Eloranta T O, Kajander E O, Raina A M
Med Biol. 1982 Oct;60(5):272-7.
The effects of arabinosyladenine, an antiviral and antitumor agent used therapeutically, on the metabolism of adenosylhomocysteine were studied in rat liver. A rapid but transient accumulation of adenosylhomocysteine and adenosylmethionine was observed after a single i.p. injection of the adenosine analogue. The extent and duration of the accumulation was increased by multiple doses of arabinosyladenine and by giving the nucleoside in combination with erythro-9-(2-hydroxy-3-nonyl)-adenine, a potent inhibitor of adenosine deaminase, which significantly increased its concentration in the liver. Hepatic adenosine concentration was also enhanced by the treatment but less dramatically. Accumulation of adenosylhomocysteine resulted from a rapid but reversible in vivo inactivation of adenosylhomocysteine hydrolase. Approximately 10% of the hydrolase activity persisted despite the inactivation treatment. After four injections with arabinosyladenine (200 mumol/kg body wt.) in combination with the adenosine deaminase inhibitor (50 mumol/kg body wt.), given at 1 h intervals, the concentration of adenosylhomocysteine was increased 30-fold and that of adenosylmethionine 5-fold as compared with the control values. The concentrations remained at that level for at least 2 h and then gradually declined to the control level. The activity of adenosylhomocysteine hydrolase stayed at the 10% level for several hours but returned to the control level within 24 h of the last injection. The results show that prolonged treatment with arabinosyladenine, especially in combination with an adenosine deaminase inhibitor, causes marked but reversible changes in methionine metabolism, resulting in the hepatic accumulation of adenosylhomocysteine to a level that is likely to interfere with biological methylation reactions. This offers an additional mechanism by which arabinosyladenine may evoke toxic effects in animal cells.
研究了治疗用抗病毒和抗肿瘤药物阿糖腺苷对大鼠肝脏中腺苷同型半胱氨酸代谢的影响。单次腹腔注射这种腺苷类似物后，观察到腺苷同型半胱氨酸和腺苷甲硫氨酸迅速但短暂地积累。多次注射阿糖腺苷以及将该核苷与强力腺苷脱氨酶抑制剂赤型-9-(2-羟基-3-壬基)-腺嘌呤联合使用，可增加积累的程度和持续时间，后者可显著提高其在肝脏中的浓度。治疗也会提高肝脏腺苷浓度，但幅度较小。腺苷同型半胱氨酸的积累是由于腺苷同型半胱氨酸水解酶在体内迅速但可逆地失活所致。尽管经过失活处理，仍有约10%的水解酶活性保留。每隔1小时注射4次阿糖腺苷（200 μmol/kg体重）与腺苷脱氨酶抑制剂（50 μmol/kg体重）后，与对照值相比，腺苷同型半胱氨酸浓度增加了30倍，腺苷甲硫氨酸浓度增加了5倍。这些浓度至少在2小时内保持在该水平，然后逐渐降至对照水平。腺苷同型半胱氨酸水解酶活性在数小时内保持在10%的水平，但在最后一次注射后24小时内恢复到对照水平。结果表明，长期使用阿糖腺苷治疗，尤其是与腺苷脱氨酶抑制剂联合使用，会导致蛋氨酸代谢发生显著但可逆的变化，导致肝脏中腺苷同型半胱氨酸积累到可能干扰生物甲基化反应的水平。这提供了阿糖腺苷可能在动物细胞中引发毒性作用的另一种机制。
