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

Author:

Fehsel K1ORCID,Schwanke K2,Kappel BA3,Fahimi E4,Meisenzahl-Lechner E1,Esser C2,Hemmrich K5,Haarmann-Stemmann T2,Kojda G4,Lange-Asschenfeldt C1

Affiliation:

1. Neurobiochemical Research Unit, Department of Psychiatry, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

2. Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany

3. Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany

4. Institute for Pharmacology and Clinical Pharmacology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

5. Department of Plastic Surgery and Hand Surgery, Burn Center, University Hospital of the Aachen University of Technology, Aachen, Germany

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.

Publisher

SAGE Publications

Subject

Pharmacology (medical),Psychiatry and Mental health,Pharmacology

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