Role of metabolism by esterase and cytochrome P-450 in cocaine-induced suppression of the antibody response.
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.
Jeong
T C
TC
Department of Pharmacology and Toxicology, Medical College, Virginia/Virginia Commonwealth University, Richmond.
Jordan
S D
SD
Matulka
R A
RA
Stanulis
E D
ED
Kaminski
E J
EJ
Holsapple
M P
MP
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003976:Diazinon / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004950:Esterases / Q000378:metabolism*; D005260:Female; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D045792:Norisoprenoids; D013729:Terpenes / Q000494:pharmacology
D045792:Norisoprenoids; D013729:Terpenes; D003577:Cytochrome P-450 Enzyme System; C008157:beta-ionone; D004950:Esterases; D003042:Cocaine; D003976:Diazinon