Characterization of 3-Epi-1α, 25-dihydroxyvitamin D_3 Involved in 1α, 25-Dihydroxyvitamin D_3 Metabolic Pathway in Cultured Cell Lines

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Using six different cultured cell models representing osteoblast, intestine, kidney and keratinocyte, we have demonstrated that 1α, 25-dihydroxyvitamin D_3 (1α, 25(OH)_2D_3) is metabolized into 3-epi-1α, 25(OH)_2D_3 in vitamin D-target cells. Although differences existed in the amount of 3-epi-1α, 25(OH)_2D_3 formed with different cell types, it was apparent that 1α, 25(OH)_2D_3 was subjected to metabolism both through the C24-oxidation and 3-epimerization pathways. Time course and dose response studies showed that the production of 3-epi-1α, 25(OH)_2D_3 was enzymatic. It is interesting to note that this epimerization proceeded from 3β towards 3α unidirectionally, and this conversion was not inhibited by ketoconazole. These data suggest that cytochrome P450 related enzymes including the 24-hydroxylase would not affect this reaction. The biological activity of 3-epi-1α, 25(OH)_2D_3 was found to be lower than the native 1α, 25(OH)_2D_3 in suppressing of proliferation of HL-60 cells, while the affinity of 3-epi-1α, 25(OH)_2D_3 for vitamin D-binding protein was 2.5-fold higher than that of 1α, 25(OH)_2D_3. The results indicate that 3-epimerization may change the pharmacokinetics and catabolism of 1α, 25(OH)_2D_3 in vitamin D-target cells.
社団法人日本薬学会の論文
2000-02-01