Modification of 1 alpha,25-dihydroxyvitamin D3 metabolism by introduction of 26,26,26,27,27,27-hexafluoro atoms in human promyelocytic leukaemia (HL-60) cells: isolation and identification of a novel bioactive metabolite, 26,26,26,27,27,27-hexafluoro-1 alpha,23(S),25-trihydroxyvitamin D3.
Modification of 1 alpha,25-dihydroxyvitamin D3 metabolism by introduction of 26,26,26,27,27,27-hexafluoro atoms in human promyelocytic leukaemia (HL-60) cells: isolation and identification of a novel bioactive metabolite, 26,26,26,27,27,27-hexafluoro-1 alpha,23(S),25-trihydroxyvitamin D3.
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通过在人早幼粒细胞白血病 (HL-60) 细胞中引入 26,26,26,27,27,27-六氟原子来修饰 1α,25-二羟基维生素 D3 代谢：新型生物活性代谢物的分离和鉴定，26,26
作者：
A. Honda;N. Nakashima;Y. Shida;Y. Mori;A. Nagata;S. Ishizuka
为了研究在1α，25-二羟基维生素D3[1α，25(OH)2D3]分子的C-26和C-27位引入氟原子是否会影响人早幼粒细胞白血病(HL-60)细胞的代谢，我们比较了26，26，26，27，27-六氟-1α，25-二羟基维生素D3[26，27-F6-1α，25(OH)2D3]和1α，25(OH)2D3在HL-60细胞中的代谢。在HL-60细胞中，26，27-F6-1α，25(OH)2D3主要转化为新的生物活性代谢产物26，26，26，27，27，27-六氟-1α，23(S)，25-三羟基维生素D3[26，27-F6-1α，23(S)，25(OH)3D3]，但不能转化为26，26，26，27，27，27-六氟-1α，24(R)，25(OH)3D3。26，27-F6-1α，23(S)，25(OH)3D3经H.P.L.C.，U.V.光谱分析和GC-MS联用。有证据表明，26，27-F6-1α，25(OH)2D2通过C-23羟基化代谢为26，27-F6-1α，23(S)，25(OH)3D3，并在细胞内积累23-羟基化生物活性代谢物，而1α，25(OH)2D3最初失活，通过侧链氧化途径代谢为1α，24(R)，25(OH)3D3，在C23-C24细胞中发生裂解，生成24，25，26，27-四核-1α，23(OH)2D3。这些结果表明，26，27-F6-1α，25(OH)2D3和1α，25(OH)2D3在HL-60细胞中通过不同的代谢途径代谢。
To study whether the introduction of fluoro atoms into C-26 and C-27 positions on the 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] molecule could affect metabolism in human promyelocytic leukaemia (HL-60) cells, we compared the metabolism of 26,26,26,27,27,27-hexafluoro-1 alpha,25-dihydroxyvitamin D3 [26,27-F6-1 alpha,25(OH)2D3] and 1 alpha,25(OH)2D3 in HL-60 cells. 26,27-F6-1 alpha,25(OH)2D3 was mainly converted into a new bioactive metabolite, 26,26,26,27,27,27-hexafluoro-1 alpha,23(S),25- trihydroxyvitamin D3 [26,27-F6-1 alpha,23(S),25(OH)3D3], but not into 26,26,26,27,27,27-hexafluoro-1 alpha,24(R),25-trihydroxyvitamin D3 [26,27-F6-1 alpha,24(R),25(OH)3D3] in HL-60 cells. 26,27-F6-1 alpha,23(S),25(OH)3D3 was identified by combinations of h.p.l.c., u.v. spectroscopy and g.c.-mass spectrometry. Evidence is presented that 26,27-F6-1 alpha,25(OH)2D2 was metabolized to 26,27-F6-1 alpha,23(S),25(OH)3D3 by C-23 hydroxylation as a first step of the metabolism, and the 23-hydroxylated bioactive metabolite was accumulated in the cells, whereas 1 alpha,25(OH)2D3 was initially deactivated and metabolized to 1 alpha,24(R),25(OH)3D3 by C-24 hydroxylation through a side-chain oxidation pathway resulting in C23-C24 cleavage, yielding 24,25,26,27-tetranor-1 alpha,23(OH)2D3 in HL-60 cells. These results show that 26,27-F6-1 alpha,25(OH)2D3 and 1 alpha,25(OH)2D3 are metabolized by different metabolic pathways in HL-60 cells.