Increased Vitamin D Receptor Level Enhances 1,25‐Dihydroxyvitamin D 3 ‐Mediated Gene Expression and Calcium Transport in Caco‐2 Cells

Altered vitamin D receptor (VDR) level has been proposed to explain differences in intestinal responsiveness to 1,25‐dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ]. We tested whether the enterocyte VDR level influences 1,25(OH) 2 D 3 ‐mediated gene expression and transepithelial calcium (Ca) transport in the human intestinal cell line Caco‐2. Cells were stably transfected with a human metallothionein (hMT) IIA promoter‐human VDR (hVDR) complementary DNA (cDNA) transgene that overexpressed hVDR in response to heavy metals. In MTVDR clones, induction of 25‐hyroxyvitamin D 3 ‐24‐hydroxylase (24‐OHase) messenger RNA (mRNA) expression by 1,25(OH) 2 D 3 (10 −9 M, 4 h) was correlated to metal‐induced changes in nuclear VDR level ( r 2 = 0.99). In MTVDR clones, basal VDR level was 2‐fold greater and 1,25(OH) 2 D 3 ‐mediated Ca transport (10 −7 M, 24 h) was 43% higher than in parental Caco‐2 cells. Treatment of MTVDR clones with Cd (1 μM, 28 h) increased VDR level by 68%, significantly enhanced 1,25(OH) 2 D 3 ‐mediated Ca transport by 24%, and increased accumulation of calbindin D 9K mRNA by 76% relative to 1,25(OH) 2 D 3 alone. These observations support the hypothesis that the enterocyte VDR level is an important modulator of intestinal responsiveness to 1,25(OH) 2 D 3.