{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T07:14:25Z","timestamp":1792826065631,"version":"4.5.0"},"reference-count":70,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T00:00:00Z","timestamp":1641168000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Psychopharmacol"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>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\u2019s effects on human preadipocyte differentiation and on vasodilatation by myography in wild-type and AhR-\/- mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>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 PGF2\u03b1-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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/02698811211055811","type":"journal-article","created":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T00:09:08Z","timestamp":1641254948000},"page":"191-201","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":26,"title":["Activation of the aryl hydrocarbon receptor by clozapine induces preadipocyte differentiation and contributes to endothelial dysfunction"],"prefix":"10.1177","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3165-4464","authenticated-orcid":false,"given":"K","family":"Fehsel","sequence":"first","affiliation":[{"name":"Neurobiochemical Research Unit, Department of Psychiatry, Medical Faculty, Heinrich Heine University D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Schwanke","sequence":"additional","affiliation":[{"name":"Leibniz Research Institute for Environmental Medicine (IUF), D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"BA","family":"Kappel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Fahimi","sequence":"additional","affiliation":[{"name":"Institute for Pharmacology and Clinical Pharmacology, 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