Mechanisms for the selective actions of vitamin D analogues

被引:25
作者
Brown, AJ [1 ]
机构
[1] Washington Univ, Sch Med, Div Renal, St Louis, MO 63110 USA
关键词
D O I
10.2174/1381612003400416
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The wide range of activities now attributed to 1,25(OH)(2)D-3 has suggested numerous potential therapeutic applications for this vitamin D hormone, including inhibiting growth of various type of cancer. Unfortunately, the potent calcemic activity of the natural hormone has precluded its use in most cases. Vitamin D analogs with higher therapeutic indices offer renewed hope for treatment of malignancies. The promising analogs currently under study were selected from hundreds of candidates by in vitro screening followed by in vivo testing. The mechanism(s) responsible for the greater effectiveness of most of these compounds is not known. Our current understanding of vitamin D physiology and biochemistry suggests that the biological profile of an analog would be determined primarily by its interaction with four classes of proteins: 1) the nuclear vitamin D receptor (VDR) that mediates transcriptional regulation; 2) the metabolic enzymes, primarily the vitamin D-24-hydroxylase but possibly others; 3) serum transporters, mainly vitamin D binding protein (DBP), and perhaps lipoproteins; and 4) a new class of receptors that reside in the plasma membrane and mediate rapid, nongenomic responses. This article discusses how the manner in which analogs associate with these proteins can potentially produce selective actions at the tissue, cell and gene level. A thorough understanding of the influence of these analog/protein interactions on the biological profile of vitamin D analogs will be invaluable for the design of future analogs with enhanced target specificity.
引用
收藏
页码:701 / 716
页数:16
相关论文
共 75 条
[1]   A NOVEL VITAMIN-D3 ANALOG, 22-OXA-1,25-DIHYDROXYVITAMIN-D3, INHIBITS THE GROWTH OF HUMAN BREAST-CANCER INVITRO AND INVIVO WITHOUT CAUSING HYPERCALCEMIA [J].
ABE, J ;
NAKANO, T ;
NISHII, Y ;
MATSUMOTO, T ;
OGATA, E ;
IKEDA, K .
ENDOCRINOLOGY, 1991, 129 (02) :832-837
[2]  
BARAN D, 1998, BONE, V23, pS176
[3]   THE RAPID NONGENOMIC ACTIONS OF 1-ALPHA,25-DIHYDROXYVITAMIN-D3 MODULATE THE HORMONE-INDUCED INCREMENTS IN OSTEOCALCIN GENE-TRANSCRIPTION IN OSTEOBLAST-LIKE CELLS [J].
BARAN, DT ;
SORENSEN, AM ;
SHALHOUB, V ;
OWEN, T ;
STEIN, G ;
LIAN, J .
JOURNAL OF CELLULAR BIOCHEMISTRY, 1992, 50 (02) :124-129
[4]   NONGENOMIC ACTIONS OF THE STEROID-HORMONE 1-ALPHA,25-DIHYDROXYVITAMIN D-3 [J].
BARAN, DT .
JOURNAL OF CELLULAR BIOCHEMISTRY, 1994, 56 (03) :303-306
[5]  
BARSONY J, 1992, J BIOL CHEM, V267, P24457
[6]   22-OXA CALCITRIOL IS A LESS POTENT REGULATOR OF KERATINOCYTE PROLIFERATION AND DIFFERENTIATION DUE TO DECREASED CELLULAR UPTAKE AND ENHANCED CATABOLISM [J].
BIKLE, DD ;
ABEHASHIMOTO, J ;
SU, MJ ;
FELT, S ;
GIBSON, DFC ;
PILLAI, S .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1995, 105 (05) :693-698
[7]   COMPARISON OF CALCIPOTRIOL WITH SELECTED METABOLITES AND ANALOGS OF VITAMIN-D(3) - EFFECTS ON CELL-GROWTH REGULATION INVITRO AND CALCIUM-METABOLISM INVIVO [J].
BINDERUP, L .
PHARMACOLOGY & TOXICOLOGY, 1993, 72 (4-5) :240-244
[8]   Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3 [J].
Boehm, MF ;
Fitzgerald, P ;
Zou, AH ;
Elgort, MG ;
Bischoff, ED ;
Mere, L ;
Mais, DE ;
Bissonnette, RP ;
Heyman, RA ;
Nadzan, AM ;
Reichman, M ;
Allegretto, EA .
CHEMISTRY & BIOLOGY, 1999, 6 (05) :265-275
[9]   STRUCTURE-FUNCTION-RELATIONSHIPS IN THE VITAMIN-D ENDOCRINE SYSTEM [J].
BOUILLON, R ;
OKAMURA, WH ;
NORMAN, AW .
ENDOCRINE REVIEWS, 1995, 16 (02) :200-257
[10]  
BOUILLON R, 1991, J BONE MINER RES, V6, P1051