Evolution and Function of the NR1I Nuclear Hormone Receptor Subfamily (VDR, PXR, and CAR) with Respect to Metabolism of Xenobiotics and Endogenous Compounds

Abstract

The NR1I subfamily of nuclear hormone receptors includes the 1,25-(OH) 2 -vitamin D 3 receptor (VDR; NR1I1), pregnane X receptor (PXR; NR1I2), and constitutive androstane receptor (CAR; NR1I3). PXR and VDR are found in diverse vertebrates from fish to mammals while CAR is restricted to mammals. Current evidence suggests that the CAR gene arose from a duplication of an ancestral PXR gene, and that PXR and VDR arose from duplication of an ancestral gene, represented now by a single gene in the invertebrate Ciona intestinalis. Aside from the high-affinity effects of 1,25-(OH) 2 -vitamin D 3 on VDRs, the NR1I subfamily members are functionally united by the ability to bind potentially toxic endogenous compounds with low affinity and initiate changes in gene expression that lead to enhanced metabolism and elimination (e.g., induction of cytochrome P450 3A4 expression in humans). The detoxification role of VDR seems limited to sensing high concentrations of certain toxic bile salts, such as lithocholic acid, whereas PXR and CAR have the ability to recognize structurally diverse compounds. PXR and CAR show the highest degree of crossspecies variation in the ligand-binding domain of the entire vertebrate nuclear hormone receptor superfamily, suggesting adaptation to species-specific ligands. This review examines the insights that phylogenetic and experimental studies provide into the function of VDR, PXR, and CAR, and how the functions of these receptors have expanded to evolutionary advantage in humans and other animals.

Xenobiotic- and vitamin D-responsive induction of the steroid/bile acid-sulfotransferase Sult2A1 in young and old mice: The role of a gene enhancer in the liver chromatin

“…In the present study young and old mice were examined for the induced expression of the phase II sulfotransferase SULT2A1 in the liver upon administration of the synthetic catatoxic steroid PCN (pregnenolone-16α-carbonitrile), which is an agonist ligand for PXR, or vitamin D 3 , which binds and activates the vitamin D receptor (VDR). Vitamin D 3 has a known role in xenobiotic metabolism in addition to its classic function in bone physiology (Makishima et al 2002;Reschly and Krasowski, 2006;Song et al, 2006). Additionally, we probed the mouse liver chromatin to investigate the association of nuclear receptors and coregulators with a vitamin D-and xenobiotic-responsive enhancer in the Sult2A1 promoter.…”

A microtiter‐plate‐based cytochrome P450 3A activity assay in fish cell lines

“…Pregnane X receptor functions as a ligand-activated transcription factor and regulates the metabolism, transport, and excretion of exogenous compounds, steroid hormones, vitamins, bile salts, and xenobiotics. Pregnane X receptor genes have been cloned and functionally characterized from a variety of vertebrate species, including human, rhesus monkey, mouse, rat, rabbit, dog, pig, chicken, frog, and zebrafish [16]. Like other nuclear receptors, PXRs have a modular structure with two major domains: an N-terminal DNA-binding domain and a larger C-terminal ligand-binding domain (LBD).…”

“…The PXR LBD is unusually divergent across species, compared with other nuclear receptors, with only 50% sequence identity between mammalian and nonmammalian PXR sequences; other nuclear receptors tend to have corresponding sequence identities at least 10 to 20% higher. Even the PXR DNA-binding domain, which is more highly conserved across species than the LBD, shows more cross-species sequence diversity than other nuclear receptors [16,17]. Due to this diversity, we would expect different sensitivities of different fish species to pharmaceuticals in regard to the alteration of CYP3A activity.…”

“…In fish, they are regulated by the same receptors as in mammals, namely, through the pregnane X receptor (PXR) [13][14][15]. The CYP3A expression can also be modulated by the constitutive androstane receptor, but the constitutive androstane receptor is restricted to mammals [16,17]. Due to these similarities, specific probes to determine CYP3A activity used in humans are supposed to be also specific for CYP3A activity in fish.…”

Resveratrol increases hepatic SHBG expression through human constitutive androstane receptor: a new Contribution to the French Paradox

“…Human CAR can also compete with HNF-4α for binding to DR-1 elements in the CYP7A1, CYP8B1, and PEPCK promoters 46 . The affinity of different ligands for CAR also varies between species 47 ; for instance human CAR is strongly activated by CITCO, while murine CAR is not 48 and is more sensitive to TCPOBOP than human CAR 49,50 . Experiments in which the addition of red wine to culture medium increased SHBG production by human HepG2 liver cells led us to discover that resveratrol was responsible for this effect through a specific interaction with human CAR binding to a DR-1 element in the SHBG promoter.…”