1α,23,25,26-四羟基维生素D3的合成与生物活性

Synthesis and biological activity of 1 alpha,23,25,26-tetrahydroxyvitamin D3.

作者信息

Ishizuka S, Reichel H, Norman A W

出版信息

Arch Biochem Biophys. 1987 Apr;254(1):188-95. doi: 10.1016/0003-9861(87)90094-4.

Abstract

The metabolic pathway from 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2D3] to 1 alpha,25-dihydroxyvitamin D3-26,23-lactone includes the formation of 1 alpha,23,25-26-tetrahydroxyvitamin D3 [1 alpha,23,25,26-(OH)4D3]. The aim of the current study was to explore the as yet unknown biological properties of this vitamin D3 sterol. The four diastereoisomers of 1 alpha,23,25,26-(OH)4D3 were chemically synthesized. They were compared to 1 alpha,25-(OH)2D3 in terms of their affinity for the chick intestinal 1 alpha,25-(OH)2D3 receptor and their biologic activity in vivo (stimulation of intestinal calcium absorption and mobilization of calcium from bone in vitamin D-deficient rats). The 1,25-(OH)2D3 receptor binding affinities of 1 alpha,23(R)25(R)26-(OH)4D3, 1 alpha,23(S)25(S)26-(OH)4 D3, 1 alpha,23(S)25(R)26-(OH)4D3, and 1 alpha,23(R)25(S)26-(OH)4D3 were 11, 100, 216, and 443 times weaker than the binding affinity of 1 alpha,25-(OH)2D3, respectively. Compared to 1 alpha,25-(OH)2D3, the relative capacities of the 1 alpha,23,25,26-(OH)4D3 compounds to stimulate intestinal calcium absorption were 1/4 for 1 alpha,23(R)25(R)26-(OH)4D3; 1/19 for 1 alpha,23(S)25(S)26-(OH)4D3; 1/90 for 1 alpha,23(S)25(R)26-(OH)4D3; and 1/136 for 1 alpha,23(R)25(S)26-(OH)4D3. Maximal stimulation of intestinal calcium transport occurred 8 h after administration of vitamin D3 metabolites. Mobilization of calcium from bone was quantitated by serum calcium concentration measurements. The activities of 1 alpha,23(R)25(R)26-(OH)4D3, 1 alpha,23(S)25(S)26-(OH)4D3, 1 alpha,23(S)25(R)26-(OH)4D3, and 1 alpha,23(R)25(S)26-(OH)4D3 to increase serum calcium were estimated to be 4, 13, 43, and 69 times weaker than that of 1 alpha,25-(OH)2D3, respectively. These results illustrate the stereospecificity of the chicken intestine 1 alpha,25-(OH)2D3 receptor for binding of 1 alpha,23,25,26-(OH)4D3 and suggest that the 1 alpha,23,25,26-(OH)4D3 exerts its biological activity in the rat through an interaction with 1,25-(OH)2D3 receptors. In summary, the 1 alpha,23,25,26-(OH)4D3 had a markedly lower biological activity than 1 alpha,25-(OH)2D3.

摘要

从1α,25 - 二羟基维生素D3 [1α,25 - (OH)2D3]到1α,25 - 二羟基维生素D3 - 26,23 - 内酯的代谢途径包括1α,23,25 - 26 - 四羟基维生素D3 [1α,23,25,26 - (OH)4D3]的形成。本研究的目的是探索这种维生素D3甾醇尚未为人所知的生物学特性。1α,23,25,26 - (OH)4D3的四种非对映异构体通过化学合成得到。将它们与1α,25 - (OH)2D3在对雏鸡肠道1α,25 - (OH)2D3受体的亲和力以及它们在体内的生物学活性（刺激肠道钙吸收和使维生素D缺乏大鼠的骨钙动员）方面进行比较。1α,23(R)25(R)26 - (OH)4D3、1α,23(S)25(S)26 - (OH)4D3、1α,23(S)25(R)26 - (OH)4D3和1α,23(R)25(S)26 - (OH)4D3与1α,25 - (OH)2D3受体的结合亲和力分别比1α,25 - (OH)2D3的结合亲和力弱11、100、216和443倍。与1α,25 - (OH)2D3相比，1α,23,25,26 - (OH)4D3化合物刺激肠道钙吸收的相对能力，对于1α,23(R)25(R)26 - (OH)4D3为1/4；对于1α,23(S)25(S)26 - (OH)4D3为1/19；对于1α,23(S)25(R)26 - (OH)4D3为1/90；对于1α,23(R)25(S)26 - (OH)4D3为1/136。维生素D3代谢产物给药后8小时出现肠道钙转运的最大刺激。通过血清钙浓度测量对骨钙动员进行定量。1α,23(R)25(R)26 - (OH)4D3、1α,23(S)25(S)26 - (OH)4D3、1α,23(S)25(R)26 - (OH)4D3和1α,23(R)25(S)26 - (OH)4D3升高血清钙的活性估计分别比1α,25 - (OH)2D3弱4、13、43和69倍。这些结果说明了雏鸡肠道1α,25 - (OH)2D3受体对1α,23,25,26 - (OH)4D3结合的立体特异性，并表明1α,23,25,26 - (OH)4D3在大鼠中通过与1,25 - (OH)2D3受体相互作用发挥其生物学活性。总之，1α,23,25,26 - (OH)4D3的生物学活性明显低于1α,25 - (OH)2D3。