Investigation on Intestinal Proteins and Drug Metabolizing Enzymes in Simulated Microgravity Rats by a Proteomics Method.

Huayan Liu,Yulin Deng,Yushi Zhang,Jingjing Guo,Yujuan Li,Jianyi Gao,Yongzhi Li,Jiaping Wang

doi:10.3390/molecules25194391

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.

Highlights

Complex space environment, including microgravity (MG), strong radiation, and high noise, could lead to multi-system damage of organisms
Combining GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) results, the present study focused on glucose metabolism, amino acids metabolism, drugs, and xenobiotics metabolism for further analysis
If the essential amino acids in food were over metabolized when they pass through the intestinal mucosa, it may alter the amount of amino acids entering the portal circulation and supplying to tissues other than the intestine, resulting in the reduction of the utilization of amino acids under simulated microgravity (SMG) [65]

Summary

Introduction

Complex space environment, including microgravity (MG), strong radiation, and high noise, could lead to multi-system damage of organisms. It was reported that microgravity or simulated. Looking for counter measures against the physio-pathological changes induced by microgravity has always been an important research topic [14]. Besides physical training, lower body negative pressure and saline supplementation, drugs were often used to prevent or treat the body injury induced by microgravity. It has been reported that more than 70% of crew members used zolpidem or temazepam as a sleep aids during both short/long duration spaceflight missions and International Space Station missions [16,17]. It is better to assess the effectiveness and safety of drugs during space flight to maintain astronaut health and performance [18]

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Results

Conclusion