Specificity of adenosine deaminase inhibitors

Henderson, J. Frank; Brox, L.; Zombor, George; Hunting, Darel J.; Lomax, Christopher A.

doi:10.1016/0006-2952(77)90003-x

Cited by 116 publications

(30 citation statements)

References 26 publications

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“…2 shows that NH3 production by 5 X I0O human RBC was inhibited by increasing concentrations of 2'-deoxycoformycin. Maximal inhibition occurred at a concentration of 0.4 ,uM deoxycoformycin, which accords with previous publications (14,16). These results confirm that NH3 measured in Fig.…”

Section: Introductionsupporting

confidence: 93%

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The erythrocyte as instigator of inflammation. Generation of amidated C3 by erythrocyte adenosine deaminase.

Hostetter¹,

Johnson²

1989

J. Clin. Invest.

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Myocardial ischemia is characterized by the liberation of adenosine and by complement-mediated inflammation. We have reported that amidated C3, formed when ammonia (NH3) disrupts the thiolester bond of C3, serves as an alternative pathway convertase, generates C5b-9, and stimulates phagocytic oxidative metabolism. We investigated whether the deamination of adenosine by adenosine deaminase in hematopoietic cells might liberate sufficient ammonia to form amidated C3 and thereby trigger complement-mediated inflammation at ischemic sites.In the presence of 4 mM adenosine, NH3 production per erythrocyte (RBC) was equal to that per neutrophil (PMN) (3.3 X 10-1' mol/cell per h). Because RBC outnumber PMN in normal blood by a thousandfold, RBC are the major source of NH3 production in the presence of adenosine. NH3 production derived only from the deamination of adenosine by the enzyme adenosine deaminase and was abolished by 0.4 ;&M 2'-deoxycoformycin, a specific inhibitor of adenosine deaminase.When purified human C3 was incubated with 5 X 108 human RBC in the presence of adenosine, disruption of the C3 thiolester increased more than twofold over that measured in C3 incubated with buffer, or in C3 incubated with RBC (P < 0.05). The formation of amidated C3 was abolished by the preincubation of RBC with 2-deoxycoformycin (P < 0.001). Amidated C3 elicited statistically significant release of superoxide, myeloperoxidase, and lactoferrin from PMN. Thus, the formation of amidated C3 by RBC deamination of adenosine triggers a cascade of complement-mediated inflammatory reactions.

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Section: Introductionsupporting

confidence: 93%

“…2'-Deoxycoformycin (Pentostatin), a tight-binding inhibitor of ADA (14)(15)(16)(17), was the gift ofMartin L. Black ofthe Warner Lambert Co., Ann Arbor, MI. The compound was dissolved in water at pH 8.4 and stored in a concentration of 0.5 mg/ml according to manufacturer's instructions.…”

Section: Introductionmentioning

confidence: 99%

The erythrocyte as instigator of inflammation. Generation of amidated C3 by erythrocyte adenosine deaminase.

Hostetter¹,

Johnson²

1989

J. Clin. Invest.

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“…In the present study it would seem most likely that ADA inhibition has not only augmented the residual nucleotide pool but has also increased endogenous precursors available for the resynthesis of renal ATP. Since the DCF is injected intramuscularly and several tissues can have their ADA activity significantly reduced (13,14,(22)(23)(24)(25), it is possible that there is a systemic increase in the concentration of adenosine. In DCF-treated rats, the tissue content of adenosine was increased.…”

Section: Discussionmentioning

confidence: 99%

Metabolic and functional consequences of inhibiting adenosine deaminase during renal ischemia in rats.

Stromski¹,

Waarde²,

Avison³

et al. 1988

J. Clin. Invest.

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The concentrations of renal ATP have been measured by 31P-nuclear magnetic resonance (NMR) before, during, and after bilateral renal artery occlusion. Using in vivo NMR, the initial postischemic recovery of ATP increased with the magnitude of the residual nucleotide pool at the end of ischemia. ATP levels after 120 min of reflow correlated with functional recovery at 24 h. In the present study the effect of blocking the degradation of ATP during ischemia upon the postischemic restoration of ATP was investigated. Inhibition of adenosine deaminase by 80% with the tight-binding inhibitor 2'-deoxycoformycin led to a 20% increase in the residual adenine nucleotide pool. This increased the ATP initial recovery after 45 min of ischemia from 52% (in controls) to 62% (in the treated animals), as compared to the basal levels. The inhibition also caused an accelerated postischemic restoration of cellular ATP so that at 120 min it was 83% in treated rats vs. 63% in untreated animals. There was a corresponding improvement in the functional recovery from the insult (increase of 33% in inulin clearance 24 h after the injury). Inhibition of adenosine deaminase during ischemia results in a injury similar to that seen after a shorter period of insult.

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“…Adenosine deaminase activity was measured over a range of substrate concentrations from 1 to 200 µ . A least-squares fit of each data set to the hyperbola V = Vmax S/(Km + S) was performed using a computer program and the resulting estimates of the parameters Km and Fmax were averaged (Henderson, 1978 (Cha et al, 1975;Henderson et al, 1977). Inhibition of adenosine deaminase activity by a range of coformycin concentrations was investigated in duplicate samples of unwashed spermatozoa on 3 occasions.…”

Section: Methodsmentioning

confidence: 99%

Enzymes of adenosine metabolism in mouse sperm suspensions

Monks

Fraser²

1988

Reproduction

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Summary. The enzymes of adenosine metabolism were investigated in suspensions of epididymal mouse spermatozoa incubated under conditions which support capacitation in vitro. High levels of adenosine deaminase activity were found in sperm suspensions, but the enzyme was located in the surrounding medium and was not intrinsic to spermatozoa. 5\m='\-Nucleotidase was also present in the surrounding medium while in sperm cells it existed as an ecto-enzyme. Adenosine was not metabolized by washed spermatozoa under conditions used for the assay of adenosine deaminase or adenosine kinase, but it was metabolized rapidly by unwashed sperm suspensions. Incubation of sperm suspensions in conditions which modulate fertilizing ability resulted in small alterations in intrinsic 5\m='\-nucleotidase activity of spermatozoa. In contrast, the activity of adenosine deaminase was not consistently modulated by such maniupulations.Adenosine deaminase and 5\m='\-nucleotidase exhibited similar kinetic parameters to enzymes from other sources and their activities were inhibited by coformycin and \ g = a \ , \ g = b \ \ x = r e q -\ methylene adenosine 5\m='\-diphosphate, respectively. These studies highlight the low adenosine-metabolizing ability of spermatozoa coupled with the extensive metabolism in the medium which surrounds them. Extracellular adenosine metabolism can therefore occur and may modulate capacitation in vitro.

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Specificity of adenosine deaminase inhibitors

Cited by 116 publications

References 26 publications

The erythrocyte as instigator of inflammation. Generation of amidated C3 by erythrocyte adenosine deaminase.

The erythrocyte as instigator of inflammation. Generation of amidated C3 by erythrocyte adenosine deaminase.

Metabolic and functional consequences of inhibiting adenosine deaminase during renal ischemia in rats.

Enzymes of adenosine metabolism in mouse sperm suspensions

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