Activation of CGS 12094 (Prinomide Metabolite) to 1,4-Benzoquinone by Myeloperoxidase: Implications for Human Idiosyncratic Agranulocytosis

Abstract

Many marketed pharmaceuticals are known to cause idiosyncratic agranulocytosis in humans. Similarly prinomide, an antiinflammatory drug, was associated with a low incidence of agranulocytosis (<0.3%) in clinical trials, even though chronic toxicity studies in rodents and primates showed no evidence of agranulocytosis with either prinomide or its parahydroxy metabolite, CGS 12094. To investigate mechanisms for this human specific toxicity, experiments were conducted to study the metabolism of prinomide and CGS 12094 by myeloperoxidase (MPO), a major enzyme of neutrophils and leukocyte progenitor cells. Although prinomide was not metabolized by human MPO, CGS 12094 was rapidly metabolized (>90%; 2 min); this reaction was dependent on H2O2 and MPO and was inhibited by azide. During the MPO-catalyzed metabolism of CGS 12094, reactive intermediates that irreversibly bound to protein and cysteine were generated. One of the reactive metabolites generated was identified by mass spectroscopy and trapping with cysteine as 1,4-benzoquinone, a compound implicated in the myelotoxicity associated with benzene. Thus during conditions which lead to elevated levels of H2O2 (e.g., active inflammation), CGS 12094 is rapidly metabolized by MPO to reactive intermediates that may be related to prinomide-induced agranulocytosis.

The chemical and biological activities of quinones: overview and implications in analytical detection

“…The binding of quinones to proteins can also lead, through the recognition of quinonebound epitopes from degraded protein, to immunological damage. For instance, quinone-protein conjugation has been implicated in playing a causative role in the incidence of certain allergic or idiosyncratic drug reactions (Lepoittevin and Benezra 1991;Parrish et al 1997;Petersen 2002). Contact allergic reactions have been linked to 2-hydroxy-2,4-naphthoquinone (henna) (27), a principal ingredient in many types of body dyes (Bolhaar et al 2001;Calogiuri et al 2010).…”

Characterization of Glutathione Conjugates of the Remoxipride Hydroquinone Metabolite NCQ-344 Formed in Vitro and Detection following Oxidation by Human Neutrophils

“…A major source of extrahepatic drug oxidation are neutrophils (13) via the MPO-generated oxidant hypochlorous acid. The MPO system in neutrophils can cause oxidation of drugs and metabolites to quinone imines or quinones as has been demonstrated for amodiaquine (14) and a metabolite of prinomide (15), respectively.…”