23-Keto-25-hydroxyvitamin D3: a vitamin D3 metabolite with high affinity for the 1,25-dihydroxyvitamin D specific cytosol receptor.
23-Keto-25-hydroxyvitamin D3: a vitamin D3 metabolite with high affinity for the 1,25-dihydroxyvitamin D specific cytosol receptor.
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23-Keto-25-羟基维生素 D3：一种维生素 D3 代谢物，对 1,25-二羟基维生素 D 特异性胞质受体具有高亲和力。
DOI：
10.1021/bi00271a002
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发表时间：
1983
期刊：
影响因子：
2.9
通讯作者：
Napoli,JL
中科院分区：
文献类型：
--
作者：
Horst,RL;Reinhardt,TA;Pramanik,BC;Napoli,JL
罗纳德湖Horst，* Timothy A. Reinhardt，Bikash C. Pramanik和Joseph L.那不勒斯摘要：一种新的代谢产物23，25-二羟维生素D3已产生与肾脏匀浆制备维生素D处理的小鸡。代谢产物纯化与三个高效液相色谱步骤，并确定为2 3-酮-2 5-羟基维生素D3的紫外吸收光谱，质谱，和化学反应。23，25-二羟基维生素D3的R立体异构体作为23-酮-25-羟基维生素D3的体外前体比天然存在的S立体异构体更有效10倍。需要大约500 ng 23-酮-25-羟基维生素D3才能产生与25 ng维生素D3相同程度的肠道钙转运-差异约为20倍。在测试的剂量和时间下，23-酮-25-羟基维生素D3在刺激骨钙再吸收方面没有活性。然而，这种新的维生素D3代谢产物对大鼠血浆维生素D结合蛋白和1，25-二羟基维生素D特异性胞质受体的亲和力比25-羟基维生素D3更大。因此，已知只有25-羟基维生素D3的羟基化代谢物或具有假羟基的类似物以比25-羟基维生素D3更高的亲和力与1，25-二羟基维生素D受体结合。因此，23位的酮形成是25-羟基维生素D3的第一个侧链修饰，其导致与1，25-二羟基维生素D受体结合蛋白的结合增强。维生素D2和维生素D3的25-羟基化和1 α-羟基化对生物活性表达的重要性已被公认（Haussler & McCain，1977; Napoli & DeLuca，1979; Norman，1979）。所得化合物1，25-二羟基维生素D2 [1，25-（OH）2D 2] 1和1，25-二羟基维生素D3 [1，25-（OH）2D 3]是在低钙血症、低磷酸盐血症或维生素D缺乏症期间主要在肾皮质中产生的生物活性形式（Kodicek，1974）。最近的证据也表明骨内存在肾外羟化酶（霍华德等人，1981）、1，25-（OH）2D的靶组织（Stumpf等人，1982年）。在正常维生素D营养或维生素D过量期间，负责羟化的其他酶的增强f来自国家动物疾病生理病理学系
Ronald L. Horst,* Timothy A. Reinhardt, Bikash C. Pramanik, andJoseph L. Napoli abstract: A new metabolite of 23, 25-dihydroxyvitamin D3 has been generated with kidney homogenates prepared from vitamin D treated chicks. The metabolite was purified with three high-performance liquid chromatographic steps and was identified as 2 3-keto-2 5-hydroxyvitamin D3 by ultraviolet absorption spectroscopy, mass spectrometry, and chemical reactivity. The R stereoisomer of 23, 25-dihydroxyvitamin D3 was 10-fold more effective as an in vitro precursor to 23-keto-25-hydroxyvitamin D3 than was the naturally occurring S stereoisomer. Approximately 500 ng of 23-keto-25-hydroxyvitamin D3 was necessary to produce the same degree of intestinal-calcium transport as 25 ng of vitamin D3—a difference of about 20-fold. 23-Keto-25-hydroxyvitamin D3 was not active at stimulating bone calcium resorption at the doses and times tested. This new vitamin D3 metabolite, however, had greater affinity than 25-hydroxyvitamin D3 to both the rat plasma vitamin D binding protein and the 1, 25-dihydroxyvitamin D specificcytosol receptor. Heretofore, only-hydroxylated metabolites of 25-hydroxyvitamin D3 or analogues possessing a pseudo-hydroxy group were known to bind to the 1, 25-dihydroxyvitamin D receptor with higher affinity than 25-hydroxyvitamin D3. Ketone formation at the 23 position, therefore, is the first side-chain modification of 25-hydroxyvitamin D3 that results in enhanced binding to the 1, 25-dihydroxyvitamin D receptor binding protein. e importance of the 25-hydroxylation and la-hydroxylation of vitamin D2 and vitamin D3 tothe expression of biological activity is recognized (Haussler & McCain, 1977; Napoli & DeLuca, 1979; Norman, 1979). The resulting compounds 1, 25-dihydroxyvitamin D2 [l, 25-(OH) 2D2] 1 and 1, 25-dihydroxyvitamin D3 [l, 25-(OH) 2D3] are biologically active forms produced primarily inthe kidney cortex (Kodicek, 1974) during hypocalcemia, hypophosphatemia, or hypovitaminosis D. Recent evidence alsosuggests the presence of an extrarenal-hydroxylase inbone (Howard et al., 1981), a target tissue for l, 25-(OH) 2D (Stumpf et al., 1982). During normal vitamin D nutrition or vitamin D excess, there is en-hancement of other enzymes responsible for the hydroxylation f From the Department of Physiopathology, National Animal Disease