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• W2000656151 abstract "1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] transactivates its target genes via the vitamin D receptor (VDR). VDR functions in physiology as a dimer complexed with retinoid X receptor (RXR), whose natural ligand is 9-cis-retinoic acid (9-c-RA). Inactivation of 1,25(OH)2D3 occurs through a cytochrome P-450 24-hydroxylase (OHase). The promoter of the human 24-OHase gene contains a 1,25(OH)2D3-responsive enhancer element (VDRE). We have used this VDRE containing gene as an endogenous reporter for vitamin D3-mediated gene activation in vivo. Normal adult human skin was keratomed after a 2-d exposure to 1,25(OH)2D3, 9-c-RA, all-trans-RA, and ketoconazole. 1,25(OH)2D3 caused a concentration-dependent increase in 24-OHase mRNA expression as determined by northern blot analysis. The activity of epidermal 24-OHase was also induced by 1,25(OH)2D3. Compared with vehicle, neither of the RA isomers nor ketoconazole alone induced 24-OHase mRNA. Addition of 9-c-RA or t-RA to 1,25(OH)2D3, however, caused a synergistic increase in 24-OHase mRNA. Similarly, 1,25(OH)2D3 plus ketoconazole increased 24-OHase mRNA synergistically. Ketoconazole inhibited ex vivo 1,25(OH)2D3-induced epidermal 24-OHase activity. Thus, 24-OHase mRNA induction is a sensitive reporter of 1,25(OH)2D3 activity in vivo; RXR bound to VDR is not a silent partner in vivo, because 9-c-RA enhances 1,25(OH)2D3-liganded RXR/VDR stimulation of the VDRE containing 24-OHase gene; ketoconazole inhibition of 24-OHase enhances 1,25(OH)2D3 activity by impeding its breakdown. Thus, the synergistic response of human skin to topical 1,25(OH)2D3 and/or 1,25(OH)2D3 analogs plus RXR retinoids and/or ketoconazole may be exploited to give a desired biologic/therapeutic response with less 1,25(OH)2D3, minimizing the potential calcemic risk from systemic absorption of 1,25(OH)2D3." @default.
• W2000656151 created "2016-06-24" @default.
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• W2000656151 date "1997-04-01" @default.
• W2000656151 modified "2023-09-29" @default.
• W2000656151 title "The Retinoid X Receptor Agonist 9-cis-Retinoic Acid and the 24-Hydroxylase Inhibitor Ketoconazole Increase Activity of 1,25-Dihydroxyvitamin D3 in Human Skin In Vivo" @default.
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• W2000656151 doi "https://doi.org/10.1111/1523-1747.ep12289736" @default.
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