Rapid and robust protection against cocaine-induced lethality in rats by the bacterial cocaine esterase.
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Cooper ZD, Narasimhan D, Sunahara RK, Mierzejewski P, Jutkiewicz EM, Larsen NA, Wilson IA, Landry DW, Woods JH
Rapid and robust protection against cocaine-induced lethality in rats by the bacterial cocaine esterase.
Mol Pharmacol. 2006 Dec;70(6):1885-91. Epub 2006 Sep 12.
- PubMed ID
- 16968810 [ View in PubMed]
- Abstract
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.