The present study aimed to investigate the change of intestinal mucosa proteins, especially the alteration of intestinal drug metabolizing enzymes (IDMEs) following 14-day simulated microgravity. Morey–Holton tail-suspension analog was used to simulate microgravity. Intestinal mucosa proteins of rats were determined by label-free quantitative proteomic strategy. A total of 335 differentially expressed proteins (DEPs) were identified, 190 DEPs were upregulated, and 145 DEPs were downregulated. According to bioinformatic analysis, most of DEPs exhibited hydrolase, oxidoreductase, transferase, ligase, or lyase catalytic activity. DEPs were mainly enriched in metabolic pathways, including metabolism of amino acid, glucose, and carbon. Moreover, 11 of DEPs were involved in exogenous drug and xenobiotics metabolism. Owing to the importance of IDMEs for the efficacy and safety of oral drugs, the expression of cytochrome P450 1A2 (CYP1A2), CYP2D1, CYP3A2, CYP2E1, alcohol dehydrogenase 1 (ADH1), and glutathione S-transferase mu 5 (GSTM5) in rat intestine mucosa was determined by Western-blot. The activity of ADH, aldehyde dehydrogenase (ALDH) and GST was evaluated. Compared with control rats, the expression of CYP1A2, CYP2D1, CYP3A2, and ADH1 in the simulated microgravity (SMG) group of rats were dramatically decreased by 33.16%, 21.93%, 48.49%, and 22.83%, respectively. GSTM5 was significantly upregulated by 53.14% and CYP2E1 expression did not show a dramatical change in SMG group rats. Moreover, 14-day SMG reduced ADH activity, while ALDH and GST activities was not altered remarkably. It could be concluded that SMG dramatically affected the expression and activity of some IDMEs, which might alter the efficacy or safety of their substrate drugs under microgravity. The present study provided some preliminary information on IDMEs under microgravity. It revealed the potential effect of SMG on intestinal metabolism, which may be helpful to understand the intestinal health of astronauts and medication use.

中文翻译：

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蛋白质组学方法研究模拟微重力大鼠肠道蛋白质和药物代谢酶

本研究旨在探讨模拟微重力14天后肠粘膜蛋白的变化，特别是肠道药物代谢酶（IDME）的变化。莫雷-霍尔顿尾部悬挂模拟用于模拟微重力。采用无标记定量蛋白质组策略测定大鼠肠粘膜蛋白。共鉴定出 335 个差异表达蛋白（DEP），其中 190 个 DEP 上调，145 个 DEP 下调。根据生物信息学分析，大多数DEP表现出水解酶、氧化还原酶、转移酶、连接酶或裂合酶催化活性。DEPs主要富集于代谢途径，包括氨基酸、葡萄糖和碳的代谢。此外，11个DEP参与外源性药物和外源性物质的代谢。由于 IDME 对口服药物的功效和安全性的重要性，细胞色素 P450 1A2 (CYP1A2)、CYP2D1、CYP3A2、CYP2E1、乙醇脱氢酶 1 (ADH1) 和谷胱甘肽 S-转移酶 mu 5 (GSTM5) 在大鼠中的表达通过Western-blot测定肠粘膜。评估 ADH、乙醛脱氢酶 (ALDH) 和 GST 的活性。与对照组大鼠相比，模拟微重力（SMG）组大鼠CYP1A2、CYP2D1、CYP3A2和ADH1的表达分别显着下降33.16%、21.93%、48.49%和22.83%。SMG组大鼠GSTM5显着上调53.14%，CYP2E1表达未出现显着变化。此外，14天的SMG降低了ADH活性，而ALDH和GST活性没有显着改变。可以得出结论，SMG 显着影响一些 IDME 的表达和活性，这可能会改变其底物药物在微重力下的功效或安全性。本研究提供了微重力下 IDME 的一些初步信息。它揭示了SMG对肠道代谢的潜在影响，这可能有助于了解宇航员的肠道健康和药物使用。