Characterization of 3-Epi-1α, 25-dihydroxyvitamin D₃ Involved in 1α, 25-Dihydroxyvitamin D₃ Metabolic Pathway in Cultured Cell Lines

抄録

Using six different cultured cell models representing osteoblast, intestine, kidney and keratinocyte, we have demonstrated that 1α, 25-dihydroxyvitamin D₃ (1α, 25(OH)₂D₃) is metabolized into 3-epi-1α, 25(OH)₂D₃ in vitamin D-target cells. Although differences existed in the amount of 3-epi-1α, 25(OH)₂D₃ formed with different cell types, it was apparent that 1α, 25(OH)₂D₃ 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)₂D₃ 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)₂D₃ was found to be lower than the native 1α, 25(OH)₂D₃ in suppressing of proliferation of HL-60 cells, while the affinity of 3-epi-1α, 25(OH)₂D₃ for vitamin D-binding protein was 2.5-fold higher than that of 1α, 25(OH)₂D₃. The results indicate that 3-epimerization may change the pharmacokinetics and catabolism of 1α, 25(OH)₂D₃ in vitamin D-target cells.