Regulation of High-Altitude Hypoxia on the Transcription of CYP450 and UGT1A1 Mediated by PXR and CAR

Abstract

Little is known about what roles the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) play in drug metabolism in high-altitude hypoxia. Likewise, the potential interaction of nuclear receptors and drug metabolism enzymes during drug metabolism of high-altitude hypoxia is not fully understood. In this work, we investigated the effects of high-altitude hypoxia on transcriptional regulation of cytochrome P450 (CYP450) and UDP-glucuronosyltransferase 1A1 (UGT1A1) genes mediated by PXR and CAR proteins. The protein and mRNA expressions of CYP450, UGT1A1, PXR, and CAR were determined by enzyme-linked immunosorbent assay and qPCR in rats and HepG2 cell lines under hypoxia. Hypoxia potently inhibited the CYP450 isoforms, UGT1A1, PXR, and CAR protein and mRNA expression. To clarify whether PXR and CAR regulate various genes involved in drug metabolism of high-altitude hypoxia, we investigated the expression of CYP1A2, CYP2C9, CYP2E1, CYP3A4, and UGT1A1 using a dualluciferase reporter assay after treatment with Ketoconazole (KCZ) and Retinoic acid (RA), or silenced PXR and CAR gene expression. In HepG2 cells, hypoxia, KCZ, and RA inhibited CYP450 isoforms and UGT1A1 expression. Activation of PXR and CAR in cells treated with 6-(4-chlorophenyl)-imidazo (2,1-b) thiazole-5-carbaldehyde (CITCO) and rifampicin (Rif) resulted in the enhancement of CYP450 isoforms, UGT1A1, PXR, and CAR. In contrast, this effect was not observed under hypoxia. Taken together, our results suggest that hypoxia inhibits CYP1A2, CYP2C9, CYP2E1, CYP3A4, and UGT1A1 expression via the PXR and CAR regulatory pathway.

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

“…Studies have shown a strong link between PXR and MDR1 Gu et al, 2013). Previous studies by the authors have demonstrated a significant reduction of PXR expression in rats and HepG2 cells under hypoxic conditions (Duan et al, 2020). This study showed that the expression of PXR in Caco-2 cells under hypoxic conditions was also reduced significantly, which is in line with the previous studies.…”

“…Drug metabolizing enzymes and transporters are the main factors affecting drug metabolism. In our previous studies, we found that high-altitude hypoxia affects the activity and expression of cytochrome P450 (Duan et al, 2020;Duan et al, 2021;Zhou et al, 2018). To date, only a few reports have addressed the ways to resolve the problem of changes in the functions and expression levels of drug transporters under high altitude hypoxic environments.…”

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

“…20,21 Moreover, PXR has been approved to play an anti-inflammatory role by inhibiting the actions of the NF-κB signaling pathway 22−24 and hypoxia can potently inhibit the expression of PXR. 25 Therefore, we hypothesize that PXR is involved in the protective effect of IPA on BBB.…”

Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4

“…( 20 , 25 ). The primers used were: (1) cyp3a4 , forward sequence 5’-CCGAGTGGATTTCCTTCAGCTG-3’, reverse sequence 5’-TGCTCGTG GTTTCATAGCCAGC-3’; (2) β-actin , forward sequence 5’-CACCATTGGCAATGA GCGGTTC-3’, reverse sequence 5-AGGTCTTTGCGGAT GTCCACGT-3’; (3) PXR/NR1I2 ( 31 ), forward sequence 5’-CCCACCTCAGA AGACAAAGC-3’, reverse sequence, 5’-GAACCCCAGACCCTACACAA-3’ ( 4 ); CAR/NR1I3 ( 31 ): forward sequence, 5’-TACTGTGCTTCGTGCTCCTG-3’, Reverse sequence, 5’-CCTGG TCTTCGGGTTCAAG-3’. The results (the relative expression level [folds of β-Actin]) of PXR or CAR was shown as heat-map.…”