Effects of deoxyadenosine on ribonucleotide reductase in adenosine deaminase-deficient lymphocytes.
To explore the relationship between ribonucleotide reductase and immunodysfunction in adenosine deaminase deficiency, the effects of deoxyadenosine on ribonucleotide reductase in ADA-deficient lymphocytes was investigated. An assay system for ribonucleotide reductase in intact permeabilized lymphocytes was developed to approximate physiological conditions. The activity of cytidine diphosphate (CDP) reductase in resting but not in proliferating lymphocytes in culture was inhibited by 1 to 10 mumol/L deoxyadenosine. The resting cells were protected from the toxicity of 1 mumol/L deoxyadenosine by 5 mmol/L nicotinamide or 30 mumol/L deoxycytidine and from that of 10 mumol/L deoxyadenosine by 30 mumol/L deoxycytidine. These findings suggest that depletion of nicotinamide adenine dinucleotide might be the principal cause of death in resting lymphocytes with ADA deficiency. It is concluded that the mechanism of deoxyadenosine toxicity on non-replicating lymphocytes, which may not be mediated by ribonucleotide reductase inhibition, is closely related to the mechanism of immunodysfunction in patients with ADA deficiency.
Takeda
E
E
Department of Paediatrics, School of Medicine, University of Tokushima, Japan.
Kuroda
Y
Y
Naito
E
E
Yokota
I
I
Saijo
T
T
Hirose
M
M
Miyao
M
M
D000243:Adenosine Deaminase / Q000172:deficiency*; D002455:Cell Division / Q000187:drug effects; D002463:Cell Membrane Permeability; D003070:Coformycin / Q000494:pharmacology; D003565:Cytidine Diphosphate / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology*; D004176:Dipyridamole / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D009536:Niacinamide / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D012262:Ribonucleoside Diphosphate Reductase / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
D003839:Deoxyadenosines; D010835:Phytohemagglutinins; D003070:Coformycin; D009536:Niacinamide; D003565:Cytidine Diphosphate; D004176:Dipyridamole; C019857:CDP reductase; D012264:Ribonucleotide Reductases; D012262:Ribonucleoside Diphosphate Reductase; D000243:Adenosine Deaminase