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

---

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

A1 adenosine receptors in the rat prepiriform cortex play an important role in the inhibition of bicuculline methiodide-induced convulsions. In the present study we evaluated manipulation of endogenous adenosine in this brain area as a strategy to effect seizure suppression. All compounds evaluated were unilaterally microinjected into the rat prepiriform cortex. Administration of exogenous adenosine afforded a dose-dependent protection (ED50 = 48.1 +/- 8.4 nmol) against bicuculline methiodide-induced seizures, and these anticonvulsant effects were significantly potentiated by treatment with an adenosine kinase inhibitor, 5'-amino-5'-deoxyadenosine; by the adenosine transport blockers, dilazep or nitrobenzylthioinosine 5'-monophosphate; and by an adenosine deaminase inhibitor, 2'-deoxycoformycin. When administered alone, 5'-amino-5'-deoxyadenosine, 5'-iodotubercidin and dilazep were found to be highly efficacious as anticonvulsants with respective ED50 values of 2.6 +/- 0.8, 4.0 +/- 2.7 and 5.6 +/- 1.5 nmol. In contrast, 2'-deoxycoformycin was both less potent and less efficacious. These results suggest that accumulation of endogenous adenosine may contribute to seizure suppression, and that adenosine kinase and adenosine transport may play a pivotal role in the regulation of extracellular levels of adenosine in the central nervous system. The adenosine antagonist, 8-(p-sulfophenyl)theophylline, increased markedly the severity of bicuculline methiodide-induced seizures. Moreover, reduction of extracellular adenosine formation by a focal injection of an ecto-5'-nucleotidase inhibitor, alpha, beta-methyleneadenosine diphosphate, produced generalized seizures (ED50 = 37.3 +/- 22.7 nmol). Together the proconvulsant effect of an adenosine receptor antagonist and the convulsant action of an ecto-5'-nucleotidase inhibitor further support the role of endogenous adenosine as a tonically active antiepileptogenic substance in the rat prepiriform cortex.
...
PMID:Manipulation of endogenous adenosine in the rat prepiriform cortex modulates seizure susceptibility. 845 Apr 75

Human fibroblast lysosomes, purified on Percoll density gradients, contain an adenosine deaminase (ADA) activity that accounts for approximately 10% of the total ADA activity in GM0010A human fibroblasts. In assays of lysosomal ADA, the conversion of [3H]adenosine into [3H]inosine was proportional to incubation time and the amount of lysosomal material added to reaction mixtures. Maximal activity was observed between pH 7 and 8, and lysosomal ADA displayed a Km of 37 microM for adenosine at 25 degrees C and pH 5.5. Lysosomal ADA was completely inhibited by 2.5 mM Cu2+ or Hg2+ salts, but not by other bivalent cations (Ba2+, Cd2+, Ca2+, Fe2+, Mg2+, Mn2+ and Zn2+). Coformycin (2.5 mM), deoxycoformycin (0.02 mM), 2'-deoxyadenosine (2.5 mM), 6-methylaminopurine riboside (2.5 mM), 2'-3'-isopropylidene-adenosine (2.5 mM) and erythro-9-(2-hydroxy-3-nonyl)adenine (0.2 mM) inhibited lysosomal ADA by > 97%. In contrast, 2.5 mM S-adenosyl-L-homocysteine and cytosine were poor inhibitors. Nearly all lysosomal ADA activity is eluted as a high-molecular-mass protein (> 200 kDa) just after the void volume on a Sephacryl S-200 column, and is very heat-stable, retaining 70% of its activity after incubation at 65 degrees C for 80 min. We speculate that compartmentalization of ADA within lysosomes would allow deamination of adenosine to occur without competition by adenosine kinase, which could assist in maintaining cellular energy requirements under conditions of nutritional deprivation.
...
PMID:Demonstration of adenosine deaminase activity in human fibroblast lysosomes. 845 34

