Mechanism of Simulated Microgravity Effect on Intestinal Drug Absorption in Rats
Abstract
Redistribution of fluids in the body caused by microgravity (MG) can lead to multiple system damage to the human body. Drugs are often used to prevent astronauts from injury and improve working performance in space. As an efflux protein located on the surface of intestinal epithelial cells, P-glycoprotein (P-gp) can actively prevent extraneous substances entering cells and maintain intestinal homeostasis. P-gp also plays a very important role in a variety of drugs transmembrane transportation through its efflux function. The present study is aimed to investigate the change of function and expression of P-gp in rat intestine under simulated microgravity (SMG) effect, and whether SMG regulated P-gp expression through Wnt/$\beta$-catenin signaling pathway. Rats were tail-suspended to simulate short (7-day) and long term (21-day) microgravity effect. Cyclosporin A was used as substrate to detect the efflux function of P-gp, and the ATPase activity of P-gp was also determined. The expression of P-gp, pathway proteins and genes related to Wnt/$\beta$-catenin signaling pathway were determined by Western Blot or Q-PCR. It was found that the efflux function and ATPase activity of P-gp decreased and the expression of P-gp were down-regulated in 7 and 21d SMG exposed rats. Meanwhile, the expression of pho-dvl2, $\beta$-catenin, MDR1 gene, the phosphorylation ratio of GSK-3$\beta$ were decreased significantly, and the expression of DKK1 was obviously increased under 7 and 21d SMG condition. This indicated that SMG may inhibit the binding of Wnt and receptor protein through the high expression of DKK1, thus inhibited the phosphorylation of dvl2 and GSK-3$\beta$. Consequently, $\beta$-catenin in the cytoplasm was degraded, which led to the decreased expression of MDR1 gene. These down-regulated function and expression of P-gp may significantly increase the blood level of P-gp substrate drugs in astronauts during space stay, which may change drug efficacy or toxicity. These findings might take a limited view for guiding medication use in space travel.
- Publication:
-
43rd COSPAR Scientific Assembly. Held 28 January - 4 February
- Pub Date:
- January 2021
- Bibcode:
- 2021cosp...43E2061L