Hypoxia is the main characteristic of a high-altitude environment, affecting drug metabolism. However, so far, the mechanism of
microRNA (
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
colon cancer (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 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 the expression of drug transporter and
nuclear receptor under
hypoxia. SIGNIFICANCE STATEMENT: This study explores if alterations to the
microRNAs (
miRNAs), induced by high-
altitude hypoxia, can be translated to altered drug transporters. Among
miRNAs, which show a significant change in a hypoxic environment, miR-873-5p can act on the
multidrug resistance protein 1 (MDR1) gene; however, there are multiple
miRNAs that can act on the
pregnane X receptor (PXR). This study speculates that the
miRNA-PXR-drug transporter axis is important in the physiological disposition of drugs.