The effect of 3'-deoxyadenosine N(1)-oxide (3'-dANO) on Ehrlich ascites tumor and a human squamous lung cell carcinoma was investigated. The 3'-dANO concentration that inhibited the cell growth 50% (IC(50)) in Ehrlich ascites tumor cells in vitro was 0.15 mM, and the killing efficiency concentration (concentration of the drug that kills all cells) was 1 mM. By simultaneous administration of 3'-dANO and the adenosine deaminase inhibitor erythro-9-(2-hydroxyl-3-nonyl) adenine (EHNA), the IC(50) of 3'-dANO was unchanged, but the killing efficiency concentration of 3'dANO was reduced to 0.3 mM. When mice bearing Ehrlich ascites tumor were treated i.p. with 3'-dANO doses of 200 mg/kg daily for 4 days, the mean increased life span (ILS) was 200%. 3'-dANO in combination with EHNA did not further increase the life span of the tumor-bearing mice. The specific growth delay (SGD) of the Ehrlich tumor and of a human squamous lung cell carcinoma growing subcutaneously in 3'-dANO-treated mice were calculated from Gomperts tumor growth curves. The Ehrlich tumor-bearing mice received 3'-dANO i.p. at doses of 250 mg/kg daily for 4 days, and the nude mice bearing human carcinoma received 3'-dANO i.p. at doses of 225 mg/kg daily for 5 days. The SGD for the investigated tumors were calculated to be 1.0 and 1.1, respectively.
...
PMID:The effect of 3'-deoxyadenosine N(1)-oxide on growth in vitro and in vivo on Ehrlich ascites tumor and on a human squamous lung cell carcinoma xenograft in nude mice. 859 87

Spinal administration of adenosine analogs and an adenosine kinase inhibitor produces antinociception in thermal threshold tests. In the present study, we determined the effects of N6-cyclohexyladenosine (adenosine A1 receptor selective), 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethyl-carboxamidoadeno sine (CGS-21680) (adenosine A2A receptor selective), and 5'-N-ethylcarboxamidoadenosine (NECA) (non-selective), on formalin induced nociceptive responses (flinching/lifting and licking/biting) using two concentrations of formalin (2% and 5%). We also examined the antinociceptive effects of 5'-amino-5'-deoxyadenosine, an adenosine kinase inhibitor, and deoxycoformycin, an adenosine deaminase inhibitor, under these conditions. Adenosine A1 receptor agonists, but not the A2A selective agent, produced significant antinociception, as did 5'-amino-5'-deoxyadenosine, but not deoxycoformycin. The extent of antinociception produced was greater with the lower stimulus intensity. The effects of NECA and 5'-amino-5'-deoxyadenosine were inhibited by caffeine, indicating the involvement of cell surface adenosine receptors in their actions. We conclude (a) that the adenosine A1, but not the A2A, receptor is involved in spinally mediated antinociception, (b) that adenosine kinase is more important than adenosine deaminase in regulating endogenous adenosine levels in the spinal cord, and (c) that stimulus intensity is an important determinant of the efficacy of purines in the spinal cord.
...
PMID:Antinociception by adenosine analogs and an adenosine kinase inhibitor: dependence on formalin concentration. 860 54

Adenosine, a modulator of pain processing in the spinal cord, is metabolized by adenosine kinase and adenosine deaminase. In this study we determined which of these mechanisms is more important for the regulation of endogenous adenosine levels in the rat spinal cord. The effects of the adenosine kinase inhibitors, 5'-amino-5'-deoxyadenosine (NH2dAD) and iodotubercidin (IOT), and the adenosine deaminase inhibitor, 2'-deoxycoformycin (DCF), on adenosine release in a spinal cord superfusion model were studied. DCF markedly increased basal adenosine levels detected in perfusates and was more potent than NH2dAD and IOT in this regard. Coadministration of DCF with NH2dAD produced an enhanced effect compared to the inhibitors alone. NH2dAD, but not DCF, potentiated morphine-evoked adenosine release. These results suggest that adenosine deaminase may be the predominant pathway for adenosine metabolism in this experimental model.
...
PMID:Modulation of adenosine release from rat spinal cord by adenosine deaminase and adenosine kinase inhibitors. 861 36

