1-oxide and adenosine deaminase inhibitors on growth of Ehrlich ascites tumor cells in vivo. 325 21

1. Extracellular degradation of adenosine by adenosine deaminase was studied in the rat duodenum using high performance liquid chromatography (HPLC) and pharmacological techniques. 2. Relaxant responses to adenosine (1-10 microM) were potentiated in a concentration-dependent manner by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and deoxycoformycin, both of which are inhibitors of adenosine deaminase. 3. Breakdown of adenosine, determined by HPLC, due to incubation with segments of rat duodenum was inhibited by both EHNA and deoxycoformycin. Cytosolic sources of adenosine deaminase were excluded. 4. Relaxant responses to adenosine were also potentiated by the adenosine transport inhibitor dilazep, which did not inhibit adenosine deaminase activity. 5. The extracellular adenosine deaminase activity (4 units/g tissue) was high compared with activity previously determined in other organs.
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PMID:Degradation of adenosine by extracellular adenosine deaminase in the rat duodenum. 326 22

Two new deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 1), 7-deaza-EHNA (6) and 1,3-dideaza-EHNA (11), were synthesized and evaluated for adenosine deaminase (ADA) inhibitory activity and compared with EHNA, 1-deaza-EHNA (2), and 3-deaza-EHNA (3). Substitution of a methine group for a nitrogen atom in the 7-position of the purine moiety of EHNA produces a dramatic drop in the inhibitory activity (Ki = 4 X 10(-4) M) whereas compounds 2 and 3 are still good inhibitors (Ki = 1.2 X 10(-7) M and 6.3 X 10(-9) M respectively). EHNA and its deaza analogues so far synthesized were also tested in vitro for their antiviral and antitumor activity in a range of cellular systems. EHNA and 1-deaza-EHNA are equiactive as inhibitors of human respiratory syncytial virus (HRSV) replication (MIC = 6.25 micrograms/mL) while the other compounds are inactive. On the other hand, all the examined compounds displayed an antitumor activity comparable to that of the reference compound 1-beta-D-arabinofuranosyladenine (ara-A), 7-deaza-EHNA being the most active of all. The results obtained showed that there is no correlation between adenosine deaminase inhibition and antiviral or antitumor activity in this series of compounds. 3-Deaza-EHNA, the most active inhibitor of ADA among the EHNA deaza analogues, greatly potentiates the antitumor activity of ara-A in vitro. In vivo activity was observed only when the two compounds were used in combination.
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PMID:Adenosine deaminase inhibitors. Synthesis and biological activity of deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine. 333 8

Anaphylactic events occurring in cardiac tissue can result in severe metabolic imbalances. The present study addresses the question of whether adenosine, produced in response to this stress, influences either the antigen-antibody-induced alterations in cardiac function or the release of histamine, which is known to be one of the important mediators of the anaphylactic reaction. Isolated hearts of passively sensitized guinea pigs were perfused at constant flow in a Langendorff preparation with physiological salt solution. Under control conditions, antigen challenge evoked a rapid transient release of histamine, an increase in coronary vascular resistance and beating rate, and an increase followed by a decrease in left ventricular systolic pressure. The antigen-induced transient increase in adenosine release from 0.26 +/- 0.07 to 4.66 +/- 0.48 nmol/min/g was associated with a 75 +/- 9% increase in the PR interval in all hearts and atrioventricular blocks in six of 17 hearts. Antigen challenge was also conducted in the presence of theophylline, 8-(4-sulfophenyl) theophylline (SP-T), erythro-9-(2-hydroxy-3-nonyl) adenosine hydrochloride (EHNA), or exogenous adenosine. The major findings were that 1) the antigen-induced prolongation of the PR interval was attenuated by the adenosine receptor blockers theophylline (to 23 +/- 6%) and SP-T (to 15 +/- 4%); 2) the incidence of antigen-induced atrioventricular blocks tended to be decreased by theophylline (to three of 10 hearts) and SP-T (to zero of seven hearts) and to be increased by the adenosine deaminase inhibitor, EHNA (to six of 10 hearts); 3) none of the interventions had major influences upon antigen-induced alterations in vascular resistance, atrial automaticity, or systolic pressure; and 4) EHNA and adenosine both significantly increased adenosine levels before anaphylaxis and also enhanced the total histamine release induced by antigen challenge from a control value of 2,321 +/- 244 ng/g to 3,424 +/- 307 ng/g and 4,298 +/- 616 ng/g, respectively. We conclude from our data that increases in levels of endogenous adenosine during cardiac anaphylaxis may contribute to the development of atrioventricular conduction delays and blocks and that increases in levels of adenosine before antigen challenge may increase the amount of histamine released during cardiac anaphylactic reactions.
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PMID:Effect of adenosine on histamine release and atrioventricular conduction during guinea pig cardiac anaphylaxis. 338 63

2-Bromo-2'-deoxyadenosine (BdA) is one of a group of recently synthesised halogenated deoxyadenosine analogues that are relatively resistant to inactivation by adenosine deaminase (ADA). Its activity has been studied in human acute myeloid leukemia (AML) in vitro. In these studies BdA behaved as a cycle-active, phase-active agent that blocked cells at the G1-S transition. It did not exhibit significant cross-resistance with cytosine arabinoside (Ara-C) in either clinical AML samples (from patients who exhibited Ara-C resistance in vivo) or in HL60 in which Ara-C resistance had been induced in vitro. Deoxycytidine kinase levels were not reduced in resistant lines. Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase (ADA) inhibitor, with BdA produced a simple additive response without the dramatic synergism reported when it is used with deoxyadenosine. This is consistent with the idea that BdA is a poor substrate for ADA. This group of compounds warrants further investigation to determine their suitability for clinical use, especially in situations where Ara-C resistance is likely to be a problem.
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PMID:Lack of cross-resistance between cytosine arabinoside and a new halogenated nucleoside analogue, 2-bromo-2'-deoxyadenosine in human acute myeloid leukaemia cells. 349 52

Adenosine is an endogenous neuromodulator with depressant effects on CNS neurons. Adenosine agonists produce biphasic effects on activity, decreases in operant response rate, and anticonvulsant effects. These effects are similar to some of the behavioral effects of ethanol. In addition, it has recently been shown that relative sensitivities to some of the behavioral effects of ethanol and purinergic drugs are similar in inbred strains of mice. These findings have prompted the speculation that ethanol's behavioral effects may be mediated by an agonist action on adenosine-receptive neurons. The present study provided a direct test of this hypothesis with respect to the discriminative stimulus properties of ethanol. In this study, neither the A1 receptor agonist N6-cyclohexyladenosine nor the A2 receptor agonist N6-ethylcarboxamide adenosine produced significant generalization to the ethanol stimulus. In addition, neither the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)-adenine nor the adenosine uptake inhibitor dipyridamole were able to enhance the level of ethanol-appropriate responding seen after a low dose of ethanol. Both caffeine and 8-phenyltheophylline partially but significantly antagonized the stimulus properties of ethanol. However, the doses required to achieve these effects were much higher than those needed to block adenosine receptors. These findings strongly suggest that the discriminative stimulus properties of ethanol are not mediated through an agonist action on adenosine-receptive neurons.
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PMID:Endogenous adenosine-receptive systems do not mediate the discriminative stimulus properties of ethanol. 382 98


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