Rapid and robust protection against cocaine-induced lethality in rats by the bacterial cocaine esterase
Rapid and robust protection against cocaine-induced lethality in rats by the bacterial cocaine esterase
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DOI：
10.1124/mol.106.025999
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发表时间：
2006-12-01
影响因子：
3.6
通讯作者：
Woods, James H.
中科院分区：
文献类型：
--
作者：
Cooper, Ziva D.;Narasimhan, Diwahar;Woods, James H.
没有任何经批准的方法可以防止可卡因的毒性作用。可卡因酯酶（CocE）存在于生长在古柯植物周围根际土壤中的红球菌菌株中，并已发现在体外水解可卡因。CocE（0.1- 1.0mg，i.v.）通过评估其在大鼠中预防可卡因诱导的惊厥和致死性的能力，在体内进行了表征和确认。通过增加可卡因剂量（100-1000 mg/kg，i. p.）需要在单次静脉注射CocE后产生毒性作用。该酶在大鼠和人血清中表现出快速的可卡因降解动力学。CocE的两个无催化活性的突变体（S117 A或Y 44 F）未能保护大鼠免受可卡因的毒性作用，证实了保护作用是由于水解活性。然而，丁酰胆碱酯酶，一种内源性可卡因水解酶，无活性（1.3-13 mg，i. v.）在这个老鼠毒性实验中此外，CocE不阻断WIN-35065-2（560 mg/kg，i. p.）的致死性，一种缺乏CocE靶向的苯甲酰酯部分的可卡因类似物。CocE的这种表征提供了初步证据，表明该酶可以作为人体可卡因毒性的合适解毒剂。
There is no approved means to prevent the toxic actions of cocaine. Cocaine esterase (CocE) is found in a rhodococcal strain of bacteria that grows in the rhizosphere soil around the coca plant and has been found to hydrolyze cocaine in vitro. The esteratic activity of CocE (0.1-1.0 mg, i.v.) was characterized and confirmed in vivo by assessing its ability to prevent cocaine-induced convulsions and lethality in the rat. The therapeutic efficiency of the enzyme was demonstrated by the increasing dose of cocaine (100-1000 mg/kg, i.p.) required to produce toxic effects after a single intravenous injection of CocE. The enzyme demonstrated rapid kinetics for cocaine degradation in rat and human serum. Two catalytically inactive mutants of CocE (S117A or Y44F) failed to protect rats from the toxic effects of cocaine, confirming the protective effects are due to hydrolytic activity. However, butyrylcholinesterase, an endogenous cocaine-hydrolyzing enzyme, was inactive (1.3-13 mg, i.v.) in this rat toxicity procedure. Furthermore, CocE did not block the lethality of WIN-35065-2 (560 mg/kg, i.p.), a cocaine analog that lacks the benzoyl ester moiety targeted by CocE. This characterization of CocE provides preliminary evidence that the enzyme could serve as a suitable antidote to cocaine toxicity in humans.