Metabolism of 2-Methyl Analogs of 1α,25-Dihydroxyvitamin D<sub>3</sub> in Rat Osteosarcoma Cells (UMR 106)
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- Rao Devara Sunita
- Department of Pediatrics, Women and Infants Hospital of Rhode Island, Brown Medical School
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- Siu-Caldera Mei-Ling
- Department of Pediatrics, Women and Infants Hospital of Rhode Island, Brown Medical School
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- Sekimoto Hiroko
- Department of Pediatrics, Women and Infants Hospital of Rhode Island, Brown Medical School
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- Gennaro Lynn
- Northeastern University
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- Vouros Paul
- Northeastern University
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- Takayama Hiroaki
- Faculty of Pharmaceutical Sciences, Teikyo University
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- Konno Katsuhiro
- Faculty of Pharmaceutical Sciences, Teikyo University
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- Fujishima Toshie
- Faculty of Pharmaceutical Sciences, Teikyo University
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- Reddy Gudimetla Satyanarayana
- Department of Pediatrics, Women and Infants Hospital of Rhode Island, Brown Medical School
Bibliographic Information
- Other Title
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- Metabolism of 2-Methyl Analogs of 1α,25-Dihydroxyvitamin D3 in Rat Osteosarcoma Cells(UMR 106)
- Metabolism of 2 Methyl Analogs of 1 アルファ 25 Dihydroxyvitamin D3 in Rat Osteosarcoma Cells UMR 106
- Metabolism of 2-Methyl Analogs of 1α,25-Dihydroxyvitamin D<sub>3</sub> in Rat Osteosarcoma Cells (UMR 106)
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Abstract
Several novel A-ring modified analogs of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] have been synthesized in order to investigate the structure–function relationships of 1α,25(OH)2D3. We synthesized A-ring modified analogs which contain a methyl group on C-2 of the A-ring. There are eight 2-methyl diastereomers, which differ in the stereochemistry of the methyl group on C-2 and the hydroxyl groups on C-1 and C-3. Further our biological activity studies of the 2-methyl diastereomers indicated that the potency of each analog is highly dependent on the stereochemistry of the A-ring substituents [Konno et al., Biorg. Med. Chem. Letts. 8(2), 151—156 (1998); Nakagawa et al., Biochem. Pharmacol. 60(12), 1937—1947 (2000)]. For example, the VDR binding affinities exhibited by the 1α-isomers are significantly higher than those exhibited by the 1β-isomers. Furthermore, out of all the 1α-isomers, the 2α-methyl isomers, when compared to the corresponding 2β-methyl isomers, showed much higher potency in inducing cell differentiation of HL-60 cells, but failed to stimulate apoptosis. In contrast the 2β-methyl isomers strongly stimulated apoptosis. At present it is unknown how the addition of the 2-methyl modification to the hormone, 1α,25(OH)2D3 alters its metabolism in target tissues. Previously, we reported that 1α,25(OH)2D3 is metabolized in rat osteosarcoma (UMR 106) cells via both the C-24 oxidation and the C-3 epimerization pathways. Therefore, we studied the metabolism of the four 1α,2-methyl diastereomers in UMR 106 cells. Our results indicated that in UMR 106 cells, all four diastereomers were metabolized into several polar metabolites via the C-24 oxidation pathway. Thus, the presence of the 2-methyl group on the A-ring did not inhibit the metabolism of the analogs via the C-24 oxidation pathway. However, it is significant to note that the 2-methyl group prevented the metabolism of the analogs via the C-3 epimerization pathway. In summary, we report that the 2-methyl group interferes with the action of the enzyme(s) involved in C-3 epimerization, but not with the enzyme 1α,25(OH)2D3-24-hydroxylase, which is responsible for C-24 oxidation pathway.
Journal
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- Biological and Pharmaceutical Bulletin
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Biological and Pharmaceutical Bulletin 25 (7), 845-852, 2002
The Pharmaceutical Society of Japan
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Keywords
Details 詳細情報について
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- CRID
- 1390001204628242432
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- NII Article ID
- 110003638771
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- NII Book ID
- AA10885497
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- COI
- 1:CAS:528:DC%2BD38XlvVChsrc%3D
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- ISSN
- 13475215
- 09186158
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- NDL BIB ID
- 6264516
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- PubMed
- 12132655
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- Abstract License Flag
- Disallowed