ITEM METADATA RECORD
Title: Removal of C-ring from the CD-ring skeleton of 1alpha,25-dihydroxyvitamin D(3) does not alter its target tissue metabolism significantly
Authors: Satyanarayana Reddy, G ×
Robinson, Matthew
Wang, Guochun
Palmore, G Tayhas R
Gennaro, Lynn
Vouros, Paul
De Clercq, Pierre
Vandewalle, Maurits
Young, Wu
Ling, Shi
Verstuyf, Annemieke
Bouillon, Roger #
Issue Date: 15-Apr-2007
Publisher: Academic Press
Series Title: Archives of Biochemistry and Biophysics vol:460 issue:2 pages:254-261
Abstract: It is now well established that 1alpha,25(OH)(2)D(3) is metabolized in its target tissues through the modifications of both side chain and A-ring. The C-24 oxidation pathway is the side chain modification pathway through which 1alpha,25(OH)(2)D(3) is metabolized into calcitroic acid. The C-3 epimerization pathway is the A-ring modification pathway through which 1alpha,25(OH)(2)D(3) is metabolized into 1alpha,25(OH)(2)-3-epi-D(3). During the past two decades, a great number of vitamin D analogs were synthesized by altering the structure of both side chain and A-ring of 1alpha,25(OH)(2)D(3) with the aim to generate novel vitamin D compounds that inhibit proliferation and induce differentiation of various types of normal and cancer cells without causing significant hypercalcemia. Previously, we used some of these analogs as molecular probes to examine how changes in 1alpha,25(OH)(2)D(3) structure would affect its target tissue metabolism. Recently, several nonsteroidal analogs of 1alpha,25(OH)(2)D(3) with unique biological activity profiles were synthesized. Two of the analogs, SL 117 and WU 515 lack the C-ring of the CD-ring skeleton of 1alpha,25(OH)(2)D(3). SL 117 contains the same side chain as that of 1alpha,25(OH)(2)D(3), while WU 515 contains an altered side chain with a 23-yne modification combined with hexafluorination at C-26 and C-27. Presently, it is unknown how the removal of C-ring from the CD-ring skeleton of 1alpha,25(OH)(2)D(3) would affect its target tissue metabolism. In the present study, we compared the metabolic fate of SL 117 and WU 515 with that of 1alpha,25(OH)(2)D(3) in both the isolated perfused rat kidney, which expresses only the C-24 oxidation pathway and rat osteosarcoma cells (UMR 106), which express both the C-24 oxidation and C-3 epimerization pathways. The results of our present study indicate that SL 117 is metabolized like 1alpha,25(OH)(2)D(3), into polar metabolites via the C-24 oxidation pathway in both rat kidney and UMR 106 cells. As expected, WU 515 with altered side chain structure is not metabolized via the C-24 oxidation pathway. Unlike in rat kidney, both SL 117 and WU 515 are also metabolized into less polar metabolites in UMR 106 cells. These metabolites displayed GC and MS characteristics consistent with A-ring epimerization and were putatively assigned as C-3 epimers of SL 117 and WU 515. In summary, we report that removal of the C-ring from the CD-ring skeleton of 1alpha,25(OH)(2)D(3) does not alter its target tissue metabolism significantly.
URI: 
ISSN: 0003-9861
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
× corresponding author
# (joint) last author

Files in This Item:

There are no files associated with this item.

Request a copy

 




All items in Lirias are protected by copyright, with all rights reserved.

© Web of science