1 alpha,25-(OH)(2)-vitamin D-3 analogs with minimal in vivo calcemic activity can stimulate significant transepithelial calcium transport and mRNA expression in vitro

被引:46
作者
Fleet, JC
Bradley, J
Reddy, GS
Ray, R
Wood, RJ
机构
[1] BROWN UNIV,WOMEN & INFANTS HOSP,SCH MED,DEPT PEDIAT,PROVIDENCE,RI 02905
[2] BOSTON UNIV,SCH MED,VITAMIN D LAB,BOSTON,MA 02118
关键词
isomer vitamin D; analog; Caco-2; human; intestine;
D O I
10.1006/abbi.1996.0213
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Several 1 alpha,25-(OH)(2)-vitamin D-3 (1 alpha,25-(OH)(2)-D-3) analogs have significant antiproliferative effects in vitro but do not elevate serum calcium in vivo. We tested whether the lack of a calcemic response of a vitamin D analog in vivo is due to its inability to stimulate intestinal calcium absorption by examining the effect of several such compounds on transepithelial calcium transport in the human colonic carcinoma cell line Caco-2. The relative stimulations of calcium transport by the four A-ring diastereomers of 1 alpha,25-(OH)(2)-D-3 (1 alpha,3 beta) and a 3 beta-bromoacetate analog (1 alpha,3 beta-BrAc) of the vitamin following 48-h treatment of cells at 10 nM were 1 alpha,3 beta (=100%), 1 alpha,3 alpha (+45.2%), 1 beta,3 beta (-15.6%), 1 beta,3 alpha (+6.5%), and 1 alpha,3 beta-BrAc (+50.6%). This was similar to the reported affinity of these compounds for the vitamin D receptor (VDR) and suggests that VDR binding predicts calcium transport. In contrast, three non-calcemic, sidechain- or D-ring-modified analogs of vitamin D, 1 alpha,25-(OH)(2)-16-ene-D-3, 1 alpha,25-(OH)(2)-16-ene-23-yne-D-3, and 1 alpha,25,28-(OH)(3)-D-2 (at 10 nM for 48 h), showed a different relationship between VDR affinity (150, 60, and 63% of 1 alpha,25-(OH)(2)-D-3, respectively) and calcium transport (74.1, 126, and 10%, respectively). Elevated calcium transport was accompanied by higher 24-hydroxylase and calbindin D-9k mRNA levels. The data demonstrate that although some vitamin D compounds cannot stimulate calcium transport due to an inability to interact with the VDR (e.g., 1 beta isomers), other factors, e.g., differential cellular metabolism, may account for variations in biological response in vivo to various vitamin D analogs. (C) 1996 Academic Press, Inc.
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页码:228 / 234
页数:7
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