ROLE OF METABOLISM IN COCAINE-INDUCED IMMUNOSUPPRESSION IN SPLENOCYTE CULTURES FROM B6C3F1 FEMALE MICE

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Cocaine has been reported to directly suppress the in vitro immune responses at very high concentrations. In the present study, the possible role of metabolism in cocaine-induced immunosuppression was investigated in splenocyte cultures isolated from B6C3F1 female mice. Since cocaine can be metabolized by both esterase and P-450 monooxygenase, we studied the direct effects of cocaine, benzoylecgonine and norcocaine on the in vitro T-dependent antibody response to SRBC. Direct exposure to cocaine only produced a modest (30%) but nonsignificant suppression of the antibody response, while benzoylecgonine, a primary product of metabolism by the esterase pathway, was devoid of activity. In contrast, direct exposure to norcocaine, the initial product of N-demethylation by the P-450 pathway, produced significant suppression at concentrations greater than or equal to 10 mu M. Similar results were observed in studies measuring LPS and Con A mitogenicity. Furthermore, a significant suppression was observed when splenocytes were preincubated for 1 h with 1 mM cocaine in the presence of liver S-9 fractions isolated from phenobarbital-induced mice. Meanwhile, no suppression was obtained when splenocytes were preincubated in the presence of untreated S-9 fractions. To characterize the mechanism of our results, the capacity of both untreated and phenobarbital-induced microsomes to produce formaldehyde from cocaine was compared. The N-demethylation of cocaine was NADPH-dependent and phenobarbital-induced microsomes produced approx, 6-times higher amounts of formaldehyde, indicating a greater portion of cocaine could be metabolized through the P-450 pathway to its toxic metabolites. Finally, because benzoylecgonine shares with cocaine the presence of a methyl group on the tropane nitrogen, we also compared the ability of N-demethylation from cocaine and benzoylecgonine in mouse liver microsomes. Our results indicated that benzoylecgonine could not be demethylated as determined by a failure to generate any formaldehyde. These results offer further support that the N-demethylation pathway is a critical step to cause its immunotoxicity.
Publisher
ELSEVIER SCIENCE BV
Issue Date
1995
Language
English
Article Type
Article
Keywords

INDUCED HEPATIC-NECROSIS; INDUCED HEPATOTOXICITY; RAT HEPATOCYTES; MIXED CULTURES; HUMAN LIVER; ETHANOL; NORCOCAINE; MOUSE; DIMETHYLNITROSAMINE; POTENTIATION

Citation

IMMUNOPHARMACOLOGY, v.29, no.1, pp.37 - 46

ISSN
0162-3109
DOI
10.1016/0162-3109(95)00042-R
URI
http://hdl.handle.net/10203/72480
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