A Decade’s Review of miRNA: A Center of Transcriptional Regulation of Drugmetabolizing Enzymes and Transporters under Hypoxia

Abstract

Background: Hypoxia has a negative effect on the cardiovascular system, nervous system, and metabolism, which contributes to potential changes in drug absorption, distribution, metabolism, and excretion (ADME). However, hypoxia can also alter the expression of microRNA (miRNA), thereby regulating drug-metabolizing enzymes, transporters, and ADME genes, such as hypoxia-inducible factor, inflammatory cytokine, nuclear receptor, etc. Therefore, it is crucial to study the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. Methods: A systematic review of published studies was carried out to investigate the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. Data and information on expression changes in miRNA, drug-metabolizing enzymes, and transporters under hypoxia were analyzed and summarized Results: Hypoxia can up- or down-regulate the expression of miRNA. The effect of hypoxia on Cytochrome P450 (CYP450) is still a subject of debate. The widespread belief is that hypoxia decreased the activity and expression of CYP1A1, CYP1A2, CYP2E1, and CYP3A1 and increased those of CYP3A6 and CYP2D1 in rats. Hypoxia increased the expression of a multidrug resistance-associated protein, breast cancer resistance protein, peptide transporter, organic cation transporter, and organic anion transporter. miRNA negatively regulated the expression of drug-metabolizing enzymes and transporters. Conclusion: The findings of this review indicated that miRNA plays a key role in the expression changes of drug-metabolizing enzymes and transporters under hypoxia.

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

“…Fradette [ 62 , 63 ] simulated a high-altitude field environment in a hypobaric oxygen chamber and observed a decrease in the protein expression of CYP1A1, CYP1A2, CYP2B4, CYP2C5, and CYP2C16, but an increase in the protein expression of CYP3A6 and CYP3A11 in rabbits. The results of studies on the effect of high-altitude hypoxia on protein and mRNA expression of CYP2C11 have been inconsistent [ 21 , 64 , 65 ]. Therefore, it is crucial to examine the response of each enzyme of the CYP450 family to high-altitude hypoxia.…”

“…Recently, considerable progress has been made on the mechanism of hypoxia on drug metabolism. As transcription factors, nuclear receptors, including pregnane X receptor (PXR), constitutive androstane receptor (CAR), and peroxisome proliferator activation receptor (PPAR), play an important role in regulating drug-metabolizing enzymes [ 65 ]. PXR and CAR have been shown to regulate the expression of CYP2C9, CYP2C18, and CYP2C19 [ 65 ].…”

“…As transcription factors, nuclear receptors, including pregnane X receptor (PXR), constitutive androstane receptor (CAR), and peroxisome proliferator activation receptor (PPAR), play an important role in regulating drug-metabolizing enzymes [ 65 ]. PXR and CAR have been shown to regulate the expression of CYP2C9, CYP2C18, and CYP2C19 [ 65 ]. Moreover, there is a considerable decrease in PXR and CAR expression under hypoxic conditions [ 66 ].…”

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

“…The total protein of the liver tissues was extracted, and Western blotting analysis was conducted as described in our previous study ( Duan et al, 2021 ). Antibodies against β-actin, CYP1A2, CYP2B1, CYP2C11, CYP2E1, CYP3A1, BCRP, MDR1, MRP2, OATP2B1, OCT1, and PEPT1 were used.…”

“…RNA was isolated from liver tissues, and cDNA synthesis and quantitative RT-qPCR were conducted as described in our previous study ( Duan et al, 2021 ). Primer sequences to amplify β-actin, CYP1A2, CYP2B1, CYP2C11, CYP2E1, CYP3A1, BCRP, MDR1, MRP2, OATP2B1, OCT1, and PEPT1 are shown in Table 1 .…”