title: Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis.
abstract: Therapy of the atypical antipsychotic drug clozapine is limited by a comparatively high incidence of agranulocytosis in 0.8% of patients. This severe side effect is possibly based on the clozapine-mediated stimulation of cytokines and soluble cytokine receptors release, followed by induction of granulocyte proliferation and induction of myeloperoxidase (MPO) and NADPH-oxidase. Because NADPH-oxidase/MPO may oxidize clozapine to highly reactive nitrenium ions, we investigated the role of hereditary polymorphisms in the NADPH oxidase/myeloperoxidase system in agranulocytosis patients who received clozapine (n = 49), ticlopidine (n = 11), and other drugs prior to the event. The low active MPO -436A allelic variant frequency was 22.2% in cases and 19.9% in controls, but AA carriers were overrepresented among cases compared with the sum of AG and GG-carriers (odds ratio 4.16, 95% confidence limits 0.86-20.3, P = 0.056). Particularly in clozapine-induced agranulocytosis, this finding was most pronounced (P = 0.04). In the CYBA gene, encoding the p22phox subunit of the NADPH-oxidase, 2 polymorphisms were investigated. C242T (His72Tyr) had an allele frequency of 31.9% and 32.2% (P = NS) and A640G in the 3'-UTR was less frequent in cases (48.7%) than controls (60.0%), odds ratio 0.63 (0.39-1.02), P = 0.048. CYBA 640GG-carriers were marginally less frequent in cases compared with controls (28.2% vs. 38.7%, P = 0.062). Sequencing the entire coding region of the NADPH subunit CYBB (gpS1phase) disclosed that CYBB is a highly conserved gene, which does not represent a risk factor for clozapine-induced agranulocytosis. The impact of the polymorphic myeloperoxidase, however, needs further verification to predict a patient's risk to develop drug-induced agranulocytosis.
authors.affiliation: Institute of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Mosyagin
authors.forename: Michael
authors.initials: M
authors.lastname: Dettling
authors.forename: Ivar
authors.initials: I
authors.lastname: Roots
authors.forename: Bruno
authors.initials: B
authors.lastname: Mueller-Oerlinghausen
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000380:Agranulocytosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics*; D014150:Antipsychotic Agents / Q000009:adverse effects; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D016001:Confidence Intervals; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000235:genetics*; D016017:Odds Ratio; D009195:Peroxidase / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy
chemical_list: D014150:Antipsychotic Agents; D009195:Peroxidase; D019255:NADPH Oxidases