Covalent binding of carbamazepine oxidative metabolites to neutrophils.
Carbamazepine therapy is associated with several types of idiosyncratic drug reactions, including hematological disorders. In previous studies, we found that carbamazepine was metabolized by the myeloperoxidase/H2O2 system of activated neutrophils, and covalent binding of the drug to neutrophils was observed. Several metabolites were identified, including 9-acridine carboxaldehyde. Iminostilbene, a minor hepatic metabolite of carbamazepine, was metabolized to a much greater extent than carbamazepine to similar metabolites, including 9-acridine carboxaldehyde. In the present study, the covalent binding of iminostilbene to activated neutrophils was also found to be 10-fold greater than that of carbamazepine. In addition, the binding of 9-acridine carboxaldehyde to neutrophils was 100-fold that of carbamazepine and did not require activation of the neutrophils. This suggests that this aldehyde is the reactive intermediate responsible for much of the binding. To understand possible mechanisms of covalent binding, we investigated the reaction of 9-acridine carboxaldehyde with nucleophiles and found that a reaction occurs with primary amines, such as n-butylamine and N-alpha-acetyllysine, with the formation of an imine. Sodium cyanoborohydride was used to reduce the imine to a stable secondary amine. This suggests a possible mechanism for 9-acridine carboxaldehyde binding to neutrophils that could involve physiological reducing systems in place of the borohydride. 9-Acridine carboxaldehyde may be responsible for some of the adverse reactions associated with carbamazepine, especially those that involve bone marrow.
Furst
S M
SM
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Sukhai
P
P
McClelland
R A
RA
Uetrecht
J P
JP
D000166:Acridines / Q000378:metabolism; D054831:Acridones; D002220:Carbamazepine / Q000378:metabolism*; D002478:Cells, Cultured; D003984:Dibenzazepines / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D018375:Neutrophil Activation / Q000502:physiology; D009504:Neutrophils / Q000378:metabolism*; D010084:Oxidation-Reduction
D000166:Acridines; D054831:Acridones; D003984:Dibenzazepines; D002220:Carbamazepine; C041300:acridone; D005978:Glutathione; C527817:dibenzazepine