The rise in adenosine deaminase (ADA) activity in the pleural fluid of tuberculous pleurisy patients, though used for diagnosis, is of unknown origin. In this work, we determined ADA activity and the activities of 2'-deoxyadenosine deaminase and ADA-2 in 350 patients. We also considered whether the results throw light on the origin of high pleural fluid ADA in tuberculous pleurisy and estimated the diagnostic efficiency of 2'-deoxyadenosine deaminase, ADA-2 and total ADA activities with and without the inclusion of the 2'-deoxyadenosine deaminase/ADA activity ratio in a combined criterion. The 350 pleural effusions were classified by previously established criteria as transudates (60 males/18 females) or as tuberculous (49 males/27 females), neoplastic (50 males/39 females), parapneumonic (36 males/19 females), empyematous (11 males/3 females), or miscellaneous (25 males/13 females) exudates. Total ADA, ADA-2 and 2'-deoxyadenosine deaminase activities were, respectively, 127.5 +/- 2.9, 103 +/- 29.5 and 42.8 +/- 14 U.L-1 in tuberculous exudates. With diagnostic thresholds of 47, 40 and 22 U.L-1 respectively, the sensitivities of ADA, ADA-2 and 2'-deoxyadenosine deaminase for tuberculosis were 100, 100 and 95%; their specificities 91, 96 and 92%; and their efficiencies 93, 97 and 93%, respectively. One hundred and one effusions (all 76 tuberculous, 12 neoplastic, 4 parapneumonic and 9 empyematous exudates) had total ADA levels > 47 U.L-1; of these, 8 neoplastic, 1 parapneumonic and all the tuberculous exudates had a 2'-deoxyadenosine deaminase/ADA activity ratio < 0.49. The criterion of simultaneously having ADA > 47 U.L-1, ADA-2 > 40 U.L-1 and a 2'-deoxyadenosine deaminase/ADA activity ratio < 0.49 was satisfied by all the tuberculous effusions but only eight others (all neoplastic) (sensitivity 100%, specificity 97%, efficiency 98%). We conclude that: 1) high total ADA activity in tuberculous pleural effusions is due mainly to an increase in ADA-2, and, therefore, originated from the only known source monocytes and macrophages; 2) ADA-2 was a more efficient diagnostic marker of tuberculous pleurisy than total ADA activity, although the difference was not statistically significant; and 3) among effusions with high total ADA the 2'-deoxyadenosine deaminase/ADA activity ratio differentiates tuberculous effusions from empyemas and parapneumonic effusions, but fails to discriminate well between tuberculous and neoplastic effusions.
...
PMID:Adenosine deaminase (ADA) isoenzyme analysis in pleural effusions: diagnostic role, and relevance to the origin of increased ADA in tuberculous pleurisy. 872 40

Endogenous extracellular adenosine provides some protection against excitotoxicity in the central nervous system, but it appears to be incomplete. Potentiating the formation of extracellular adenosine that occurs when excitatory amino acid receptors are activated might provide additional protection. We studied the effects of AICAR (AICA riboside, acadesine) and of inhibitors of adenosine metabolism on the release of adenosine from rat cortical slices. AICAR had no effects on basal N-methyl-D-aspartate (NMDA)- or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA)-evoked adenosine release, but it increased kainate-evoked adenosine release 1.4-fold. This selective action of AICAR may make it useful for treating kainate receptor-mediated excitotoxicity. Inhibition of adenosine kinase with either 20 microM 5'-amino-5'-deoxyadenosine or 5'-iodotubercidin had a much greater effect on excitatory amino acid-evoked adenosine release than on basal adenosine release. Inhibition of adenosine kinase increased excitatory amino acid-evoked adenosine release 3-7-fold whereas inhibition of adenosine deaminase only increased evoked adenosine release 2-2.5-fold. Finally, 0.2 microM 5'-iodotubercidin and 200 microM 2'-deoxycoformycin caused similar increases in the basal rates of extracellular adenosine formation, but 5'-iodotubercidin produced over twice as much potentiation of the rate of NMDA-evoked adenosine formation than did 2'-deoxycoformycin. These findings suggest that adenosine kinase inhibitors may produce an event-specific potentiation of evoked adenosine formation, i.e. more effect on evoked formation than on basal formation. If so, adenosine kinase inhibitors may prove useful for preventing/treating diseases associated with excessive excitation in the brain, such as seizures, excitotoxicity and neurodegeneration.
...
PMID:Potentiation of excitatory amino acid-evoked adenosine release from rat cortex by inhibitors of adenosine kinase and adenosine deaminase and by acadesine. 880 8

