Reactive iminoquinone metabolites of indomethacin and carbamazepine, implications for drug-induced idiosyncratic reactions
Year: 1999
Type: dissertation
Abstract: Indomethacin is a potent nonsteroidal anti-inflammatory drug. Its use has been limited because of a relatively high incidence of adverse reactions including agranulocytosis. Carbamazepine is an anticonvulsant and its use is associated with a range of serious idiosyncratic adverse reactions including blood disorders. We postulated that indomethacin and carbamazepine can be oxidized to reactive intermediates by myeloperoxidase in activated neutrophils, which may be responsible for the adverse effects caused by these two drugs. We found that desmethyldeschlorobenzoylindomethacin (DMBI), a major metabolite of indomethacin, was oxidized to a reactive iminoquinone intermediate. This iminoquinone intermediate could be trapped with glutathione (GSH) and N-acetylcysteine (NAC) to form conjugates. The same oxidation was observed when DMBI was oxidized by the MPO system or hypochlorous acid. The iminoquinone intermediate with a MH+ ion at m/z 204 was directly detected by mass spectrometry in the reaction between DMBI and hypochlorous acid. In the urine of patients taking carbamazepine, we detected 2-hydroxyiminostilbene as its glucuronide conjugate and found that it is a major metabolite of carbamazepine. We have also demonstrated that 2-hydroxyiminostilbene can undergo autoxidation to a reactive iminoquinone intermediate. The iminoquinone intermediate reacts with sulfhydryl-containing nucleophiles, such as GSH and NAC. To further investigate the role of the iminoquinone intermediate in carbamazepine-induced adverse reactions, we developed a polyclonal antibody against the iminoquinone epitope and used it to study covalent binding of the iminoquinone to proteins. The antibodies were able to detect covalent binding in bone marrow cells of rats treated with carbamazepine 'in vivo'. This binding was inhibited by 2-hydroxyiminostilbene but not by carbamazepine or iminostilbene, which suggested that the polypeptides recognized by the antibodies were likely to be covalently modified by the iminoquinone reactive intermediate. Furthermore, we also observed increased protein oxidation in the liver from carbamazepine-treated rats compared to that of control rats. This implied that the iminoquinone, as an oxidizing agent, may undergo redox cycling and lead to protein oxidation ' in vivo'. Our studies suggest that the iminoquinone intermediates may react with protein sulfhydryl groups 'in vivo' and play an important role in indomethacin- and carbamazepine-induced idiosyncratic reactions.
Author: Changqing Ju
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2528798856