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

K Fehsel,K Hemmrich,C Lange-Asschenfeldt,G Kojda,T Haarmann-Stemmann,E Fahimi,C Esser,Ba Kappel,K Schwanke,E Meisenzahl-Lechner

doi:10.1177/02698811211055811

Abstract

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.

Highlights

The antipsychotic drug (APD) clozapine is effective even in treatment-refractory schizophrenia, but it shows common adverse effects which occur to a lesser extend with other antipsychotic drugs (APDs)
EROD activity induced by both concentrations of clozapine was completely abolished in the presence of MNF demonstrating that the aryl hydrocarbon receptor (AhR) antagonist MNF completely reversed AhR agonist activity of clozapine
Further analysis of gene expression in clozapine-treated HepG2 cells revealed only slight induction of other genes upregulated by AhR activation like cytochrome P450 monooxygenase 1A2 (Cyp1A2), plasminogen activator inhibitor (PAI2), nuclear factor-erythroid 2 p45-related factor 2 (NRF2), NAD(P)H:quinone oxidoreductase 1 (NQO1) after 4 and 8 h

Summary

Introduction

The antipsychotic drug (APD) clozapine is effective even in treatment-refractory schizophrenia, but it shows common adverse effects which occur to a lesser extend with other APDs. Unique components of clozapine’s chemical structure, that is a halogenated diazepine, might trigger specific cellular responses such as activation of the aryl hydrocarbon receptor (AhR). Our assumption that this ligand-activated transcription factor plays a key role in clozapine-triggered adverse effects is supported by the fact that AhR signaling causes weight gain, hyperglycemia, and hypertension (Chang et al, 2017; Rojas et al, 2021) too. 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). 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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