Adenosine metabolism in human whole blood. Effects of nucleoside transport inhibitors and phosphate concentration.
Adenosine (Ado, 10 microM) was metabolized in whole blood within 1 min, primarily to hypoxanthine and ATP. The concentration of Ado, the activities of adenosine deaminase (ADA) and Ado kinase, the Km values for Ado with ADA and Ado kinase, and the substrate inhibition of Ado kinase are factors that govern the Ado metabolism between deamination and phosphorylation. If ADA activity was blocked by 2'-deoxycoformycin (dCF, 5 microM), a tight-binding inhibitor of ADA, most of the Ado (96%) was incorporated into adenine nucleotides, whereas if Ado kinase activity was blocked with 5-iodotubercidin (10 microM), Ado was mainly (95%) metabolized into hypoxanthine. A high phosphate concentration (25 mM) caused marked increases in the formation of IMP. The nucleoside transport inhibitors dilazep (1 microM), dipyridamole (10 microM) and nitrobenzylthioinosine (NBMPR, 1 microM) strongly blocked cellular Ado metabolism. In the presence of nucleoside transport inhibitors, Ado which slowly enters the cell was metabolized principally by Ado kinase rather than ADA. Dilazep, NBMPR and dipyridamole were more effective in blocking Ado uptake and metabolism by erythrocytes suspended in a protein-free medium than by cells suspended in plasma.
Dawicki
D D
DD
Section of Biochemical Pharmacology, Brown University, Providence, RI 02912.
Agarwal
K C
KC
Parks
R E
RE
D000241:Adenosine / Q000097:blood*; D000243:Adenosine Deaminase / Q000032:analysis; D000248:Adenosine Kinase / Q000032:analysis; D001692:Biological Transport / Q000187:drug effects; D004109:Dilazep / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D006801:Humans; D010710:Phosphates / Q000494:pharmacology*; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology
D010710:Phosphates; D013868:Thioinosine; D004176:Dipyridamole; D000248:Adenosine Kinase; D000243:Adenosine Deaminase; D004109:Dilazep; C001789:4-nitrobenzylthioinosine; D000241:Adenosine