ACTIVATION OF CGS-12094 (PRINOMIDE METABOLITE) TO 1,4-BENZOQUINONE BYMYELOPEROXIDASE - IMPLICATIONS FOR HUMAN IDIOSYNCRATIC AGRANULOCYTOSIS

Many marketed pharmaceuticals are known to cause idiosyncratic agranul ocytosis in humans. Similarly prinomide, an antiinflammatory drug, was associated with a low incidence of agranulocytosis (<0.3%) in clinica l trials, even though chronic toxicity studies in rodents and primates showed no evidence of agranulocytosis with either prinomide or its pa rahydroxy metabolite, CGS 12094. To investigate mechanisms for this hu man specific toxicity, experiments were conducted to study the metabol ism of prinomide and CGS 12094 by myeloperoxidase (MPO), a major enzym e of neutrophils and leukocyte progenitor cells. Although prinomide wa s not metabolized by human MPO, CGS 12094 was rapidly metabolized (>90 %; 2 min); this reaction was dependent on H2O2 and MPO and was inhibit ed by azide. During the MPO-catalyzed metabolism of CGS 12094, reactiv e intermediates that irreversibly bound to protein and cysteine were g enerated. One of the reactive metabolites generated was identified by mass spectroscopy and trapping with cysteine as 1,4-benzoquinone, a co mpound implicated in the myelotoxicity associated with benzene. Thus d uring conditions which lead to elevated levels of H2O2 (e.g., active i nflammation), CGS 12094 is rapidly metabolized by MPO to reactive inte rmediates that may be related to prinomide-induced agranulocytosis. (C ) 1997 Society of Toxicology.