The Xenobiotic-Sensing Nuclear Receptors Pregnane X Receptor, Constitutive Androstane Receptor, and Orphan Nuclear Receptor Hepatocyte Nuclear Factor 4α in the Regulation of Human Steroid-/Bile Acid-Sulfotransferase

Abstract

The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are the primary transcription factors coordinating induced expression of the enzymes and proteins directing oxidative, conjugative, and transport phases of endobiotic and xenobiotic metabolism, whereas hepatocyte nuclear factor 4alpha (HNF4alpha), a regulator of hepatic lipid homeostasis, can modify the PXR/CAR response. Steroid- and bile acid-sulfotransferase (SULT2A1) promotes phase II metabolism through its sulfonating action on certain endobiotics, including steroids and bile acids, and on diverse xenobiotics, including therapeutic drugs. This study describes characterization of a PXR- and CAR-inducible composite element in the human SULT2A1 promoter and its synergistic interaction with HNF4alpha. Inverted and direct repeats of AG(G/T)TCA (IR2 and DR4), both binding to PXR and CAR, define the composite element. Differential recognition of the composite element by PXR and CAR is evident because single-site mutation at either IR2 or DR4 in the natural gene abolished the PXR response, whereas mutations at both repeats were necessary to abrogate completely the CAR response. The composite element conferred xenobiotic response to a heterologous promoter, and the cognate ligands induced PXR and CAR recruitment to the chromatin-associated response region. An HNF4alpha element adjacent to the -30 position enhanced basal promoter activity. Although functioning as a synergizer, the HNF4alpha element was not essential for the PXR/CAR response. An emerging role of SULT2A1 in lipid and caloric homeostasis suggests that illumination on the regulatory interactions driving human SULT2A1 expression may reveal new avenues to control certain metabolic disorders.

Nuclear Receptor Coactivator 6 Mediates the Synergistic Activation of Human Cytochrome P-450 2C9 by the Constitutive Androstane Receptor and Hepatic Nuclear Factor-4α

“…HNF4␣ has long been suggested to have a positive role in the PXRmediated induction of CYP3A4. Possible potentiation between HNF4␣ and CAR has also been reported recently in the regulation of CYP3A4 (Li and Chiang, 2006) and steroid and bile acid sulfotransferase (SULT2A1) (Echchgadda et al, 2007).…”

Regulation of Human Cytosolic Sulfotransferases 1C2 and 1C3 by Nuclear Signaling Pathways in LS180 Colorectal Adenocarcinoma Cells

“…Several members of the nuclear receptor superfamily, including peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), pregnane X receptor (PXR), vitamin D receptor (VDR), liver X receptor (LXR), and farnesoid X receptor (FXR), have been identified as transcriptional regulators of other SULT family members (Echchgadda et al, 2004(Echchgadda et al, , 2007Fang et al, 2005Fang et al, , 2007Jiang et al, 2005;Miyata et al, 2006;Kodama et al, 2011). Using TaqMan primer/probes, we detected mRNA expression of SULT1C2 and SULT1C3, but not SULT1C4, in LS180 colorectal adenocarcinoma cells.…”

17β-Estradiol Induces Sulfotransferase 2A1 Expression through Estrogen Receptorα

“…1A). The extent of increases in SULT2A1 mRNA expression by E2 was comparable to that by rifampicin, a known inducer of SULT2A1 expression (Echchgadda et al, 2007). Results from Western blot showed a 2-fold increase in SULT2A1 protein level in E2-treated group in human hepatocytes (Fig.…”

“…Expression of SULT2A1 is regulated at the transcriptional level by multiple nuclear receptors including constitutive androstane receptor and pregnane X receptor (Echchgadda et al, 2007). The role of E2 in the regulation of SULT2A1 expression and the underlying molecular mechanisms remain unknown.…”