QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.025999v1 70/6/1885    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cooper, Z. D. Articles by Woods, J. H. Search for Related Content PubMed PubMed Citation Articles by Cooper, Z. D. Articles by Woods, J. H.

Rapid and Robust Protection against Cocaine-Induced Lethality in Rats by the Bacterial Cocaine Esterase

Departments of Pharmacology (Z.D.C., D.N., R.K.S., E.M.J., J.H.W.), Psychology (Z.D.C., J.H.W.), and Psychiatry (P.M.), University of Michigan, Ann Arbor, Michigan; Harvard Medical School, Cambridge, Massachusetts (N.A.L.); Department of Molecular Biology, The Scripps Institute, La Jolla, California (I.A.W.); and Department of Medicine, New York-Presbyterian Hospital/Columbia University Medical Center, New York, New York (D.W.L.)

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.

Received for publication April 24, 2006.

Accepted for publication September 11, 2006.

Address correspondence to: James Woods, Department of Pharmacology, The University of Michigan, 1301 MSRB III, 1150 West Med Cntr Dr., Ann Arbor, MI 48109-0632; e-mail: jhwoods{at}umich.edu

This article has been cited by other articles:

				G. T. Collins, R. L. Brim, D. Narasimhan, M.-C. Ko, R. K. Sunahara, C.-G. Zhan, and J. H. Woods Cocaine Esterase Prevents Cocaine-Induced Toxicity and the Ongoing Intravenous Self-Administration of Cocaine in Rats J. Pharmacol. Exp. Ther., November 1, 2009; 331(2): 445 - 455. [Abstract] [Full Text] [PDF]

				Y. Gao and S. Brimijoin Lasting Reduction of Cocaine Action in Neostriatum-- A Hydrolase Gene Therapy Approach J. Pharmacol. Exp. Ther., August 1, 2009; 330(2): 449 - 457. [Abstract] [Full Text] [PDF]

				D. Gao, D. L. Narasimhan, J. Macdonald, R. Brim, M.-C. Ko, D. W. Landry, J. H. Woods, R. K. Sunahara, and C.-G. Zhan Thermostable Variants of Cocaine Esterase for Long-Time Protection against Cocaine Toxicity Mol. Pharmacol., February 1, 2009; 75(2): 318 - 323. [Abstract] [Full Text] [PDF]

				M.-C. Ko, L. D. Bowen, D. Narasimhan, A. A. Berlin, N. W. Lukacs, R. K. Sunahara, Z. D. Cooper, and J. H. Woods Cocaine Esterase: Interactions with Cocaine and Immune Responses in Mice J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 926 - 933. [Abstract] [Full Text] [PDF]