N-chlorination of phenytoin by myeloperoxidase to a reactive metabolite.

Several types of phenytoin toxicity appear to involve leukocytes. We had previously demonstrated that other drugs were metabolized to reactive metabolites by activated neutrophils and monocytes or the combination of myeloperoxidase (MPO) and hydrogen peroxide. In this study we found that phenytoin was chlorinated by MPO/H2O2/Cl- to N,N'-dichlorophenytoin which is chemically reactive. Failure to demonstrate that activated neutrophils also formed N,N'-dichlorophenytoin appeared to be due to the rapid reaction of N,N'-dichlorophenytoin with neutrophils. We were able to demonstrate that phenytoin covalently bound to albumin in the presence of MPO/H2O2/Cl- and to neutrophils, but only if the cells were activated. Such activation leads to the release of MPO and the generation of H2O2. We, therefore, speculate that the toxicity of phenytoin may be due to the formation of N,N'-dichlorophenytoin by activated neutrophils or monocytes.