Harada M, Miyahara T, Kajita-Kondo S, Kozakai A, Higuchi S, Otomo S, Kozuka H
Department of Pharmacology II, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Res Commun Mol Pathol Pharmacol. 1994 Nov;86(2):183-93.
We investigated the metabolism of 26,26,26,27,27,27-hexafluoro-1 alpha,25-dihydroxyvitamin D3 (26,27-F6-1,25(OH)2D3, ST-630) and 1 alpha,25-dihydroxyvitamin (1,25(OH)2D3) in cultured neonatal mouse calvaria to elucidate why ST-630 is more potent than 1,25(OH)2D3 in stimulating bone resorption in organ culture. The metabolites were extracted with ethyl acetate or chloroform/methanol (1:1) from cultured calvaria or medium incubated with [3H]-ST-630 or [3H]-1,25(OH)2D3 for various periods, and separated by high performance liquid chromatography. [3H]-ST-630 in cultured calvaria was converted to [3H]-26,26,26,27,27,27-hexafluoro-1 alpha,23(S),25-trihydroxyvitamin D3(26,27-F6-1,23,25(OH)3D3,ST-232), which stimulated bone resorption equipotently as 1,25(OH)2D3. The amount of [3H]-ST-232 produced in the bone increased with passage of the culture period. In contrast, the amount of [3H]-ST-630 in the bones decreased in the 2 day cultures. In the medium, [3H]-ST-630 was hardly detectable for 2 days. This suggests that ST-630 is metabolized to ST-232 which is retained in the bones. On the other hand, some [3H]-1,25(OH)2D3 was metabolized to inactive forms detectable in the medium. Therefore, the high potency of ST-630 in stimulating bone resorption in organ culture may be associated with a difference between ST-630 and 1,25(OH)2D3 in the mode of metabolism in the cultured bones.
我们研究了26,26,26,27,27,27-六氟-1α,25-二羟基维生素D3（26,27-F6-1,25(OH)2D3，ST-630）和1α,25-二羟基维生素D（1,25(OH)2D3）在培养的新生小鼠颅骨中的代谢情况，以阐明为何ST-630在器官培养中刺激骨吸收的能力比1,25(OH)2D3更强。用乙酸乙酯或氯仿/甲醇（1:1）从培养的颅骨或与[3H]-ST-630或[3H]-1,25(OH)2D3孵育不同时间的培养基中提取代谢产物，并用高效液相色谱法进行分离。培养的颅骨中的[3H]-ST-630转化为[3H]-26,26,26,27,27,27-六氟-1α,23(S),25-三羟基维生素D3（26,27-F6-1,23,25(OH)3D3，ST-232），其刺激骨吸收的能力与1,25(OH)2D3相当。随着培养时间的推移，骨中产生的[3H]-ST-232的量增加。相反，在2天的培养中，骨中[3H]-ST-630的量减少。在培养基中，2天内几乎检测不到[3H]-ST-630。这表明ST-630代谢为ST-232并保留在骨中。另一方面，一些[3H]-1,25(OH)2D3代谢为在培养基中可检测到的无活性形式。因此，ST-630在器官培养中刺激骨吸收的高效性可能与ST-630和1,25(OH)2D3在培养骨中的代谢方式差异有关。
