23-Keto-25-hydroxyvitamin D3: a vitamin D3 metabolite with high affinity for the 1,25-dihydroxyvitamin D specific cytosol receptor

Publisher Website
Google Scholar
Abstract
A new metabolite of 23,25-dihydroxyvitamin D3 was generated with kidney homogenates prepared from vitamin D treated chicks. The metabolite was purified with 3 high-performance liquid chromatographic steps and was identified as 23-keto-25-hydroxyvitamin D3 by UV absorption spectroscopy, mass spectrometry, and chemical reactivity. The R stereoisomer of 23,25-dihydroxyvitamin D3 was 10-fold more effective as an in vitro precursor to 23-keto-25-hydroxyvitamin D3 than was the naturally occurring S stereoisomer. Approximately 500 ng of 23-keto-25-hydroxyvitamin D3 was necessary to produce the same degree of intestinal Ca transport as 25 ng of vitamin D3, a difference of about 20-fold. 23-Keto-25-hydroxyvitamin D3 was not active at stimulating bone Ca resorption at the doses and times tested. This new vitamin D3 metabolite, however, had greater affinity than 25-hydroxyvitamin D3 to both the rat plasma vitamin D binding protein and the 1,25-dihydroxyvitamin D specific [bovine thymus] cytosol receptor. Heretofore, only 1.alpha.-hydroxylated metabolites of 25-hydroxyvitamin D3 or analogs possessing a pseudo 1.alpha.-hydroxy group were known to bind to the 1,25-dihydroxyvitamin D receptor with higher affinity than 25-hydroxyvitamin D3. Ketone formation at the 23 position, therefore, is the first side-chain modification of 25-hydroxyvitamin D3 that results in enhanced binding to the 1,25-dihydroxyvitamin D receptor binding protein.