S-substituted derivatives of 6-mercaptopurine ribosides interact both with the transport and metabolic phosphorylation of uridine by virus-transformed hamster fibroblasts.
The uptake of uridine by mammalian cells consists of transport of uridine across the plasma membrane followed by its metabolic conversion, mainly by phosphorylation. S-substituted aromatic derivatives of 6-mercaptopurine ribosides are potent inhibitors of the nucleoside uptake systems in human erythrocytes and in mammalian cells in culture and have been studied extensively. We present here a theoretical analysis which enables one to decide whether transport of metabolites, their metabolic trapping within the cell, or both, are susceptible to inhibition. This analysis was applied in the study of the effect of some inhibitors on uridine and cytosine-beta-D-arabinoside uptake by transformed Nil-8 cells. It was found that in Nil-SV cells, both transport and metabolic conversion are susceptible to inhibition by nitrobenzylmercaptoinosine and by dansylaminoethylmercaptoguanosine. Nitrobenzylmercaptoinosine displays inhibition constants of 20 and 7 nM for transport and phosphorylation, respectively, while for dansylaminoethylmercaptoguanosine the inhibition constants are 1.8 and 0.6 microM, respectively, for the same processes. Cytosine-beta-D-arabinoside is a synthetic nucleoside which is not metabolizable in Nil cells. Its uptake properties are determined by the transport mechanism alone. The transport of this nucleoside into Nil-SV cells in inhibited by nitrobenzylmercaptoinosine and the inhibition constant found is approx. 5 times greater than that for uridine.
D000818:Animals; D002460:Cell Line; D002472:Cell Transformation, Viral; D006224:Cricetinae; D003561:Cytarabine / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D007288:Inosine / Q000031:analogs & derivatives*; D007700:Kinetics; D008647:Mesocricetus; D010766:Phosphorylation; D009053:Sarcoma Viruses, Murine; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D014529:Uridine / Q000378:metabolism*
D003561:Cytarabine; D013868:Thioinosine; D007288:Inosine; D003847:Deoxyglucose; D014529:Uridine