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 H 2 O 2 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 H 2 O 2 (e.g., active inflammation), CGS 12094 is rapidly metabolized by MPO to reactive intermediates that may be related to prinomide-induced O 1997 Soetely of Toxicology.

Bioactivation of the Nontricyclic Antidepressant Nefazodone to a Reactive Quinone-Imine Species in Human Liver Microsomes and Recombinant Cytochrome P450 3a4

“…A similar P450-catalyzed N-dearylation sequence involving the phenylpiperazine ring system has been reported with the phenylpiperazine-containing antiemetic agent mociprazine and several of its analogs (Enreille et al, 1991;Galmier et al, 1991). Apart from P450, the role of myeloperoxidase in N-dearylation has also been established as exemplified by the phosphodiesterase inhibitor vesarinone (Uetrecht et al, 1994) and the anti-inflammatory agent prinomide (Parrish et al, 1997). Potential mechanisms of nefazodone N-dearylation to afford 8 and 2-chloro-1,4-benzoquinone are shown in Fig.…”

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.…”