Nucleoside Transporters in Leishmania Major: Diversity in Adenosine Transporter Expression or Function in Different Strains

Cytotoxic nucleoside derivatives may become useful in the treatment of parasitic infections. As part of our drug development studies, the effect of a number of nucleosides (100 microM) on the cellular transport of 3H-adenosine and 3H-inosine (each at 1 microM) in promastigotes from four Leishmania major strains was investigated. When 3H-inosine was used as permeant, all strains exhibited essentially the same inhibition profile, with unlabeled inosine, guanosine, formycin B, and 3'-deoxyinosine being strongly inhibitory, and adenosine-related compounds such as 2'-deoxyadenosine and tubercidin being inactive. However, when 3H-adenosine was used as permeant, considerable differences in the inhibition profiles were noted among strains. Thus, both inosine transporter-selective nucleosides such as inosine and guanosine and adenosine transporter-selective nucleosides such as 2'-deoxyadenosine and tubercidin showed variable activity as inhibitors of 3H-adenosine transport in different strains. These observations indicated that an adenosine transporter was variably expressed in different strains, and that inhibition profiles for adenosine transport indicated cellular entry via both the inosine and adenosine transporters. The existence of different types of adenosine transporters as an alternative explanation could not be ruled out. The apparent uniform expression of an inosine transporter among different species and strains of Leishmania suggests that inosine derivatives may be useful as anti-leishmanial drugs.