ビタミンDの代謝および生理活性発現機構の解明と栄養疫学研究

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1α,25-Dihydroxyvitamin D_3 [1,25(OH)_2D_3] has been shown to modulate not only proliferation and differentiation but also apoptosis of malignant cells, indicating that it would be useful for the treatment of hyperproliferative diseases such as cancer and psoriasis. Little information is available concerning structural motifs of the 1,25(OH)_2D_3 molecule responsible for modulation of cell differentiation and apoptosis. We evaluated the biological activities of a variety of A-ring analogs in human promyelocytic leukemia (HL-60) cells. Surprisingly, the potent analogs could be clearly divided into two groups: (1) those bearing the 1α- and 3β-hydroxyl groups on the A-ring were potent inducers of differentiation and growth inhibitors of HL-60 cells, and (2) those bearing the 1β-hydroxyl group together with either 3α- or 3β-hydroxyl group on the A-ring were potent stimulators of apoptosis. We have clearly identified for the first time the structural motifs on the basis of stereochemistry of both hydroxyl groups at positions 1 and 3 of the A-ring of the 1,25(OH)_2D_3 molecule responsible for the induction of differentiation and apoptosis of HL-60 cells. These findings would provide useful information not only for structure-activity studies of 1,25(OH)_2D_3 analogs but also for the development of therapeutic agents for the treatment of cancers. It has been well established that 1,25(OH)_2D_3 and its precursor, 25-hydroxyvitamin D_3 (25-OH-D_3), are metabolized via C-24 and C-23/26 oxidation pathways. In addition to these pathways, we identified a new pathway, C-3 epimerization that may be a common metabolic pathway not only for major natural D_3 metabolites including 1,25(OH)_2D_3, 25-OH-D_3 and 24,25(OH)_2D_3 but also for a synthetic analog, 22-oxa-1,25(OH)_2D_3. This pathway was found to be cell-selective and contribute to the D_3 metabolism in concert with the C-23/24 oxidation pathway. 3-Epi-1,25(OH)_2D_3 has been shown to be almost equipotent to 1,25(OH)_2D_3 in suppressing PTH secretion in bovine parathyroid cells and in inhibiting keratinocyte proliferation and more potent in inducing HL-60 cell apoptosis. Thus, the C-3 epimerization pathway appears to play an important role not only in the regulation of intracellular concentration of 1,25(OH)_2D_3 and its analogs but also in the formation of metabolites with a different biological profile. 1,25(OH)_2D_3 has been shown to reduce invasive potential of a number of different cancer cells in vitro. These findings, in conjunction with the fact that the vitamin D receptor (VDR) is present in normal and tumor cells, suggest that it acts primarily as an intrinsic and preventive factor to inhibit the growth and metastasis of cancer cells. To test this possibility, we have created metastatic Lewis lung carcinoma (LLC) cells expressing green fluorescent protein (GFP) and succeeded in demonstrating that serum 1,25(OH)_2D_3 inhibited tumorigenesis by the LLC-GFP cells within physiological levels of serum 1,25(OH)_2D_3. Vitamin D is an important factor for prevention of osteoporosis and bone fracture. To evaluate age-related vitamin D requirement, we measured plasma levels of 25-OH-D_3 and PTH in healthy Japanese women. Plasma 25-OH-D_3 levels correlated significantly and negatively with plasma PTH levels, and the concentration 50nmol/L of 25-OH-D_3 is thought to be the cut-off value of vitamin D insufficiency in elderly women. Based on this value, almost half the elderly subjects enrolled in our study were judged as vitamin D insufficient. Our results suggest that Japanese elderly women might require more vitamin D and calcium intakes from diets and supplements.
2009-01-25

ビタミンDの代謝および生理活性発現機構の解明と栄養疫学研究

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