Exposure to High Altitude Environment Is Associated With Drug Metabolism Change: miRNA-873-5p-Mediated Alteration of Function and Expression Levels of Drug Transporters Under Hypoxia

Abstract

Background: Hypoxia is the main characteristic of a high-altitude environment, affecting drug metabolism. However, little is known about the role of microRNA (miRNA) in drug metabolism under high-altitude hypoxia. This study aims to investigate the functions and the expression levels of multidrug resistance mutation 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 vivo and in vitro after exposure to high-altitude hypoxia. Methods: Western blot and qPCR analyses were used to analyze the protein and mRNA expression levels of MDR1, MRP2, BCRP, PEPT1, and OATP2B1. 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 after exposure to high-altitude hypoxia, and uptake and transport studies were performed in Caco-2 cells. To clarify whether miRNA-873-5p regulates MDR1 and pregnane X receptor (PXR) under hypoxia, Caco-2 cells were transfected with mimics or inhibitors of miRNA-873-5p and negative control (NC). Findings: Hypoxia increased the expression and activity of most of the drug transporters in vivo and in vitro. We found that miRNA-873-5p regulated MDR1 and PXR expression, thereby affecting drug metabolism. Interpretation: Herein, it was shown that miRNA might affect the expression of drug transporter and nuclear receptor under hypoxia. miRNA-873-5p play important roles in the process of drug metabolism under hypoxia. Funding Information: This work was supported by the National Natural Science Foundation of China (No. 81760673 and 81460568), the Qinghai Innovation Platform Construction Project (No. 2021-ZJ-T03), and the Key Research Foundation of Development and Transformation of Qinghai Province (2021-SF-158). Declaration of Interests: None of the authors has any potential conflict of interest or financial interests to disclose. Ethics Approval Statement: All experimental procedures were performed strictly according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The protocol was approved by the Animal Ethics Committee of The Qinghai University.