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Effects of several atypical antipsychotics closapine, sertindole or ziprasidone on hepatic antioxidant enzymes: Possible role in drug-induced liver dysfunction
Journal of Toxicology and Environmental Health, Part A ( IF 2.3 ) Pub Date : 2020-11-24 , DOI: 10.1080/15287394.2020.1844827
Lena Platanić Arizanović 1 , Aleksandra Nikolić-Kokić 2 , Jelena Brkljačić 3 , Nikola Tatalović 2 , Marko Miler 4 , Zorana Oreščanin-Dušić 2 , Teodora Vidonja Uzelac 2 , Milan Nikolić 1 , Verica Milošević 4 , Duško Blagojević 1 , Snežana Spasić 5 , Čedo Miljević 6
Affiliation  

ABSTRACT

Chronic use of atypical antipsychotics may produce hepatic damage. Atypical antipsychotics, including clozapine, sertindole, and ziprasidone, are extensively metabolized by the liver and this process generates toxic-free radical metabolic intermediates which may contribute to liver damage. The aim of this study was to investigate whether clozapine, sertindole, or ziprasidone affected hepatic antioxidant defense enzymes which consequently led to disturbed redox homeostasis. The expression and activity of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferases (GST) were measured in rat livers at doses corresponding to human antipsychotic therapy. Clozapine increased activity of SOD types 1 and 2, GR and GST, but reduced CAT activity. Sertindole elevated activities of both SODs. In ziprasidone-treated rats only decreased CAT activity was found. All three antipsychotics produced mild-to-moderate hepatic histopathological changes categorized as regenerative alterations. No apparent signs of immune cell infiltration, microvesicular or macrovesicular fatty change, or hepatocytes in mitosis were observed. In conclusion, a 4-week long daily treatment with clozapine, sertindole, or ziprasidone altered hepatic antioxidant enzyme activities and induced histopathological changes in liver. The most severe alterations were noted in clozapine-treated rats. Data indicate that redox disturbances may contribute to liver dysfunction after long-term atypical antipsychotic drug treatment.



中文翻译:

几种非典型抗精神病药氯沙平、舍吲哚或齐拉西酮对肝脏抗氧化酶的影响:在药物性肝功能障碍中的可能作用

摘要

长期使用非典型抗精神病药可能会导致肝损伤。非典型抗精神病药,包括氯氮平、舍吲哚和齐拉西酮,在肝脏中广泛代谢,这一过程产生有毒自由基代谢中间体,可能导致肝损伤。本研究的目的是调查氯氮平、舍吲哚或齐拉西酮是否影响肝脏抗氧化防御酶,从而导致氧化还原稳态紊乱。抗氧化酶超氧化物歧化酶 (SOD)、谷胱甘肽过氧化物酶 (GPx)、谷胱甘肽还原酶 (GR)、过氧化氢酶 (CAT) 和谷胱甘肽-S-转移酶 (GST) 在大鼠肝脏中的表达和活性在相当于人类抗精神病药的剂量下进行测量治疗。氯氮平增加了 SOD 1 型和 2 型、GR 和 GST 的活性,但降低了 CAT 活性。Sertindole 提高了两种 SOD 的活性。在齐拉西酮治疗的大鼠中,仅发现 CAT 活性降低。所有三种抗精神病药都产生了轻度至中度的肝脏组织病理学变化,归类为再生性改变。未观察到明显的免疫细胞浸润、微泡或大泡脂肪变化或肝细胞有丝分裂迹象。总之,每天使用氯氮平、舍吲哚或齐拉西酮进行为期 4 周的治疗会改变肝脏抗氧化酶活性并诱导肝脏组织病理学变化。在氯氮平治疗的大鼠中注意到最严重的改变。数据表明,在长期非典型抗精神病药物治疗后,氧化还原紊乱可能导致肝功能障碍。所有三种抗精神病药都产生了轻度至中度的肝脏组织病理学变化,归类为再生性改变。未观察到明显的免疫细胞浸润、微泡或大泡脂肪变化或肝细胞有丝分裂迹象。总之,每天使用氯氮平、舍吲哚或齐拉西酮进行为期 4 周的治疗会改变肝脏抗氧化酶活性并诱导肝脏组织病理学变化。在氯氮平治疗的大鼠中注意到最严重的改变。数据表明,在长期非典型抗精神病药物治疗后,氧化还原紊乱可能导致肝功能障碍。所有三种抗精神病药都产生了轻度至中度的肝脏组织病理学变化,归类为再生性改变。未观察到明显的免疫细胞浸润、微泡或大泡脂肪变化或肝细胞有丝分裂迹象。总之,每天使用氯氮平、舍吲哚或齐拉西酮进行为期 4 周的治疗会改变肝脏抗氧化酶活性并诱导肝脏组织病理学变化。在氯氮平治疗的大鼠中注意到最严重的改变。数据表明,在长期非典型抗精神病药物治疗后,氧化还原紊乱可能导致肝功能障碍。或观察到肝细胞有丝分裂。总之,每天使用氯氮平、舍吲哚或齐拉西酮进行为期 4 周的治疗会改变肝脏抗氧化酶活性并诱导肝脏组织病理学变化。在氯氮平治疗的大鼠中注意到最严重的改变。数据表明,在长期非典型抗精神病药物治疗后,氧化还原紊乱可能导致肝功能障碍。或观察到肝细胞有丝分裂。总之,每天使用氯氮平、舍吲哚或齐拉西酮进行为期 4 周的治疗会改变肝脏抗氧化酶活性并诱导肝脏组织病理学变化。在氯氮平治疗的大鼠中注意到最严重的改变。数据表明,在长期非典型抗精神病药物治疗后,氧化还原紊乱可能导致肝功能障碍。

更新日期:2021-01-11
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