Role of vitamin D receptor in the regulation of CYP3A gene expression

Abstract

Vitamin D3 (VD3) is a multifunctional nutrient which can be either synthesized or absorbed from the diet. It plays a pivotal role in systemic calcium and phosphate homeostasis, as well as in various physiological and pathological processes. VD3 is converted to the active form, 1α,25-dihydroxyvitamin D3 (1,25-D3), by cytochrome P450 2R1 (CYP2R1)/CYP27A1 and CYP27B1 sequentially, and deactivated by multiple enzymes including CYP3A4. On the other hand, 1,25-D3 is capable of activating the transcription of CYP3A genes in humans, mice and rats. The vitamin D receptor (VDR)-mediated transactivation of human CYP3A4 and CYP3A5 resembles that known for pregnane X receptor (PXR). Activated VDR forms a heterodimer with retinoid X receptor α (RXRα), recruits co-activators, translocates to the cell nucleus, binds to the specific vitamin D responsive elements (VDRE), and activates the gene transcription. In mice, intestinal Cyp3a11 mRNA levels, but not those of hepatic CYP3As, were induced by in vivo administration of VDR and PXR agonists. In rats, intestinal Cyp3a1 and Cyp3a2 mRNAs were induced by 1,25-D3 or lithocholic acid (LCA), whereas hepatic Cyp3a2, but not Cyp3a1 and Cyp3a9, was modulated to 1,25-D3 treatment. In general, the VDR-mediated regulation of CYP3A presents species and organ specificity.

Elucidation of metabolic pathways of 25-hydroxyvitamin D3 mediated by CYP24A1 and CYP3A using Cyp24a1 knockout rats generated by CRISPR/Cas9 system

“…The plasma concentrations of 25(OH)D3, 25(OH)D3-3- O -sulfate, 24 R ,25(OH) 2 D3, and 4β,25(OH) 2 D3 in healthy humans were 131, 96, 12, and 0.26 nM, respectively ( 27 ). Furthermore, some studies demonstrated that the increased expression of VDR induced the transcription of CYP3A ( 29 ) and SULT2A1 ( 30 ). Based on these results, it is likely that CYP3A and SULT2A1 play critical roles in vitamin D metabolism, especially in cases of CYP24A1 dysfunction.…”

Uncovering the role of Cow urine as bioenhancer investigated towards network pharmacology

“…In a grim scenario of the evolution of drug resistance and drug insensitivity, there is a need for quick and affordable solutions [Cheng et al,2017;Kalow,1982]. The microbes acquire resistance through metabolizing the drug that poses a severe threat to existing therapeutics [Qin et al,2019 Drug effectiveness depends on several biological processes, including membrane transport/binding to blood plasma proteins/vasodilation of human intestinal tight junctions/endocytosis [Randhawa,2010]. These processes mainly exalt drug absorption and distribution in the human body.…”

Nanoformulations of Ursolic Acid: A Modern Natural Anticancer Molecule

“…culture, but no significant conversion has been observed in the absence of NADPH (Qin and Wang, 2019). A pharmacodynamic test showed that after administering 19.69 mg/kg UA to healthy Sprague-Dawley rats, some kinetic parameters measured as follows: apparent volume of distribution (V/F 0.0169 ± 0.0030 L/g), half-life time distribution (t 1/2α 6.95 ± 1.42 h), half-life time elimination (t 1/2β 40.94 ± 4.91 h), and maximum plasma concentration (C max 487.47 ± 138.94 ng/ml) .…”