Metabolism of 1α,25-Dihydroxyvitamin D3in Vitamin D Receptor-Ablated Mice in Vivo

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Abstract
The metabolism of 1α,25-dihydroxyvitamin D3 was studied in vitamin D receptor-ablated mice following the administration of a physiological dose of 1α,25-dihydroxy-[26,27-3H]vitamin D3. The degradation of 1α,25-dihydroxy-[26,27-3H]vitamin D3 in the vitamin D receptor null mutant mice was substantially reduced compared to the wild-type control mice. At 24 h postadministration of radiolabeled 1α,25-dihydroxyvitamin D3 more than 50% of the radioactivity was recovered unmetabolized, whereas in wild-type mice nearly all of the 1α,25-dihydroxy-[26,27-3H]vitamin D3 was degraded. In wild-type mice three polar metabolites other than 1α,25-dihydroxyvitamin D3 were detected and identified on straight-phase and reverse-phase high-performance liquid chromatography as 1α,24(R),25-trihydroxy-[26,27-3H]vitamin D3, 1α,25(S),26-trihydroxy-[26,27-3H]vitamin D3, and (23S,25R)-1α,25-dihydroxy-[3H]vitamin D3-26,23-lactone. Only one metabolite was detected in the plasma and kidneys of vitamin D receptor null mutant mice at 3 h following an intrajugular dose of 1α,25-dihydroxy-[26,27-3H]vitamin D3. This metabolite was clearly identified as 1α,25(S),26-trihydroxy-[26,27-3H]vitamin D3 by comigration on two HPLC systems and periodate cleavage reaction. At 6, 12, and 24 h postinjection 1α,24(R),25-trihydroxy-[26,27-3H]vitamin D3 was also detected at low levels in plasma, kidneys, and liver of some but not all mutant mice. The presence of 25-hydroxyvitamin D3-24-hydroxylase mRNA in the kidneys of these vitamin D receptor null mutant mice was confirmed by ribonuclease protection assay.