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.
The Pharmaceutical Society of Japan