In the human erythrocyte, adenosine and other nucleosides are transported by facilitated diffusion via a single type of nitrobenzylthioinosine (NBMPR)-sensitive transporter. Erythrocytes contribute substantially to the uptake, metabolism, and release of adenosine metabolites in the circulation and thus, modulation of transporter activity could indirectly mediate responses to adenosine or its metabolites. We shaw here that supplementation of the human diet with oleic acid-rich oil or with fish oil containing high levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), results in decreases in nucleoside uptake across the erythrocyte plasma membrane. Oil feeding resulted in decreases in transport rates (pmol/10(7) cells/sec) for adenosine (1.65 +/- 0.04 to 1.27 +/- 0.02), thymidine (11.4 +/- 0.3 to 9.4 +/- 0.1), and uridine (8.3 +/- 0.26 to 7.02 +/- 0.09) on day 0 and day 42, respectively. Although changes in fatty acid composition were documented in the fish oil supplemented group, over the 6 week treatment period, changes in the oleic acid-rich ail supplemented group were not statistically significant. We suggest that fatty acid changes in membrane phospholipids may be responsible for the observed decreases in the rates of nucleoside transport in fish oil-fed subjects bur that oleic acid supplementation may alter nucleoside uptake by another mechanism. Thus, in addition to having direct effects on platelet and neutrophil activity, oils or foods rich in oleic acid and/or omega-3 fatty acids may have indirect effects on the erythrocyte that potentiate the activity of adenosine on platelets and the vascular endothelium.