Cocaine esterase: interactions with cocaine and immune responses in mice.
Cocaine esterase (CocE) is the most efficient protein catalyst for the hydrolysis of cocaine characterized to date. The aim of this study was to investigate the in vivo potency of CocE in blocking cocaine-induced toxicity in the mouse and to assess CocE's potential immunogenicity. Cocaine toxicity was quantified by measuring the occurrence of convulsions and lethality. Intravenous administration of CocE (0.1-1 mg) 1 min before cocaine administration produced dose-dependent rightward shifts of the dose-response curve for cocaine toxicity. More important, i.v. CocE (0.1-1 mg), given 1 min after the occurrence of cocaine-induced convulsions, shortened the recovery time after the convulsions and saved the mice from subsequent death. Effects of repeated exposures to CocE were evaluated by measuring anti-CocE antibody titers and the protective effects of i.v. CocE (0.32 mg) against toxicity elicited by i.p. cocaine (320 mg/kg) (i.e., 0-17% occurrence of convulsions and lethality). CocE retained its potency against cocaine toxicity in mice after a single prior CocE exposure (0.1-1 mg), and these mice did not show an immune response. CocE retained similar effectiveness in mice after three prior CocE exposures (0.1-1 mg/week for 3 weeks), although these mice displayed 10-fold higher antibody titers. CocE partially lost effectiveness (i.e., 33-50% occurrence of convulsions and lethality) in mice with four prior exposures to CocE (0.1-1 mg/2 week for four times), and these mice displayed approximately 100-fold higher antibody titers. These results suggest that CocE produces robust protection and reversal of cocaine toxicity, indicating CocE's therapeutic potential for acute cocaine toxicity. Repeated CocE exposures may increase its immunogenicity and partially reduce its protective ability.
Ko
Mei-Chuan
MC
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109-0632, USA. mko@umich.edu
Bowen
Luvina D
LD
Narasimhan
Diwahar
D
Berlin
Aaron A
AA
Lukacs
Nicholas W
NW
Sunahara
Roger K
RK
Cooper
Ziva D
ZD
Woods
James H
JH
D000818:Animals; D000906:Antibodies / Q000097:blood; D002265:Carboxylic Ester Hydrolases / Q000276:immunology* / Q000494:pharmacology*; D003042:Cocaine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D012640:Seizures / Q000139:chemically induced; D013997:Time Factors
D000906:Antibodies; D002265:Carboxylic Ester Hydrolases; C019921:cocaine esterase; D003042:Cocaine