Demonstration that 1 beta,25-dihydroxyvitamin D3 is an antagonist of the nongenomic but not genomic biological responses and biological profile of the three A-ring diastereomers of 1 alpha,25-dihydroxyvitamin D3.
The steroid hormone 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3) generates biological responses via both genomic and nongenomic mechanisms. This article reports the biological profile of four A-ring diastereomers of this secosteroid (results are expressed as percentage of the response of 1 alpha,25-(OH)2D3. The activity of the compounds, 1 alpha,25-(OH)2D3, 1 alpha,25-(OH)2-3-epivitamin D3, 1 beta,25-(OH)2D3, 1 beta,25-(OH)2-3-epivitamin D3, for in vivo intestinal Ca2+ absorption and bone Ca2+ mobilization and in vitro binding to the nuclear receptor (genomic responses) was, respectively, 100, 2.8, < 0.1, and < 0.1% (intestinal Ca2+ absorption); 100, 1.5, < 0.1, and < 0.1% (bone Ca2+ mobilization); 100, 24, 0.2, and 0.8% (receptor binding). In the in vivo nongenomic transcaltachia assay the results were 100, 80, 0, and 20-30%, and in ROS 17/2.8 cells (45Ca2+ uptake through voltage-gated Ca2+ channels) 1 alpha,25-(OH)2D3 had 100% activity and 1 beta,25-(OH)2D3 (the only diastereomer evaluated) had no agonist activity. Keratinocyte proliferation was inhibited in the order 1 alpha,25-(OH)2D3 > 1 alpha,25-(OH)2-3-epivitamin D3 > 1 beta,25-(OH)2D3 > 1 beta,25-(OH)2-3-epivitamin D3. 1 beta,25-(OH)2D3 was a potent antagonist of 1 alpha,25-(OH)2D3-mediated transcaltachia and 45Ca2+ uptake in ROS 17/2.8 cells but was unable to block the genomic 1 alpha,25-(OH)2D3 induction of chick calbindin-D28k (in vivo), induction of MG-63 cell osteocalcin, and HL-60 cell differentiation. These results suggest that analogs of 1 alpha,25-(OH)2D3 may be synthesized which are selective agonists or antagonists of genomic or nongenomic responses in the vitamin D endocrine system.
Norman
A W
AW
Department of Biochemistry, University of California, Riverside 92521.
Bouillon
R
R
Farach-Carson
M C
MC
Bishop
J E
JE
Zhou
L X
LX
Nemere
I
I
Zhao
J
J
Muralidharan
K R
KR
Okamura
W H
WH
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002117:Calcitriol / Q000378:metabolism* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D005796:Genes / Q000187:drug effects*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D012516:Osteosarcoma; D051381:Rats; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism*; D012867:Skin / Q000166:cytology; D013237:Stereoisomerism; D013481:Superoxides / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D013481:Superoxides; D002117:Calcitriol; D002118:Calcium; D013936:Thymidine