Risperidone-induced bioenergetic disruption in the isolated human peripheral blood monocytes

IF 2.6 3区医学 Q3 TOXICOLOGY Toxicology in Vitro Pub Date : 2024-09-03 DOI:10.1016/j.tiv.2024.105936

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Abstract

Risperidone (RIS) is a widely used antipsychotic drug with reported alteration in immune response. The current study investigated mitochondrial disruption as the underlying mechanism of RIS-induced immunotoxicity in isolated human peripheral blood monocytes (hPBM). RIS was cytotoxic to hPBM in exposure duration and concentration-dependent patterns. Functionally, RIS was shown to increase the release of IL-6, TNF-α, and IL-8 with a decrease in test particle phagocytosis in concertation and exposure time-based patterns. It was found that RIS decreased ATP production in isolated monocytes' mitochondria, with an estimated EC50 of around 70 μM after 24 h with parallel inhibition of mitochondrial complexes I and III activities and decreased mitochondrial membrane potential and oxygen consumption rates with increased lactate production from by the treated cells in comparison to controls. Structurally, RIS in 100 μM concentration significantly increased the mitochondrial membrane fluidity with significant increase in increased unsaturated/saturated fatty acids ratios of the mitochondrial membranes of the treated cells. Interestingly, water-soluble CoQ10 formulation significantly decreased the cytotoxic effect of RIS and improved the phagocytic activity of RIS-treated cells. To conclude, the current data suggests mitochondrial disruption as the underlying mechanism of RIS-induced immunotoxicity with shown protective effect of water-soluble CoQ10 formulation.

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利培酮诱导的离体人类外周血单核细胞生物能紊乱。

利培酮（RIS）是一种广泛使用的抗精神病药物，据报道会改变免疫反应。本研究调查了线粒体破坏作为利培酮诱导离体人外周血单核细胞（hPBM）免疫毒性的基本机制。在暴露持续时间和浓度依赖性模式下，RIS 对 hPBM 具有细胞毒性。在功能方面，研究表明 RIS 会增加 IL-6、TNF-α 和 IL-8 的释放，并以协同和暴露时间为基础降低测试颗粒的吞噬能力。研究发现，与对照组相比，RIS 会降低离体单核细胞线粒体中 ATP 的产生，24 小时后的 EC50 估计约为 70 μM，同时抑制线粒体复合物 I 和 III 的活性，降低线粒体膜电位和耗氧率，增加处理细胞的乳酸盐产生。从结构上看，浓度为 100 μM 的 RIS 能显著增加线粒体膜的流动性，处理细胞线粒体膜的不饱和/饱和脂肪酸比显著增加。有趣的是，水溶性 CoQ10 配方能明显降低 RIS 的细胞毒性作用，并提高 RIS 处理细胞的吞噬活性。总之，目前的数据表明线粒体破坏是 RIS 诱导免疫毒性的基本机制，而水溶性 CoQ10 制剂具有保护作用。

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来源期刊

Toxicology in Vitro 医学-毒理学

CiteScore

6.50

自引率

3.10%

发文量

181

审稿时长

65 days

期刊介绍： Toxicology in Vitro publishes original research papers and reviews on the application and use of in vitro systems for assessing or predicting the toxic effects of chemicals and elucidating their mechanisms of action. These in vitro techniques include utilizing cell or tissue cultures, isolated cells, tissue slices, subcellular fractions, transgenic cell cultures, and cells from transgenic organisms, as well as in silico modelling. The Journal will focus on investigations that involve the development and validation of new in vitro methods, e.g. for prediction of toxic effects based on traditional and in silico modelling; on the use of methods in high-throughput toxicology and pharmacology; elucidation of mechanisms of toxic action; the application of genomics, transcriptomics and proteomics in toxicology, as well as on comparative studies that characterise the relationship between in vitro and in vivo findings. The Journal strongly encourages the submission of manuscripts that focus on the development of in vitro methods, their practical applications and regulatory use (e.g. in the areas of food components cosmetics, pharmaceuticals, pesticides, and industrial chemicals). Toxicology in Vitro discourages papers that record reporting on toxicological effects from materials, such as plant extracts or herbal medicines, that have not been chemically characterized.