Document Detail

Role of metabolism by esterase and cytochrome P-450 in cocaine-induced suppression of the antibody response.
MedLine Citation:
PMID:  7815357     Owner:  NLM     Status:  MEDLINE    
To investigate the role of metabolism in cocaine-induced immunosuppression, diazinon and beta-ionone were administered as an esterase inhibitor and a cytochrome P-450 (P-450) inducer, respectively, to B6C3F1 female mice. When 10 or 30 mg/kg of diazinon was administered 30 min before cocaine (30 mg/kg) was administered i.p. for 7 consecutive days, the suppression of the T-dependent antibody response to sheep red blood cells was potentiated greatly when compared to the suppression by cocaine alone. Spleen and thymus weights were decreased significantly and serum glutamate-pyruvate transaminase activities were elevated dramatically when cocaine and diazinon were administered together. beta-Ionone was administered s.c. for 7 consecutive days and the P-450 activities were determined 3 days after the last administration. beta-Ionone induced cocaine N-demethylation, which is the first step in the activation of cocaine to the metabolites capable of producing hepatotoxicity, as well as P-450IA1- and P-450IIB1-specific monooxygenases. The inductive effects of beta-ionone on P-450IA1/2 and P-450IIB1/2 proteins were confirmed by using Western immunoblotting with selective monoclonal antibodies. In addition, when beta-ionone (600 mg/kg) was administered with cocaine for 7 days, the suppression of the antibody response was potentiated greatly, thymus weight was decreased significantly and serum glutamate-pyruvate transaminase was elevated. Our present results suggest that inhibition of the esterase pathway of cocaine shunts the metabolism of cocaine into an immunotoxic pathway, and that the metabolism of cocaine by P-450 may be the critical pathway for the generation of the metabolites capable of suppressing the antibody response.
T C Jeong; S D Jordan; R A Matulka; E D Stanulis; E J Kaminski; M P Holsapple
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  272     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1995 Jan 
Date Detail:
Created Date:  1995-02-08     Completed Date:  1995-02-08     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  407-16     Citation Subset:  IM    
Department of Pharmacology and Toxicology, Medical College, Virginia/Virginia Commonwealth University, Richmond.
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MeSH Terms
Antibody Formation / drug effects*
Cocaine / metabolism,  pharmacology*
Cytochrome P-450 Enzyme System / metabolism*
Diazinon / pharmacology
Drug-Induced Liver Injury
Enzyme Induction / drug effects
Esterases / metabolism*
Microsomes, Liver / enzymology
Terpenes / pharmacology
Grant Support
Reg. No./Substance:
0/Norisoprenoids; 0/Terpenes; 14901-07-6/beta-ionone; 333-41-5/Diazinon; 50-36-2/Cocaine; 9035-51-2/Cytochrome P-450 Enzyme System; EC 3.1.-/Esterases

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