Effects of adenosine analogues on ATP concentrations in human erythrocytes. Further evidence for a route independent of adenosine kinase.
Adenosine derivatives are frequently used in chemotherapy because of their potent antitumor, antiviral and antiparasitic activity. We investigated the metabolism of some adenosine analogues in adenosine deaminase inhibited normal and adenine phosphoribosyltransferase (APRT) deficient human erythrocytes. The ATP and GTP concentrations and the formation of unusual nucleotides were measured. Some of the analogues studied (tubercidin, 9 beta-D-arabinofuranosyladenine, 2'-deoxyadenosine, 2-chloroadenosine, neplanocin A) were phosphorylated to the corresponding nucleoside triphosphates and this process was abolished by iodotubercidin--an adenosine kinase inhibitor. With the exception of 2'-deoxyadenosine, nucleotide analogue formation was accompanied by ATP depletion. ATP decrease was not observed after adenosine kinase inhibition and ATP concentration even increased in the presence of 2'-deoxyadenosine, neplanocin A and 5'-iodo-5'-deoxyadenosine. However, the latter increment was not observed in APRT deficient erythrocytes. Bredinin, S-adenosylhomocysteine, deoxycoformycin and adenosine dialdehyde did not form nucleotide derivatives or exert any effects on ATP concentration. It is concluded that adenosine analogues can either enter the nucleotide pool via phosphorylation mechanisms, or may be converted to ATP by the pathways involving the intermediate formation of adenine.
Purine Research Laboratory, Clinical Science Laboratories, UMDS Guy's Hospital, London, U.K.
R T
RT
Smolenski
C
C
Montero
J A
JA
Duley
H A
HA
Simmonds
D000228:Adenine Phosphoribosyltransferase / Q000032:analysis; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000494:pharmacology; D015649:Pentostatin / Q000494:pharmacology; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology
D007042:Hypoxanthines; C034214:5-iodotubercidin; D019271:Hypoxanthine; D015649:Pentostatin; D000255:Adenosine Triphosphate; D000228:Adenine Phosphoribosyltransferase; D000248:Adenosine Kinase; D014372:Tubercidin