Goldberg B, Rattendi D, Lloyd D, Sufrin J R, Bacchi C J
University of Wales, School of Pure and Applied Biology, Cardiff, UK.
Biochem Pharmacol. 1998 Jul 1;56(1):95-103. doi: 10.1016/s0006-2952(98)00118-x.
The effects of purine nucleoside analogs, polyamines, and established trypanocidal agents on the uptake of [8-14C]adenosine and S-[methyl-3H]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 omithine or methionine (500 microM), adenosine (100 microM), or other purine nucleosides, including methylthioadenosine (MTA) at 500 microM. 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 P2 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 P2 adenosine transport but did not inhibit AdoMet transport at 100 microM. Methylglyoxalbis(guanylhydrazone) (MGBG), an analog of dAdoMet, was a strong competitive inhibitor of adenosine transport at 100 microM, but did not inhibit AdoMet transport. The polyamines putrescine, spermine, and spermidine (1 mM) were examined for competition with adenosine and AdoMet transport. Putrescine significantly inhibited P2 adenosine transport in both strains (in the presence of saturating inosine), but AdoMet transport was not affected by these polyamines. P2 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 P2 adenosine transporter remains functional in melarsen- and diamidine-resistant clinical isolates.
比较了嘌呤核苷类似物、多胺和已确定的杀锥虫剂对药物敏感的布氏布氏锥虫和一株耐药的罗德西亚布氏锥虫临床分离株的血液型锥虫摄取[8-14C]腺苷和S-[甲基-3H]腺苷甲硫氨酸（AdoMet）的影响。鸟氨酸或甲硫氨酸（500微摩尔）、腺苷（100微摩尔）或其他嘌呤核苷，包括500微摩尔的甲硫基腺苷（MTA），均未拮抗AdoMet的摄取。甲硫基腺苷的杀锥虫类似物羟乙基硫代腺苷（HETA）和AdoMet的类似物辛伐他汀，在两种分离株中均与AdoMet转运存在竞争。腺苷P2转运体的拮抗剂双嘧达莫在两种分离株中也与AdoMet转运存在竞争。杀锥虫双脒类药物喷他脒、贝尼尔、CGP 40215以及脱羧的S-腺苷甲硫氨酸（dAdoMet）类似物MDL 73811（5'-[(Z)-4-氨基-2-丁烯基]甲基氨基-5'-脱氧腺苷）与P2腺苷转运存在竞争，但在100微摩尔时不抑制AdoMet转运。dAdoMet的类似物甲基乙二醛双（胍腙）（MGBG）在100微摩尔时是腺苷转运的强竞争性抑制剂，但不抑制AdoMet转运。研究了多胺腐胺、精胺和亚精胺（1毫摩尔）与腺苷和AdoMet转运的竞争情况。腐胺在两种菌株中均显著抑制P2腺苷转运（在存在饱和肌苷的情况下），但这些多胺不影响AdoMet转运。两种菌株中的P2腺苷转运均受到美拉胂氧及其关键有机成分三聚氰胺的高度抑制，而AdoMet摄取不受这些药物影响。这些发现进一步阐明了非洲锥虫中独特的AdoMet转运体的区别特征，并表明P2腺苷转运体在耐美拉胂和双脒的临床分离株中仍具有功能。
