Hepatic gene expression explains primary drug toxicity in bipolar disorder.,Translational Psychiatry

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Hepatic gene expression explains primary drug toxicity in bipolar disorder.
Translational Psychiatry ( IF 5.8 ) Pub Date : 2019-12-09 , DOI: 10.1038/s41398-019-0666-4
Anna Maria Birkl-Toeglhofer _{1,

2} , Christoph Birkl ₃ , Ida Cirila Llenos ₄ , Serge Weis _{4,

5,

6} , Johannes Haybaeck _{1,

2,

7,

8}

Affiliation

In bipolar disorder (BPD), long-term psychotropic drug treatment is often necessary to prevent relapse or recurrence. Nevertheless, adverse drug effects including disturbances in hepatic metabolism are observed and still poorly understood. Here, the association between hepatic gene expression and histopathological changes of the liver was investigated. By the use of microarrays (Affymetrix U133 plus2.0), a genome-wide expression study was performed on BPD patients with psychotropic drug treatment (n = 29) compared to unaffected controls (n = 20) and validated by quantitative real-time PCR. WebGestalt was used to identify over-represented functional pathways of the Reactome database. Association analyses between histopathological changes and differentially expressed genes comprised in the over-represented functional pathways were performed using regression analyses, from which feature-expression heatmaps were drawn. The majority of identified genes were underexpressed and involved in energy supply, metabolism of lipids and proteins, and the innate immune system. Positive associations were found for genes involved in all pathways and degenerative changes. The strongest negative association was observed between genes involved in energy supply and hepatic activity, as well as inflammation. In summary, we found a possible association between gene expression involved in various biological pathways and histopathological changes of the liver in BPD. Further, we found support for the probable primary toxic effect of psychotropic drugs on hepatic injury in BPD. Even if the safety of psychotropic drugs improves, adverse effects especially on hepatic function should not be underestimated.

中文翻译：

肝基因表达解释了双相情感障碍的主要药物毒性。

在双相情感障碍 (BPD) 中，通常需要长期的精神药物治疗来预防复发或复发。然而，观察到包括肝脏代谢紊乱在内的药物副作用，但仍知之甚少。在这里，研究了肝脏基因表达与肝脏组织病理学变化之间的关联。通过使用微阵列 (Affymetrix U133 plus2.0)，与未受影响的对照组 (n = 20) 相比，对接受精神药物治疗的 BPD 患者 (n = 29) 进行了全基因组表达研究，并通过定量实时 PCR 验证. WebGestalt 用于识别 Reactome 数据库中过度代表的功能途径。使用回归分析进行组织病理学变化和包含在过度代表的功能途径中的差异表达基因之间的关联分析，从中绘制特征表达热图。大多数已鉴定的基因表达不足，并与能量供应、脂质和蛋白质的代谢以及先天免疫系统有关。发现参与所有途径和退行性变化的基因呈正相关。在参与能量供应和肝脏活动以及炎症的基因之间观察到最强的负相关。总之，我们发现参与各种生物学途径的基因表达与 BPD 中肝脏的组织病理学变化之间可能存在关联。更远，我们发现支持精神药物对 BPD 肝损伤可能的主要毒性作用。即使精神药物的安全性有所提高，也不能低估不良反应，尤其是对肝功能的影响。

更新日期：2019-12-11

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