Significance of the Vitamin D Receptor on Crosstalk with Nuclear Receptors and Regulation of Enzymes and Transporters

Keumhan Noh; Edwin C Y Chow; Holly P Quach; Geny M M Groothuis; Rommel G Tirona; K Sandy Pang

doi:10.1208/s12248-022-00719-9

Significance of the Vitamin D Receptor on Crosstalk with Nuclear Receptors and Regulation of Enzymes and Transporters

AAPS J. 2022 Jun 1;24(4):71. doi: 10.1208/s12248-022-00719-9.

Authors

Keumhan Noh^{1

2}, Edwin C Y Chow^{1

3}, Holly P Quach¹, Geny M M Groothuis⁴, Rommel G Tirona⁵, K Sandy Pang⁶

Affiliations

¹ Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
² Drug Metabolism and Pharmacokinetics, Biogen, 225 Binney Street, Cambridge, Massachusetts, 02142, USA.
³ Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
⁴ Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.
⁵ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.
⁶ Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada. ks.pang@utoronto.ca.

PMID: 35650371
DOI: 10.1208/s12248-022-00719-9

Abstract

The vitamin D receptor (VDR), in addition to other nuclear receptors, the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), is involved in the regulation of enzymes, transporters and receptors, and therefore intimately affects drug disposition, tissue health, and the handling of endogenous and exogenous compounds. This review examines the role of 1α,25-dihydroxyvitamin D₃ or calcitriol, the natural VDR ligand, on activation of the VDR and its crosstalk with other nuclear receptors towards the regulation of enzymes and transporters, notably many of the cytochrome P450s including CYP3A4 and sulfotransferase 2A1 (SULT2A1) as well as cholesterol 7α-hydroxylase (CYP7A1). Moreover, the VDR upregulates the intestinal channel, TRPV6, for calcium absorption, LDL receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) in brain for β-amyloid peptide efflux and influx, the sodium phosphate transporters (NaP_i), the apical sodium-dependent bile acid transporter (ASBT) and organic solute transporters (OSTα-OSTβ) for bile acid absorption and efflux, respectively, the renal organic anion transporter 3 (OAT3) and several of the ATP-binding cassette protein transporters-the multidrug resistance protein 1 (MDR1) and the multidrug resistance-associated proteins (MRPs). Hence, the role of the VDR is increasingly being recognized for its therapeutic potential and pharmacologic activity, giving rise to drug-drug interactions (DDI). Therapeutically, ligand-activated VDR shows anti-inflammatory effects towards the suppression of inflammatory mediators, improves cognition by upregulating amyloid-beta (Aβ) peptide clearance in brain, and maintains phosphate, calcium, and parathyroid hormone (PTH) balance and kidney function and bone health, demonstrating the crucial roles of the VDR in disease progression and treatment of diseases.

Keywords: 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]; crosstalk; drug-metabolizing enzymes; transporters; vitamin D receptor (VDR).

Publication types

Review

MeSH terms

Calcium* / metabolism
Ligands
Membrane Transport Proteins
Receptors, Calcitriol* / metabolism
Receptors, Cytoplasmic and Nuclear / metabolism

Substances

Ligands
Membrane Transport Proteins
Receptors, Calcitriol
Receptors, Cytoplasmic and Nuclear
Calcium