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.