Research paper
The effect of carbamazepine and its reactive metabolite, 9-acridine carboxaldehyde, on immune cell function in vitro

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Abstract

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 μM 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 carboxaldehyde, was demonstrated by an increased proliferation at low concentrations (0.08-1.0 μM) and inhibition at high concentrations (20–100 μM) 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. We postulate that 9-acridine carboxaldehyde, produced by activated neutrophils and monocytes, is responsible for some of the hematological toxicity and effects on the immune system associated with the use of carbamazepine.

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    A preliminary report of this work was presented at the Society of Toxicology, 32nd Annual Meeting, New Orleans, Louisiana, 1993.

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