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

• Published in: The Journal of biological chemistry 1993-09, Vol.268 (27), p.20022-20030
• Main Authors: Norman, A.W, Bouillon, R, Farach-Carson, M.C, Bishop, J.E, Zhou, L.X, Nemere, I, Zhao, J, Muralidharan, K.R, Okamura, W.H
• Format: Article
• Language: English
• Subjects: ABSORCION; ABSORCION DIGESTIVA; ABSORPTION; ABSORPTION DIGESTIVE; Analytical, structural and metabolic biochemistry; Animals; ANTIVITAMINAS; ANTIVITAMINE; Biological and medical sciences; Bone and Bones - drug effects; Bone and Bones - metabolism; CALCIO; Calcitriol - metabolism; Calcitriol - pharmacology; CALCIUM; Calcium - metabolism; CATION; CATIONES; Cell Division - drug effects; Cell Nucleus - metabolism; Cells, Cultured; Chickens; CHIMIORECEPTEUR; Coenzymes, vitamins; CULTIVO DE CELULAS; CULTURE DE CELLULE; DIFERENCIACION CELULAR; DIFFERENCIATION CELLULAIRE; Duodenum - drug effects; Duodenum - metabolism; ESTRUCTURA QUIMICA; FORMACION OSEA; FORMATION DES OS; Fundamental and applied biological sciences. Psychology; Genes - drug effects; Humans; Intestinal Absorption - drug effects; Keratinocytes - cytology; Keratinocytes - drug effects; LEUCEMIA; LEUCEMIE; Leukemia, Promyelocytic, Acute; Male; NOYAU CELLULAIRE; NUCLEO; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteosarcoma; Other biological molecules; POLLO; POULET; PROTEINAS; PROTEINE; QUIMIORECEPTORS; Rats; Receptors, Calcitriol; Receptors, Steroid - metabolism; SARCOMA; SARCOME; Skin - cytology; Stereoisomerism; STRUCTURE CHIMIQUE; Superoxides - metabolism; Thymidine - metabolism; Tumor Cells, Cultured; VITAMINA D; VITAMINE D
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(20)80689-9

The steroid hormone 1alpha,25-dihydroxyvitamin D3 (1alpha,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 1alpha,25-(OH)2D3. The activity of the compounds, 1alpha,25-(OH)2D3, 1alpha,25-(OH)2- 3-epivitamin D3, 1beta,25-(OH)2D3, 1beta,25-(OH)2-3-epivitamin D3, for in vivo intestinal Ca(2+) absorption and bone Ca(2+) mobilization and in vitro binding to the nuclear receptor (genomic responses) was, respectively, 100, 2.8, O.1, and 0.1% (intestinal Ca(2+) absorption); 100, 1.5, 0.1, and 0.1% (bone Ca(2+) 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 ((45)Ca(2+) uptake through voltage-gated Ca(2+) channels) 1alpha,25-(OH)2D3 had 100% activity and 1beta,25- (OH)2D3 (the only diastereomer evaluated) had no agonist activity. Keratinocyte proliferation was inhibited in the order 1alpha,25-(OH)2D3 is greater than 1alpha,25-(OH)2-3-epivitamin D3 is greater than 1beta,25-(OH)2D3 is greater than 1beta,25-(OH)2-3-epivitamin D3. 1beta,25-(OH)2D3 was a potent antagonist of 1alpha,25-(OH)2D3- mediated transcaltachia and (45)Ca(2+) uptake in ROS 17/2.8 cells but was unable to block the genomic 1alpha,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 1alpha,25-(OH)2D3 may be synthesized which are selective agonists or antagonists of genomic or nongenomic responses in the vitamin D endocrine system