Exposure to High-Altitude Environment Is Associated with Drug Transporters Change: microRNA-873-5p-Mediated Alteration of Function and Expression Levels of Drug Transporters under Hypoxia

Abstract

Hypoxia is the main characteristic of a high-altitude environment, affecting drug metabolism. However, so far, the mechanism of miRNA involved in the regulation of drug metabolism and transporters under high-altitude hypoxia is still unclear. This study aims to investigate the functions and expression levels of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein (BCRP), peptide transport 1 (PEPT1), and organic anion-transporting polypeptides 2B1 (OATP2B1) in rats and Caco-2 cells after exposure to high-altitude hypoxia. The protein and mRNA expression of MDR1, MRP2, BCRP, PEPT1, and OATP2B1 were determined by Western blot and qPCR. The functions of MDR1, MRP2, BCRP, PEPT1, and OATP2B1 were evaluated by determining the effective intestinal permeability and absorption rate constants of their specific substrates in rats under high-altitude hypoxia, and uptake and transport studies were performed on Caco-2 cells. To screen the miRNA associated with hypoxia, Caco-2 cells were examined by high throughput sequencing. We observed that the miR-873-5p was significantly decreased under hypoxia and might target MDR1 and pregnane X receptor (PXR). To clarify whether miR-873-5p regulates MDR1 and pregnane X receptor (PXR) under hypoxia, Caco-2 cells were transfected with mimics or inhibitors of miR-873-5p and negative control (NC). The function and expression of drug transporters were found to be significantly increased in rats and Caco-2 cells under hypoxia. We found that miR-873-5p regulated MDR1 and PXR expression. Herein, it is shown that miRNA may affect

Indole-3-propionic Acid Attenuates HI-Related Blood–Brain Barrier Injury in Neonatal Rats by Modulating the PXR Signaling Pathway

“…PXR is widely expressed in different areas of the brain, including BBB endothelial cells. ,, Otherwise, the expression of PXR has been approved to be potently inhibited under hypoxia . The in vitro experiment of Caco-2 cells also showed that the mRNA and protein expression levels of PXR were significantly decreased in various hypoxia concentrations and hypoxia time compared to the normoxia group . Are these above observations in our study relevant to PXR?…”

“…25 The in vitro experiment of Caco-2 cells also showed that the mRNA and protein expression levels of PXR were significantly decreased in various hypoxia concentrations and hypoxia time compared to the normoxia group. 54 Are these above observations in our study relevant to PXR? We observed that overexpression of PXR in rBMECs could significantly counteract the decrease of junction proteins and downregulate the increased p-IκB-α and p-NF-κB from OGD injury, but the difference was not significant between the two normoxia groups.…”

High-altitude Hypoxia Influences the Activities of the Drug-Metabolizing Enzyme CYP3A1 and the Pharmacokinetics of Four Cardiovascular System Drugs

“…In a previous study, we observed upregulation in the expression of 27 miRNAs and downregulation in the expression of 56 miRNAs in Caco-2 cells exposed to hypoxia. Further analysis confirmed that hypoxia led to a significant decrease in the expression of miRNA-873-5p; moreover, miRNA-873-5p possesses a similar effect as PXR on drug-metabolizing enzymes [ 68 ].…”

Regulation of CYP450 and drug transporter mediated by gut microbiota under high-altitude hypoxia

“…Most notably, downregulation of CYP3A1 and MDR1 expressions at both the protein and mRNA levels was observed. Moreover, according to our previous studies, the metabolism of midazolam and rhodamine 123, the corresponding substrates of CYP3A1 and MDR1 respectively, has changed accordingly ( Duan et al, 2022 ). In addition, CYP3A1 and MDR1 participate in the metabolism and transport of over half of currently used pharmacological agents ( Takano et al, 2021 ).…”