The induction of quinone oxidoreductases NQO1 and NQO2 by clozapine: Potential implications for clozapine-induced agranulocytosis
Bibliographic record
Abstract
Clozapine exhibits superior efficacy in the management of treatment-resistant schizophrenia. However, clozapine is currently considered under-prescribed as it carries a risk of idiosyncratic drug reactions (including severe neutropenia or agranulocytosis). The mechanisms of clozapine-induced agranulocytosis mechanisms are evolving. Reports of polymorphisms with NADPH: Quinone Oxidoreductase 2 (NQO2) being associated with clozapine-induced agranulocytosis prompted the studies described herein. Clozapine is known to produce reactive, electrophilic metabolites. It is not known if the latter can interact with NQO2 or with NQO1, its more well-characterized isoform, as quinoid electrophiles do. We hypothesized that clozapine or its metabolites can induce both NQO1 and NQO2 expression via the Nrf2 signaling pathway, as observed with quinoid electrophiles. HL-60 cells were used in this study as they are similar to granulocytes/neutrophils and contain enzymes to metabolize clozapine. A UV-Vis spectrophotometric assay was performed to determine NQO1 and NQO2 enzymatic activity using selective substrates and inhibitors. Immunoblotting was used to investigate NQO1, NQO2, and Nrf2 protein expression. NQO1 and NQO2 gene expression was determined using RT-PCR. Clozapine treatment induced NQO1 and NQO2 enzyme activity, mRNA, and protein expression significantly more than vehicle control accompanied by translocation of the transcription factor, Nrf2, from cytoplasm to nucleus. A structurally related antipsychotic, quetiapine, did not show these effects. The upregulation of both NQO1 and NQO2 enzymatic activity, protein, and gene expression indicated that these enzymes may be involved in the biological response to clozapine toxicity. The translocation of the Nrf2 suggested that the Nrf2 signaling pathway is involved in these response pathways. Further studies are required to determine if NQO2 expression levels and activity are protective mechanisms against clozapine-induced agranulocytosis or if NQO2 levels are a prognostic risk factor for clozapine-induced agranulocytosis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".