Clozapine inhibits cell survival-related genes in bone marrow cells

Lee, H J; Jin, Shenghao; Hong, Mi-Sook; Park, H J; Kim, M K; Yim, Sung Vin; Kim, J W; Park, H K; Kim, S S; Chung, Joo‐Ho

doi:10.1038/sj.mp.4001489

Cited by 3 publications

(1 citation statement)

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“…Beside transcriptional upregulation of drug-metabolizing enzymes, the receptor activates multiple genomic as well as non-genomic pathways involved in stem cell differentiation, cell plasticity, and immunosuppression (Abel and Haarmann-Stemmann, 2010;Matsumura, 2009). In addition, PAH exposure as well as clozapine treatment increase the risk of bone marrow toxicity (Lee et al, 2004;Luster et al, 1985) and liver steatosis (Rojas et al, 2021;Von Wilmsdorff et al, 2014) as well as the incidence of diabetes, abdominal obesity (Lee et al, 2014;Teff and Kim, 2011), and hypertension (Alberich et al, 2019;Lee et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Activation of the aryl hydrocarbon receptor by clozapine induces preadipocyte differentiation and contributes to endothelial dysfunction

et al. 2022

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Background: The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension. Aims: These adverse vascular/ metabolic events under clozapine are similar to those caused by polycyclic aromatic hydrocarbons (PAHs), and clozapine shows structural similarity to well-known ligands of the aryl hydrocarbon receptor (AhR). Therefore, we speculated that the side effects caused by clozapine might rely on AhR signaling. Methods: We examined clozapine-induced AhR activation by luciferase reporter assays in hepatoma HepG2 cells and we proved upregulation of the prototypical AhR target gene Cyp1A1 by realtime-PCR (RT-PCR) analysis and enzyme activity. Next we studied the physiological role of AhR in clozapine’s effects on human preadipocyte differentiation and on vasodilatation by myography in wild-type and AhR-/- mice. Results: In contrast to other antipsychotic drugs (APDs), clozapine triggered AhR activation and Cyp1A1 expression in HepG2 cells and adipocytes. Clozapine induced adipogenesis via AhR signaling. After PGF2α-induced constriction of mouse aortic rings, clozapine strongly reduced the maximal vasorelaxation under acetylcholine in rings from wild-type mice, but only slightly in rings from AhR-/- mice. The reduction was also prevented by pretreatment with the AhR antagonist CH-223191. Conclusion: Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level.

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