24-homologated 1,25-dihydroxyvitamin D3 compounds: separation of calcium and cell differentiation activities.
24-homologated 1,25-dihydroxyvitamin D3 compounds: separation of calcium and cell differentiation activities.
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24-同源 1,25-二羟基维生素 D3 化合物：钙分离和细胞分化活性。
DOI：
10.1021/bi00453a026
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发表时间：
1990
期刊：
影响因子：
2.9
通讯作者：
DeLuca,HF
中科院分区：
文献类型：
--
作者：
Perlman,K;Kutner,A;Prahl,J;Smith,C;Inaba,M;Schnoes,HK;DeLuca,HF
摘要：化学合成了一系列24同源的1,25 -二羟基维生素D3化合物，并研究了它们在诱导人早幼粒细胞HL-60细胞向单核细胞分化和维生素D缺乏大鼠钙动员活性方面的活性。1,25 -二羟基维生素D3或其22类似物1或2个碳的同源性使HL-60分化活性增加10倍，3个碳的同源性使HL-60分化活性降低一半。另一方面，ho- moologation导致体内钙动员活性大幅降低。24位每个碳的加入使其与HL-60受体或大鼠肠道受体的结合降低了5-10倍，因此三homo化合物对受体的结合亲和力比1,25 -二羟基维生素D3低130倍。因此，受体的结合亲和力不能解释24种同源化合物诱导细胞分化的优先活性。自从发现维生素D的活性形式，即1.25-二羟基维生素D3 [1,25 -(OH) 2D3]以来，我们对维生素D在生理上的作用的认识有了很大的扩展。例如，1,25 -(OH) 2D3不仅刺激肠道钙吸收、骨钙的调动和肾钙的再吸收（DeLuca & Schnoes, 1983; DeLuca, 1988），而且似乎还抑制甲状旁腺功能（Russellet al., 1986）。
Revised Manuscript Received July 14, 1989 abstract: A series of 24-homologated 1, 25-dihydroxyvitamin D3 compounds have been chemically synthesized and studied with regard to theiractivity in inducing differentiation of human promyelocyte HL-60 cells to monocytes and in calcium mobilizing activity in vitamin D deficient rats. Homologation of 1, 25-dihydroxyvitamin D3 or its 22 analogue by one or two carbons increases by 10-fold and three-carbon homologation reduces by half the activity in causing differentiation of HL-60. On the other hand, ho-mologation causes a substantial decrease in in vivo calcium mobilization activity. The addition of each carbon at the 24-position decreases binding to the HL-60 receptor or rat intestinal receptor by 5-10-fold so that binding affinity of the trihomo compound for the receptors is 130 times less that of 1, 25-dihydroxyvitamin D3. Thus, binding affinity for the receptor cannotaccount for the preferential activity of the 24-homologated compounds in inducing cell differentiation.Since the discovery of the active form of vitamin D, namely 1.25-dihydroxyvitamin D3 [l, 25-(OH) 2D3],‘considerable ex-pansion in our understanding of the role of vitamin D in physiology has been realized. For example, l, 25-(OH) 2D3 not only stimulates intestinal calcium absorption, the mobilizing of calcium from bone, and renal reabsorption of calcium (DeLuca & Schnoes, 1983; DeLuca, 1988) but also appears to suppress parathyroid gland function (Russellet al., 1986),