Importance of apical membrane delivery of 1,25-dihydroxyvitamin D3 to vitamin D-responsive gene expression in the colon

Koszewski NJ, Horst RL, Goff JP. Importance of apical membrane delivery of 1,25-dihydroxyvitamin D-3 to vitamin D-responsive gene expression in the colon. Am J Physiol Gastrointest Liver Physiol 303: G870-G878, 2012. First published July 26, 2012; doi:10.1152/ajpgi.00149.2012.-Synthetic conjugation of a glucuronide to 1,25-dihydroxyvitamin D-3 (1,25D(3)) to produce beta-25-monoglucuronide-1,25D(3) (beta Gluc-1,25D(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 (Cyp24a1) gene expression was strongly enhanced in the duodenum, but not in the colon, despite circulating concentrations of 1,25D(3) that peaked at similar to 3.0 nmol/l. In contrast, in mice treated with an equimolar dose of beta Gluc-1,25D(3), Cyp24a1 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 Cyp24a1 gene expression while beta Gluc-1,25D(3) again resulted in strong enhancement. Surgical ligation to block passage of ingesta beyond the upper intestinal tract abolished upregulation of colon Cyp24a1 gene expression by orally and subcutaneously administered beta Gluc-1,25D(3). Feeding beta Gluc-1,25D(3) for 5 days revealed a linear, dose-dependent increase in colon Cyp24a1 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 beta Gluc-1,25D(3) in their treatment.