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 dual-
luciferase 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.