Metabolism of A-ring diastereomers of 1α,25-dihydroxyvitamin D3 by CYP24A1
Metabolism of A-ring diastereomers of 1α,25-dihydroxyvitamin D3 by CYP24A1
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DOI：
10.1016/j.bbrc.2004.07.040
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发表时间：
2004-09-03
影响因子：
3.1
通讯作者：
Inouye, K
中科院分区：
文献类型：
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作者：
Kusudo, T;Sakaki, T;Inouye, K
1 α，25（OH）（2）D-3的代谢（1 α，3 β）及其A环非对映异构体，1 β，25（OH）（2）D-3（1beta，3beta），1alpha，25（OH）（2）-3-epi-D-3（1alpha，3alpha）和1beta，25（OH）（2）-3-epi-D-3（1 β，3 α），以比较人和大鼠之间CYP 24 A1的底物特异性和反应特异性。在人CYP 24 A1依赖性代谢（1 α，30（）和（1 β，3））中，C-23和C-24氧化途径之间的比例为1：1，尽管（1 α，3 β）和（1 β，3 β）的比例为1：4。这些结果表明，C-3位羟基的取向决定了C-23和C-24氧化途径之间的比例。在大鼠CYP 24 A1依赖性代谢中也观察到C-23氧化途径中的代谢物显著增加。人CYP 24 A1与A环非对映体的结合亲和力为（1 α，3 β）>（1 α，3 α）>（1 β，3 β）>（1 β，3 α），表明C-1和C-3位的羟基均显著影响底物结合。本研究获得的信息对于理解CYP 24 A1的底物识别和设计新的维生素D类似物是非常有用的。(C)2004年爱思唯尔公司All rights reserved.
The metabolism of 1alpha,25(OH)(2)D-3 (1alpha,3beta) and its A-ring diastereomers, 1beta,25(OH)(2)D-3 (1beta,3beta), 1alpha,25(OH)(2)-3-epi-D-3 (1alpha,3alpha), and 1beta,25(OH)(2)-3-epi-D-3 (1beta,3alpha), was examined to compare the substrate specificity and reaction specificity of CYP24A1 between humans and rats. The ratio between C-23 and C-24 oxidation pathways in human CYP24A1 -dependent metabolism of (1alpha,30() and (1beta,3) was 1:1, although the ratio for (1alpha,3beta) and (1beta,3beta) was 1:4. These results indicate that the orientation of the hydroxyl group at the C-3 position determines the ratio between C-23 and C-24 oxidation pathways. A remarkable increase of metabolites in the C-23 oxidation pathway was also observed in rat CYP24A1 -dependent metabolism. The binding affinity of human CYP24A1 for A-ring diastereomers was (1alpha,3beta) > (1alpha,3alpha) > (1beta,3beta) > (1beta,3alpha), indicating that both hydroxyl groups at C-1 and C-3 positions significantly affect substrate-binding. The information obtained in this study is quite useful for understanding substrate recognition of CYP24A1 and designing new vitamin D analogs. (C) 2004 Elsevier Inc. All rights reserved.