Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes: no association with myeloperoxidase and cytochrome P4502D6.
The pathomechanisms of most drug-induced agranulocytoses are unclear; however, there are some studies pointing to genetic determinants. Some drug-induced agranulocytoses such as clozapine-induced agranulocytosis (CA) may be regarded as an idiosyncratic drug reaction because of its preclinical and clinical characteristics. To study some aspects of the genetic background of CA further, polymorphisms of specific metabolizing enzyme systems of clozapine were examined. Thirty-one schizophrenic patients with CA and 77 schizophrenic comparison subjects without this adverse effect underwent genotyping of a recently discovered G(-463)A polymorphism of myeloperoxidase (MPO) gene and cytochrome P4502D6. Neither the MPO mutation nor specific genotypes of cytochrome P4502D6 were associated with CA. Both were equally distributed among CA patients and controls. Thus, our data suggest lack of evidence of 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 final conclusions about these genetically based hypotheses.
Dettling
M
M
Department of Psychiatry, University Hospital Benjamin Franklin, Free University of Berlin, Germany. michael.dettling@charite.de
Sachse
C
C
Müller-Oerlinghausen
B
B
Roots
I
I
Brockmöller
J
J
Rolfs
A
A
Cascorbi
I
I
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000380:Agranulocytosis / Q000139:chemically induced* / Q000235:genetics; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D003024:Clozapine / Q000009:adverse effects* / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009195:Peroxidase / Q000235:genetics*; D011110:Polymorphism, Genetic; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics
D014150:Antipsychotic Agents; D009195:Peroxidase; D019389:Cytochrome P-450 CYP2D6; D003024:Clozapine