Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.11.1.7 (peroxidase)
 65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Covalent binding of carbamazepine oxidative metabolites to neutrophils. 758 36

Carbamazepine is an anticonvulsant which is associated with a significant incidence of hypersensitivity reactions including agranulocytosis. We have postulated that many drug hypersensitivity reactions, especially agranulocytosis and lupus, are due to reactive metabolites generated by the myeloperoxidase (MPO) (EC 1.11.1.7) system of neutrophils and monocytes. This led to a study of the metabolism and covalent binding of carbamazepine with MPO/H2O2/Cl- and neutrophils. Metabolism and covalent binding were observed in both systems and the same pathway appeared to be involved; however, the metabolism observed with the MPO system was approximately 500-fold greater than that observed with neutrophils. The metabolites identified were an intermediate aldehyde, 9-acridine carboxaldehyde, acridine, acridone, choloroacridone, and dichloroacridone. We postulate that the first intermediate in the metabolism of carbamazepine is a carbonium ion formed by reaction of hypochlorous acid (HOCl) with the 10,11 double bond. Although we have no direct proof for the proposed carbonium ion, it provides the most likely mechanism for the observed ring contraction. Iminostilbene, a known metabolite of carbamazepine, was also metabolized by a similar pathway leading to ring contraction; however, the rate was much faster and the first step may involve N-chlorination and a nitrenium ion intermediate. These data confirm that carbamazepine is metabolized to reactive intermediates by activated leukocytes. Such metabolites could be responsible for some of the adverse reactions associated with carbamazepine, especially reactions such as agranulocytosis and lupus which involve leukocytes.
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PMID:Carbamazepine metabolism to a reactive intermediate by the myeloperoxidase system of activated neutrophils. 838 60