Padua R, Geiger J D, Dambock S, Nagy J I
Department of Pharmacology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
J Neurochem. 1990 Apr;54(4):1169-78. doi: 10.1111/j.1471-4159.1990.tb01945.x.
2'-Deoxycoformycin (DCF), a potent inhibitor of adenosine deaminase (ADA), is increasingly used as a tool to investigate adenosine metabolism and neuromodulation. To advance further the usefulness of DCF for studies of purines in the CNS, we determined the inhibitory potency of this compound against ADA and adenylate deaminase (AMPDA) in brain, the rate of ADA recovery in various brain regions after single or repeated intraperitoneal DCF administrations, and the effect of DCF on several neurotransmitter synthetic enzymes. In vitro, the Ki values for inhibition of ADA and AMPDA were found to be 23 pM and 233 microM, respectively. In vivo, DCF inhibited ADA with ED50 values ranging from 155 to 280 micrograms/kg at 2 h posttreatment, and 98% inhibition was achieved with 1 mg/kg. AMPDA activity was not affected by doses up to 5.0 mg/kg. In contrast to the greater than 95% inhibition of ADA seen 1 day after DCF at 5 mg/kg, the effectiveness of a second similar DCF treatment on the activity that had recovered by 14 days was dramatically reduced. Eight days after DCF treatment with doses of 5-50 mg/kg, the degree of ADA activity recovery in 10 brain regions examined was similar; it averaged 35% of control values at the low dose but showed some heterogeneity, ranging from 15 to 54% of control values, at the higher doses. Forty days after treatment with a single dose of 5 mg/kg, ADA activity recovered by 68-78% of control values in brain regions with normally high levels of activity and by 44-59% of control values in other regions. The activities of choline acetyltransferase, glutamic acid decarboxylase, and histidine decarboxylase (an enzyme colocalized with ADA in hypothalamic neurons) were unaffected by DCF treatment, a result suggesting the lack of a generalized neurotoxic effect. The very low doses of DCF required for ADA inhibition in vivo are consistent with the high potency of this drug against ADA in vitro, and any physiological effects observed at low doses might therefore be ascribed to inhibition of ADA.
2'-脱氧助间型霉素（DCF）是一种有效的腺苷脱氨酶（ADA）抑制剂，越来越多地被用作研究腺苷代谢和神经调节的工具。为了进一步提高DCF在中枢神经系统嘌呤研究中的实用性，我们测定了该化合物对脑内ADA和腺苷酸脱氨酶（AMPDA）的抑制效力、单次或重复腹腔注射DCF后不同脑区ADA的恢复速率，以及DCF对几种神经递质合成酶的影响。在体外，发现抑制ADA和AMPDA的Ki值分别为23 pM和233 microM。在体内，DCF在治疗后2小时抑制ADA的ED50值范围为155至280微克/千克，1毫克/千克可实现98%的抑制。高达5.0毫克/千克的剂量对AMPDA活性没有影响。与5毫克/千克DCF给药1天后ADA抑制率大于95%形成对比的是，第二次类似的DCF治疗对14天内已恢复活性的效果显著降低。用5至50毫克/千克剂量的DCF治疗8天后，所检测的10个脑区的ADA活性恢复程度相似；低剂量时平均为对照值的35%，但在高剂量时显示出一定的异质性，范围为对照值的15%至54%。单次给予5毫克/千克剂量治疗40天后，在正常活性水平较高的脑区，ADA活性恢复至对照值的68 - 78%，在其他区域则恢复至对照值的44 - 59%。胆碱乙酰转移酶、谷氨酸脱羧酶和组氨酸脱羧酶（一种与下丘脑神经元中的ADA共定位的酶）的活性不受DCF治疗的影响，这一结果表明不存在普遍的神经毒性作用。体内抑制ADA所需的DCF剂量极低，这与该药物在体外对ADA的高效力一致，因此在低剂量下观察到的任何生理效应可能归因于对ADA的抑制。
