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Investigation on Intestinal Proteins and Drug Metabolizing Enzymes in Simulated Microgravity Rats by a Proteomics
Huayan Liu1, Jingjing Guo1, Yujuan Li1
1School of Life Science, Beijing Institute of Technology, No.5 Zhongguancun South Street, Haidian District, Beijing 100081, China.
Abstract:
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.
Insights
Simulated microgravity significantly altered intestinal drug metabolizing enzymes (IDMEs) in rats, impacting protein expression and activity. This finding suggests potential changes in oral drug efficacy and safety for astronauts in space.
Area of Science:
- Proteomics
- Space Biology
- Pharmacology
Background:
- Intestinal drug metabolizing enzymes (IDMEs) are crucial for oral drug efficacy and safety.
- Understanding how microgravity affects these enzymes is vital for astronaut health and medication use.
- Previous research has not fully elucidated the impact of microgravity on intestinal protein metabolism.
Purpose of the Study:
- To investigate changes in intestinal mucosa proteins, particularly IDMEs, after 14-day simulated microgravity.
- To assess the expression and activity of key drug-metabolizing enzymes under simulated microgravity conditions.
- To provide preliminary data on the effects of microgravity on intestinal metabolism.
Main Methods:
- Utilized the Morey-Holton tail-suspension analog to simulate microgravity.
- Employed label-free quantitative proteomic strategy to analyze intestinal mucosa proteins in rats.
- Confirmed protein expression via Western-blot and evaluated enzyme activity (ADH, ALDH, GST).
Main Results:
- Identified 335 differentially expressed proteins (DEPs), with 190 upregulated and 145 downregulated.
- Found significant alterations in the expression of key IDMEs: CYP1A2, CYP2D1, CYP3A2, ADH1 (decreased), and GSTM5 (upregulated).
- Observed a reduction in alcohol dehydrogenase (ADH) activity, while aldehyde dehydrogenase (ALDH) and glutathione S-transferase (GST) activities remained largely unchanged.
Conclusions:
- Simulated microgravity significantly impacts the expression and activity of specific intestinal drug metabolizing enzymes.
- These alterations may affect the efficacy and safety of orally administered drugs in microgravity environments.
- The study offers insights into intestinal health and medication considerations for astronauts.
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