title: Immunosuppression induced by acute exposure to cocaine is dependent on metabolism by cytochrome P-450.
abstract: The primary objective of this paper was to characterize the role of metabolism in immunosuppression by acute exposure to cocaine. beta-Ionone has been used to study the role of metabolism in hepatotoxicity associated with acute exposure to cocaine, and was shown to produce a greater effect than other cytochrome P-450 (P-450) inducers. When beta-ionone (600 mg/kg s.c.) was pretreated 72 and 48 hr before the acute administration of cocaine (30 mg/kg i.p.) in B6C3F1 female mice, the antibody response to sheep red blood cells was significantly suppressed. Exposure to cocaine alone produced little or no suppression. The immunosuppression in cocaine + beta-ionone-treated mice was accompanied by a decrease in thymus weight and an increase in liver weight. Administration of metyrapone (40 mg/kg i.p.) 30 min before cocaine administration (40 mg/kg) blocked completely the suppression of the antibody response by cocaine in beta-ionone-pretreated mice. The reversal by metyrapone was additional evidence that a P-450 pathway was the critical metabolic pathway of cocaine to be immunosuppressive, and the inhibitory effect of metyrapone on cocaine N-demethylase was confirmed in liver microsomes. The inductive effects of beta-ionone were also characterized further. Cocaine N-demethylase activity was significantly induced by beta-ionone. The induction of P-450IIB1/2, the only isozyme shown previously to be associated with the hepatotoxicity by cocaine, was demonstrated by Western immunoblotting to be induced by beta-ionone at doses as low as 300 mg/kg; but was less than the induction associated with phenobarbital. Studies confirmed that acute exposure to cocaine also was immunosuppressive in phenobarbital-pretreated mice. Taken together, our present results suggest that the immunosuppression by acute exposure to cocaine is associated with the increased metabolism of cocaine to toxic metabolites by P-450, probably P-450IIB1/2, as demonstrated previously for its hepatotoxicity.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Jeong
authors.forename: S D
authors.initials: SD
authors.lastname: Jordan
authors.forename: R A
authors.initials: RA
authors.lastname: Matulka
authors.forename: E D
authors.initials: ED
authors.lastname: Stanulis
authors.forename: S S
authors.initials: SS
authors.lastname: Park
authors.forename: M P
authors.initials: MP
authors.lastname: Holsapple
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003042:Cocaine / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007165:Immunosuppression Therapy; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D003577:Cytochrome P-450 Enzyme System; D003042:Cocaine; D008797:Metyrapone