长期使用氯氮平（CLZ）（一种非典型抗精神病药物）治疗精神分裂症，会导致代谢紊乱的发生率增加，而代谢紊乱的发病机制尚不清楚。我们在此报告，CLZ 在减缓 SW872 细胞脂肪形成过程中发生的形态变化和脂质积累的同时，还会导致 CAAT/增强子结合蛋白 β 和过氧化物酶体增殖物激活受体的表达/核易位的早期（第 3 天）抑制γ。在相同条件下，CLZ 通过涉及酶抑制和 ROS 清除的双重机制来减弱 NADPH 氧化酶衍生的活性氧 (ROS)。与对照组相比，这些效应还伴随着核因子（红细胞衍生2）样2（Nrf2）依赖性抗氧化反应的激活受到阻碍，并且线粒体超氧化物的形成加剧。 CLZ 未能在线粒体区室中发挥 ROS 清除活性，但似乎能主动清除来自线粒体超氧化物的胞质 H2O2。 CLZ 促进线粒体 ROS 的早期形成也与线粒体功能障碍的迹象有关。使用小鼠胚胎成纤维细胞重现了上述一些发现。我们得出的结论是，CLZ 的 NADPH 氧化酶抑制和胞质 ROS 清除活性可减缓 SW872 细胞脂肪生成并抑制其 Nrf2 激活，这一事件显然与线粒体 ROS 形成增加有关，而线粒体 ROS 形成与胰岛素抵抗和代谢综合征有关。因此，本文表征的细胞事件可能有助于阐明更详细的分子机制，解释 CLZ 的一些不利代谢影响。版权所有 © 2023 作者。由 Elsevier B.V. 出版。保留所有权利。

Long-term treatment of schizophrenia with clozapine (CLZ), an atypical antipsychotic drug, is associated with an increased incidence of metabolic disorders mediated by poorly understood mechanisms. We herein report that CLZ, while slowing down the morphological changes and lipid accumulation occurring during SW872 cell adipogenesis, also causes an early (day 3) inhibition of the expression/nuclear translocation of CAAT/enhancer-binding protein β and peroxisome proliferator-activated receptor γ. Under the same conditions, CLZ blunts NADPH oxidase-derived reactive oxygen species (ROS) by a dual mechanism involving enzyme inhibition and ROS scavenging. These effects were accompanied by hampered activation of the nuclear factor (erythroid-derived2)-like 2 (Nrf2)-dependent antioxidant responses compared to controls, and by an aggravated formation of mitochondrial superoxide. CLZ failed to exert ROS scavenging activities in the mitochondrial compartment but appeared to actively scavenge cytosolic H2O2 derived from mitochondrial superoxide. The early formation of mitochondrial ROS promoted by CLZ was also associated with signs of mitochondrial dysfunction. Some of the above findings were recapitulated using mouse embryonic fibroblasts. We conclude that the NADPH oxidase inhibitory and cytosolic ROS scavenging activities of CLZ slow down SW872 cell adipogenesis and suppress their Nrf2 activation, an event apparently connected with increased mitochondrial ROS formation, which is associated with insulin resistance and metabolic syndrome. Thus, the cellular events characterised herein may help to shed light on the more detailed molecular mechanisms explaining some of the adverse metabolic effects of CLZ.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.