Importance of apical membrane delivery of 1,25-dihydroxy vitamin D_3 to vitamin D-responsive gene expression in the colon

摘要

Synthetic conjugation of a glucuronide to 1,25-dihydroxy vitamin D3 (1,25D_3) to produce beta-25-monoglucuronide-l,25D3 (betaGluc-l,25D_3) renders the hormone biologically inactive and resistant to mammalian digestive enzymes. However, beta-glucuronidase produced by bacteria in the lower intestinal tract can cleave off the glucuronide, releasing the active hormone. In mice given a single oral dose of 1,25D_3, 24-hydroxylase (Cyp24al) gene expression was strongly enhanced in the duodenum, but not in the colon, despite circulating concentrations of 1,25D_3 that peaked at -3.0 nmol/1. In contrast, in mice treated with an equimolar dose of PGluc-l,25D_3, Cyp24al gene expression increased 700-fold in the colon but was significantly weaker in the duodenum compared with mice treated with 1,25D_3. Similar results were observed with another vitamin D-dependent gene. When administered subcutaneously, 1,25D_3 weakly stimulated colon Cyp24al gene expression while betaGluc-l,25D_3 again resulted in strong enhancement. Surgical ligation to block passage of ingesta beyond the upper intestinal tract abolished upregulation of colon Cyp24al gene expression by orally and subcutaneously administered (3Gluc-l,25D_3. Feeding (3Gluc-l,25D_3 for 5 days revealed a linear, dose-dependent increase in colon Cyp24al gene expression but did not significantly increase plasma 1,25D_3 or calcium concentrations. This study indicates that the colon is relatively insensitive to circulating concentrations of 1,25D_3 and that the strongest gene enhancement occurs when the hormone reaches the colon via the lumen of the intestinal tract. These findings have broad implications for the use of vitamin D compounds in colon disorders and set the stage for future therapeutic studies utilizing 3Gluc-l,25D_3 in their treatment.