Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes: No association with myeloperoxidase and cytochrome P450206

The pathomechanisms of most drug-induced agranulocytoses are unclear; howev er, there are some studies pointing to genetic determinants. Some drug-indu ced agranulocytoses such as clozapine-induced agranulocytosis (CA) may be r egarded as an idiosyncratic drug reaction because of its preclinical and cl inical characteristics. To study some aspects of the genetic background of CA further, polymorphisms of specific metabolizing enzyme systems of clozap ine were examined, Thirty-one schizophrenic patients with CA and 77 schizop hrenic comparison subjects without this adverse effect underwent genotyping of a recently discovered G(-463)A polymorphism of myeloperoxidase (MPO) ge ne and cytochrome P4502D6. Neither the MPO mutation nor specific genotypes of cytochrome P4502D6 were associated with CA. Both were equally distribute d among CA patients and controls. Thus, our data suggest lack of evidence o f an association of CA and genetically variable activity of these specific drug metabolizing enzymes; however, this may be due to statistical reasons only. Thus, further studies with greater CA samples are necessary to draw f inal conclusions about these genetically based hypotheses.