Inhibitors of adenosine kinase, but not adenosine deaminase, produce antinociception when administered spinally. In this study, we evaluated the relative contribution of adenosine kinase and adenosine deaminase to the regulation of adenosine release into the extracellular space within the spinal cord by determining the effects of the adenosine kinase inhibitors 5'-amino-5'-deoxyadenosine and 5-iodotubercidin, and the adenosine deaminase inhibitor 2'-deoxycoformycin on adenosine release from spinal cord slices in an in vitro perfusion system. Both 5'-amino-5'-deoxyadenosine (5-50 microM) and 5-iodotubercidin (5-50 microM), but not 2'-deoxycoformycin (50 microM), augmented adenosine release. 5-Iodotubercidin was slightly more potent and effective than 5'-amino-5'-deoxyadenosine in augmenting release except at the highest concentration, where it was considerably more effective. Combinations of 2'-deoxycoformycin (50 microM) and minimally active concentrations of 5'-amino-5'-deoxyadenosine and 5-iodotubercidin (5 microM each) produced a synergistic enhancement of release. These results support a predominant involvement of adenosine kinase in regulating extracellular adenosine levels in the spinal cord, but adenosine deaminase also can play a significant role.
...
PMID:Adenosine kinase inhibitors augment release of adenosine from spinal cord slices. 883 17

We show here that 2'-deoxyadenosine (2'-dAdo) but not adenosine was toxic to chromaffin cells of 3-4-week-old rat adrenal glands. More than 75% of the cells plated in culture gradually died over a 3-day period in the presence of 100 microM 2'-dAdo plus 3 microM deoxycoformycin (DCF). Morphological observations together with bisbenzimide staining and terminal deoxynucleotidyl transferase-mediated nick and labeling showed membrane blebbing, shrinkage of cell bodies, chromatin condensation, and DNA fragmentation, suggesting apoptosis-like cell death by 2'-dAdo. Lethal effects of 2'-dAdo were potentiated by DCF, a drug that inhibits adenosine deaminase. 2'-dAdo-prompted cell death was not prevented by inhibitors of nucleoside transporter (3 microM dilazep or 1 microM nitrobenzylthioinosine), precursors of pyrimidine nucleotide biosynthesis (300 microM uridine or 100 microM 2'-deoxycytidine), or 5 mM nicotinamide. Cells incubated with 2'-dAdo (100 and 300 microM) showed a three- and ninefold, respectively, increase in content of dATP, a product known to be an inhibitor of ribonucleotide reductase, an enzyme essential for DNA synthesis. Formation of dATP was completely prevented by iodotubercidin (ITu), a drug that inhibits phosphorylation of 2'-dAdo to dATP by nucleoside kinase. It is interesting that nanomolar concentrations of ITu also completely protected chromaffin cells from 2'-dAdo lethality. Our study demonstrates for the first time that mammalian adrenal chromaffin cells undergo apoptotic cell death by a natural nucleoside and suggests that this model could be used to study apoptosis and cell function.
...
PMID:2'-deoxyadenosine induces apoptosis in rat chromaffin cells. 893 58

2'-Deoxycoformycin (dCF), a specific and potent inhibitor of adenosine deaminase, has demonstrated significant antitumor effect on lymphoid malignancies. The drug induced functional and morphologic differentiation of myeloid leukemia cells in combination with 2'-deoxyadenosine (dAd), but not dCF alone. NB4, a cell line derived from a patient with t(15; 17) acute promyelocytic leukemia (APL) underwent granulocytic differentiation when treated with all-trans retinoic acid (ATRA) or dCF plus dAd, but not with cytosine arabinoside. Pre-exposure of NB4 cells to ATRA greatly potentiated differentiation induced by dCF plus dAd, but pretreatment with dCF plus dAd before exposure to ATRA was less effective. Differentiation of NB4 cells was effectively induced by clinically applicable concentrations of dCF in combination with dAd. These findings may provide useful information about induction of differentiation in vivo.
...
PMID:Induction of differentiation of human myeloid leukemia cells by 2'-deoxycoformycin in combination with 2'-deoxyadenosine. 929 60


<< Previous 1 2 3 4 5 6 7 8 9 10

---