Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Smętna Street 12, Poland.
Institute for Regenerative Medicine and Biotherapy, Univ Montpellier, Inserm U1183, CHU Montpellier, Montpellier, France.
Food Chem Toxicol. 2018 Jun;116(Pt B):369-378. doi: 10.1016/j.fct.2018.04.051. Epub 2018 Apr 23.
The aim of this study is to assess a potential mechanism by which the serotonergic system can control the expression and activity of cytochrome (CYP) 2C11 and CYP3A isoforms during liver insufficiency. A rat model of diethylnitrosamine (DEN)-induced liver insufficiency was developed by administering 50 mg/kg of DEN twice a week for 7 weeks. Dysfunction of the serotonergic system was evoked by feeding the rats with a tryptophan-free diet for three weeks. Dysfunction of the serotonergic system during liver insufficiency decreased the level of proinflammatory cytokines (TGF-β and IL-1β) and increased the level of an anti-inflammatory cytokine (IL-4). Simultaneously, activation of the repressive mechanism IL-4/JAK1/STAT6/SOCS1 of the JAK2/STAT5b-mediated signal transduction pathway and the pERK1/2/GR/STAT6 signal transduction pathway resulted in the suppression of the CYP2C11 and CYP3A isoforms. Moreover, dysfunction of the serotonergic system during liver insufficiency equalized the level of testosterone to the basal level, did not change the steady state of the corticosterone level and significantly enhanced the reduced level of growth hormone. An altered cytokine profile under control of the serotonergic system determines the regulation of CYP2C11 and CYP3A isoforms during liver insufficiency through mechanisms based on posttranscriptional and posttranslational processes.
本研究旨在评估血清素能系统控制肝不全期间细胞色素（CYP）2C11 和 CYP3A 同工酶表达和活性的潜在机制。通过每周两次给予大鼠 50mg/kg 二乙基亚硝胺（DEN）7 周来建立 DEN 诱导的肝不全大鼠模型。通过三周的色氨酸缺乏饮食喂养大鼠来诱发血清素能系统功能障碍。肝不全期间血清素能系统功能障碍降低了促炎细胞因子（TGF-β 和 IL-1β）的水平，并增加了抗炎细胞因子（IL-4）的水平。同时，IL-4/JAK1/STAT6/SOCS1 抑制机制的激活和 JAK2/STAT5b 介导的信号转导通路的 pERK1/2/GR/STAT6 信号转导通路的激活导致 CYP2C11 和 CYP3A 同工酶的抑制。此外，肝不全期间血清素能系统功能障碍使睾丸酮水平均等化至基础水平，不改变皮质酮水平的稳态，并显著增强降低的生长激素水平。在血清素能系统控制下改变的细胞因子谱通过基于转录后和翻译后过程的机制决定 CYP2C11 和 CYP3A 同工酶在肝不全期间的调节。
