Synthesis and metabolic studies of 1α,2α,25-, 1α,4α,25- and 1α,4β,25-trihydroxyvitamin D3
| Autor: | G. Satyanarayana Reddy, Daisuke Sawada, Masashi Takano, Miyu Nishikawa, Tai C. Chen, Kaori Yasuda, Kyohei Horie, Atsushi Kittaka, Ken Ichiro Takagi, Akiko Takeuchi, Toshiyuki Sakaki |
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| Rok vydání: | 2015 |
| Předmět: |
Vitamin
Glucuronate Stereochemistry Endocrinology Diabetes and Metabolism Metabolite Clinical Biochemistry Biochemistry Calcitriol receptor chemistry.chemical_compound Endocrinology Calcitriol CYP24A1 Vitamin D and neurology Animals Humans Molecular Biology Molecular Structure Stereoisomerism Biological activity Vitamins Cell Biology Metabolism Rats chemistry Molecular Medicine |
| Zdroj: | The Journal of Steroid Biochemistry and Molecular Biology. 148:34-37 |
| ISSN: | 0960-0760 |
| Popis: | Three different A-ring perhydroxylated trihydroxyvitamin D3 metabolites were synthesized from their appropriate A-ring precursors and CD-ring for their potential therapeutic applications. We first chemically synthesized 1α,2α,25-trihydroxyvitamin D3 [1α,2α,25(OH)3D3] to study its VDR binding affinity because this metabolite is a product of recombinant human CYP3A4 catalysis when 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 (O2C3), a more potent vitamin D receptor (VDR) binder than 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], is used as the substrate. We found that this metabolite retained 27.3% of the VDR binding affinity compared to 1α,25(OH)2D3. The kcat/Km value of CYP24A1 for 1α,2α,25(OH)3D3 is 60% of that for 1α,25(OH)2D3. Since the biological activity and the metabolic fate of a naturally occurring C4-hydroxylated vitamin D2 metabolite found in the serum of rats treated with pharmacological doses of vitamin D2 have never been described, we next synthesized 1α,4α,25-trihydroxyvitamin D3 and its diastereoisomer, 1α,4β,25-trihydroxyvitamin D3, to study their metabolism and biological activities. Both 4-hydroxylated isomers showed weaker VDR binding affinity than 1α,25(OH)2D3. Although either 4-hydroxylated isomer can be metabolized by CYP24A1 almost at the same level as 1α,25(OH)2D3, their metabolic patterns catalyzed by uridine 5'-diphosphoglucuronosyltransferase (UGT) are different; only the 4α-hydroxylated analog can be metabolized by UGT to produce a glucuronate conjugate. The results provide important information for the synthesis of new novel chemotherapeutic vitamin D analogs which would be less subjective to degradation and therefore more bioavailable than 1α,25(OH)2D3. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. |
| Databáze: | OpenAIRE |
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