The effect of carbamazepine and its reactive metabolite, 9-acridine carboxaldehyde, on immune cell function in vitro.
Carbamazepine, a widely used anticonvulsant, is associated with a wide range of adverse reactions including agranulocytosis, aplastic anemia and drug-induced lupus. It has also been reported to alter immune function in a variety of ways. We had previously demonstrated that carbamazepine is oxidized by activated neutrophils to several metabolites and this leads to covalent binding of the drug to the cells. It appears that the major metabolite responsible for this binding is 9-acridine carboxyaldehyde. In this study the effects on leukocyte function of carbamazepine and its leukocyte-generated metabolites were compared. Incubation of lymphocytes with 100 microM 9-acridine carboxaldehyde resulted in 40% cell death while carbamazepine at this concentration had no effect on viability. The effect on the immune cell function was investigated using the autologous mixed lymphocyte reaction (AMLR), allogeneic mixed lymphocyte reaction (MLR), lymphocyte transformation test (LTT) and mitogenesis assays. Alteration of immune cell function by the reactive metabolite, 9-acridine carboxyaldehyde, was demonstrated by an increased proliferation at low concentrations (0.08-1.0 microM) and inhibition at high concentrations (20-100 microM) in the allogeneic MLRs. Carbamazepine had no measurable effect. 9-Acridine appears to have more of an effect on B-cells since this augmentation-suppression phenomenon was also observed in mitogenesis assays with Staphylococcus aureus, a B-cell mitogen, in contrast to mostly inhibition observed in the mitogenesis assay with phytohemagglutinin, a T-cell mitogen. Again, carbamazepine had no measurable effects at comparable concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Furst
S M
SM
Faculty of Pharmacy, University of Toronto, Canada.
Uetrecht
J P
JP
D000166:Acridines / Q000009:adverse effects / Q000494:pharmacology*; D002220:Carbamazepine / Q000378:metabolism / Q000494:pharmacology*; D016923:Cell Death; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000276:immunology; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors
D000166:Acridines; D010835:Phytohemagglutinins; D002220:Carbamazepine; C002814:9-acridinecarboxaldehyde; D013936:Thymidine