Metabolism of 2α-propoxy-1α,25-dihydroxyvitamin D3 and 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 by human CYP27A1 and CYP24A1
Metabolism of 2α-propoxy-1α,25-dihydroxyvitamin D3 and 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 by human CYP27A1 and CYP24A1
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DOI：
10.1124/dmd.104.003038
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发表时间：
2005-06-01
影响因子：
3.9
通讯作者：
Inouye, K
中科院分区：
文献类型：
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作者：
Abe, D;Sakaki, T;Inouye, K
最近，我们发现一些A环修饰的维生素D-3类似物具有独特的生物活性。在这些类似物中，通过CYP 27 A1和CYP 24 A1检查了2 α-丙氧基-1 α，25（OH）（2）D-3（C3 O 1）和2 α-（3-羟基丙氧基）-1 α，25（OH）（2）D-3（O2 C3）的代谢。令人惊讶的是，CYP 27 A1催化C3 O 1转化为O2 C3，O2 C3对维生素D受体的亲和力是C3 O 1的3倍。因此，认为CYP 27 A1将C3 O 1转化为O2 C3是一种代谢活化过程。通过人CYP 24 A1在C3 O 1和O2 C3代谢中检测到5种代谢产物，包括C-23和C-24氧化途径。另一方面，在大鼠CYP 24 A1代谢中检测到C-24氧化途径的三种代谢物，表明人类和大鼠之间C3 O 1和O2 C3的CYP 24 A1依赖性代谢存在种属差异。动力学分析显示，O2 C3对人CYP 24 A1的Km和k（cat）值分别比1 α，25（OH）（2）D-3的Km和k（cat）值高约16倍和低约3倍。因此，人CYP 24 A1对O2 C3的催化效率k（cat）/K-m仅为1 alpha，25（OH）（2）D-3的2%。这些结果以及C3 O 1和O2 C3在大鼠动物实验中的高钙效应表明，C3 O 1和O2 C3有希望用于骨质疏松症的临床治疗。
Recently, we demonstrated that some A-ring-modified vitamin D-3 analogs had unique biological activity. Of these analogs, 2 alpha-propoxy-1 alpha, 25(OH)(2)D-3 (C3O1) and 2 alpha- (3-hydroxypropoxy)-1 alpha, 25(OH)(2)D-3 (O2C3) were examined for metabolism by CYP27A1 and CYP24A1. Surprisingly, CYP27A1 catalyzed the conversion from C3O1 to O2C3, which has 3 times more affinity for vitamin D receptor than C3O1. Thus, the conversion from C3O1 to O2C3 by CYP27A1 is considered to be a metabolic activation process. Five metabolites were detected in the metabolism of C3O1 and O2C3 by human CYP24A1 including both C-23 and C-24 oxidation pathways. On the other hand, three metabolites of the C-24 oxidation pathway were detected in their metabolism by rat CYP24A1, indicating a species-based difference in the CYP24A1-dependent metabolism of C3O1 and O2C3 between humans and rats. Kinetic analysis revealed that the K-m and k(cat) values of human CYP24A1 for O2C3 are, respectively, approximately 16 times more and 3 times less than those for 1 alpha, 25(OH)(2)D-3. Thus, the catalytic efficiency, k(cat)/K-m, of human CYP24A1 for O2C3 is only 2% of 1 alpha, 25(OH)(2)D-3. These results and a high calcium effect of C3O1 and O2C3 in animal experiments using rats suggest that C3O1 and O2C3 are promising for clinical treatment of osteoporosis.