Altered Pharmacokinetics of 1α,25-Dihydroxyvitamin D<sub>3</sub>and 25-Hydroxyvitamin D<sub>3</sub>in the Blood and Tissues of the 25-Hydroxyvitamin D-24-Hydroxylase (<i>Cyp24a1</i>) Null Mouse
Bibliographic record
Abstract
The 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) plays an important role in regulating concentrations of both the precursor 25-hydroxyvitamin D3 [25(OH)D3] and the hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)(2)D3]. Previous studies suggest that Cyp24a1-null mice cannot clear exogenous 1alpha,25(OH)2D3 efficiently. Here, we examined the metabolic clearance in Cyp24a1-null mice in vivo and in vitro using a physiological dose of [1beta-3H]1alpha,25(OH)2D3 or [26,27-methyl-3H]25(OH)D3. Cyp24a1-null mice showed difficulty in eliminating [1beta-3H]1alpha,25(OH)2D3 from the bloodstream and tissues over a 96-h time course, whereas heterozygotic mice eliminated the hormone within 6-12 h, although there was clearance of labeled hormone into water-soluble products involving liver in both genotypes. RT-PCR showed that Cyp24a1-null mice have decreased expression of 25-hydroxyvitamin D-1alpha-hydroxylase that must play a role in their survival. After the administration of [26,27-methyl-3H]25(OH)D3, Cyp24a1-null mice showed higher [26,27-methyl-3H]25(OH)D3 levels and no [26,27-methyl-3H]24,25(OH)2D3 formation, whereas heterozygotic mice showed significant [26,27-methyl-3H]24,25(OH)2D3 production. Based upon in vitro experiments, keratinocytes from Cyp24a1-null mice fail to synthesize [1beta-3H]calcitroic acid from [1beta-3H]1alpha,25(OH2D3 or [26,27-methyl-3H]24,25(OH)2D3 from [26,27-methyl-3H]25(OH)D3 as do control mice, confirming the target cell catabolic role of CYP24A1 in these processes. Finally, the role of vitamin D receptor (VDR) in the vitamin D catabolic cascade was examined using VDR-null mice. Keratinocytes from VDR-null mice failed to metabolize [1beta-3H]1alpha,25(OH)2D3 confirming the importance of vitamin D-inducible, VDR-mediated, C24 oxidation pathway in target cells. These results suggest that the absence of CYP24A1 or VDR retards catabolism of 1alpha,25(OH)2D3 and 25(OH)D3, reinforcing the physiological importance of CYP24A1 in vitamin D homeostasis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.003 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".