Effects of intermediates of methionine metabolism and nucleoside analogs on S-adenosylmethionine transport by Trypanosoma brucei brucei and a drug-resistant Trypanosoma brucei rhodesiense

The effects of purine nucleoside analogs, polyamines, and established trypanocidal agents on the uptake of [8-C-14]adenosine and S-[methyl-H-3]adenosylmethionine (AdoMet) by bloodform trypanosomes of drug-susceptible Trypanosoma brucei brucei and a drug resistant Trypanosoma brucei rhodesiense clinical isolate were compared. AdoMet uptake was not antagonized by ornithine or methionine (500 mu M), adenosine (100 mu M), or other purine nucleosides, including methylthioadenosine (MTA) at 500 mu M. Hydroxyethylthioadenosine (HETA), a trypanocidal analog of methylthioadenosine, and sinefungin, an analog of AdoMet, were competitive with AdoMet transport in both isolates. Dipyridamole, an antagonist of the adenosine P-2 transporter, also competed with AdoMet transport in both isolates. The trypanocidal diamidines pentamidine, Berenil, CGP 40215, and the decarboxylated S-adenosylmethionine (dAdoMet) analog MDL 73811 (5'-{[(Z)-4-amino-2-butenyl]}methyl- amino}-5'-deoxyadenosine) competed with P-2 adenosine transport but did not inhibit Adoiviet transport at 100 mu M. Methylglyoxalbis(guanylhydrazone) (MGBG), an analog of dAdoMet, was a strong competitive inhibitor of adenosine transport at 100 mu M, but did not inhibit AdoMet transport. The polyamines putrescine, spermine, and spermidine (1 mM) were examined for competition with adenosine and Adoiviet transport. Putrescine significantly inhibited P-2 adenosine transport in both strains tin the presence of saturating inosine), but AdoMet transport was not affected by these polyamines. P-2 adenosine transport in both strains was highly inhibited by melarsen oxide and melamine, its key organic component, whereas AdoMet uptake was not affected by these agents. These findings further characterize distinguishing features of the unique AdoMet transporter in African trypanosomes, and indicate that the P-2 adenosine transporter remains functional in melarsen- and diamidine-resistant clinical isolates. BIOCHEM PHARMACOL 56;1:95-103, 1998. (C) 1998 Elsevier Science Inc.