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The role of myeloperoxidase and NADPH oxidase polymorphisms in clozapine-induced agranulocytosis
It is well-known that clozapine is oxidized by the combination of NADPH-oxidase and MPO to nitrenium ions (1). We compared the frequency of functional relevant polymorphisms in MPO and NADPH CYBA genes and screened CYBB for genetic variants in patients with clozapine induced agranulocytosis (CA), patients with other drug-induced agranulocytosis (DA) and controls. MPO AA carriers were significantly overrepresented among the clozapine group (odds ratio 5.30). MPO genotype distribution in patients suffering from ticlopidine-related agranulocytosis showed a marginally significant odds ratio of 8.44. There was no evidence for an association of the C242T polymorphism in CYBA to the risk of DA in all subjects as well as in subgroups. The CYBB gene was highly conserved. Sequencing of all exons of DA patients did not reveal deviations from the known DNA-sequence. Further research is necessary to find genetic markers for prediction of DA.
1. Liu ZC, Uetrecht JP: Clozapine is oxidized by activated human neutrophils to a reactive nitrenium ion that irreversibly binds to the cells. J.Pharmacol.Exp.Ther. 1995; 275:1476–1483