Neurobiochemical Research Unit, Department of Psychiatry, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
J Psychopharmacol. 2022 Feb;36(2):191-201. doi: 10.1177/02698811211055811. Epub 2022 Jan 3.
The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension.
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.
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.
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.
Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level.
氯氮平的优越治疗效果通常与代谢紊乱有关，如肥胖、胰岛素抵抗、心动过速、血压升高甚至高血压。
这些与氯氮平相关的不良血管/代谢事件与多环芳烃（PAHs）引起的事件相似，并且氯氮平显示出与芳烃受体（AhR）的已知配体的结构相似性。因此，我们推测氯氮平引起的副作用可能依赖于 AhR 信号。
我们通过荧光素酶报告基因测定在肝癌 HepG2 细胞中检查氯氮平诱导的 AhR 激活，并通过实时 PCR（RT-PCR）分析和酶活性证明了典型 AhR 靶基因 Cyp1A1 的上调。接下来，我们研究了 AhR 在氯氮平对人前脂肪细胞分化和野生型和 AhR-/-小鼠的血管舒张作用的肌描记中的生理作用。
与其他抗精神病药物（APDs）相比，氯氮平在 HepG2 细胞和脂肪细胞中触发 AhR 激活和 Cyp1A1 表达。氯氮平通过 AhR 信号诱导脂肪生成。在 PGF2α 诱导的小鼠主动脉环收缩后，氯氮平在来自野生型小鼠的环中强烈降低了乙酰胆碱诱导的最大血管舒张作用，但在 AhR-/-小鼠的环中仅略有降低。用 AhR 拮抗剂 CH-223191 预处理也可防止这种降低。
氯氮平作为 AhR 配体的鉴定为在分子水平上解释常见的氯氮平治疗相关不良作用开辟了新的视角。
