ANTITRYPANOSOMAL EFFECTS OF POLYAMINE BIOSYNTHESIS INHIBITORS CORRELATE WITH INCREASES IN TRYPANOSOMA-BRUCEI-BRUCEI S-ADENOSYL-L-METHIONINE
ANTITRYPANOSOMAL EFFECTS OF POLYAMINE BIOSYNTHESIS INHIBITORS CORRELATE WITH INCREASES IN TRYPANOSOMA-BRUCEI-BRUCEI S-ADENOSYL-L-METHIONINE
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DOI：
10.1042/bj2740527
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发表时间：
1991-03-01
影响因子：
4.1
通讯作者：
BITONTI, AJ
中科院分区：
文献类型：
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作者：
BYERS, TL;BUSH, TL;BITONTI, AJ
我们最近报道了5‘-{[(Z)-4-amino-2-butenyl]methylamino}-5’-deoxyadenosine(MDL 73811)，一种酶激活的不可逆S-腺苷-L-蛋氨酸脱羧酶(ADO MetDC；EC 4.1.1.50)的不可逆抑制剂，用于治疗小鼠的非洲锥虫感染。MDL 73811的确切作用机制尚不清楚，因为在亚精胺显著耗尽之前，治疗大鼠的血液中锥虫迅速消失。给感染布氏锥虫的大鼠注射MDL 73811后，1h内寄生虫血症下降70%，5h后寄生虫完全消失，并在注射MDL 73811后10min内完全抑制ADOMetDC活性，抑制作用至少维持4h。在感染后1h内，锥虫体内的多胺水平未受影响，但寄生虫的ADOMet水平在此期间增加了20倍。相比之下，培养的哺乳动物细胞暴露在MDL 73811中，在6小时的时间过程中，ADOMet的水平只增加了1.5-2倍。用鸟氨酸脱羧酶(ODC)抑制剂进行的实验也表明，ADOMet水平的增加可能是抗锥虫疗效的一个重要因素。用ODC抑制剂依氟鸟氨酸处理36h的大鼠锥虫体内的腐胺被耗尽，精胺水平显著降低。这些生物体的ADOMetDC活性也不到对照的10%，脱羧基ADOMet(>；4000倍)和ADOMet(高达50倍)水平提高。治疗布氏锥虫感染的α-单氟甲基-3，4-脱氢鸟氨酸甲酯(Delta-MFMO-CH3)和该化合物的乙酯类似物(Delta-MFMO-C2H5)，不能治愈这种感染，在水解时成为ODC抑制剂，因此测试了它们对锥虫多胺、ADOMet和脱羧基ADOMet水平的影响。虽然Delta-MFMO的两种酯都会耗尽锥虫多胺，但经Delta-MFMO-CH3处理的感染小鼠的布氏锥虫体内的ADOMet和脱羧基ADMet水平升高，而经Delta-MFMO-C2H5处理的小鼠的寄生虫中则没有。这些数据表明，无论是直接用MDL 73811抑制ADOMetDC，还是间接用ODC抑制剂抑制，显然都会导致锥虫特异性的ADOMet升高。这些药物的抗锥虫作用可能是由于ADOMet的重大变化，而不是多胺的变化。
We reported recently that administration of 5'-{[(Z)-4-amino-2-butenyl]methylamino}-5'-deoxyadenosine (MDL 73811), an enzyme-activated irreversible inhibitor of S-adenosyl-L-methionine decarboxylase (AdoMetDC; EC 4.1.1.50), a key enzyme in the synthesis of spermidine, cures African trypanosome infections in mice. The precise mechanism of action of MDL 73811 was not clear because a rapid disappearance of trypanosomes from the bloodstream of treated rats occurred before significant depletion of spermidine. Administration of MDL 73811 to Trypanosoma brucei brucei-infected rats resulted in a 70% decrease in parasitaemia within 1 h and a complete disappearance of parasites by 5 h. The reduction in parasitaemia was accompanied by complete inhibition of AdoMetDC activity by 10 min after injection of MDL 73811; inhibition was sustained for at least 4 h. Polyamine levels in trypanosomes were unaffected during the first 1 h in which the marked decrease in parasitaemia was observed, but parasite AdoMet levels increased 20-fold within this time. In contrast, exposure of cultured mammalian cells to MDL 73811 resulted in only a 1.5-2-fold increase in AdoMet levels over a 6 h time course. Experiments with inhibitors of ornithine decarboxylase (ODC) also suggested that the increased AdoMet levels might be an important factor for antitrypanosomal efficacy. Trypanosomes taken from rats treated for 36 h with eflornithine, an inhibitor of ODC, were depleted of putrescine and had markedly decreased spermidine levels. These organisms also had less than 10% of control AdoMetDC activity, and had elevated decarboxy AdoMet (> 4000-fold) and AdoMet (up to 50-fold) levels. The methyl ester of alpha-monofluromethyl-3,4-dehydro-ornithine (DELTA-MFMO-CH3), which cures murine T. b. brucei infections, and the ethyl ester analogue of this compound (DELTA-MFMO-C2H5), which does not cure this infection, become ODC inhibitors upon hydrolysis and thus were tested for their effects on trypanosomal polymines, AdoMet and decarboxy AdoMet levels. Although both esters of DELTA-MFMO depleted trypanosomal polyamines, AdoMet and decarboxy AdoMet levels were elevated in T. b. brucei from infected mice treated with DELTA-MFMO-CH3 but not in parasites from mice treated with the DELTA-MFMO-C2H5. These data suggest that inhibition of AdoMetDC, either directly with MDL 73811 or indirectly with inhibitors of ODC, apparently leads to a trypanosome-specific elevation of AdoMet. It is possible that major changes in AdoMet, rather than changes in polyamines, may be responsible for the antitrypanosomal effects of these drugs.