Hepatic activation and inactivation of clinically-relevant vitamin D analogs and prodrugs.
Bibliographic record
Abstract
Like most pharmaceutical agents, vitamin D analogs are subject to hepatic metabolism by a variety of cytochrome P450 (CYP)-based systems. Metabolism can involve activation as well as inactivation of the vitamin D analog and one of the more successful families includes the 1alpha-hydroxyvitamin D prodrugs (1alpha-OH-D2, 1alpha-OH-D3, 1alpha-OH-D4, 1alpha-OH-D5), that all require a step of activation. Some of these prodrugs are in use or clinical trial because they have a therapeutic advantage over calcitriol. However, the nature of the activation of these molecules is poorly understood, particularly with regard to the CYP isoform involved. Various transfected CYPs and hepatic cell lines combined with tandem LC-MS analysis were used to investigate the metabolism of a spectrum of vitamin D analogs, including 1alpha-OH-Ds and the topical analog, calcipotriol. In the case of the 1alpha-OH-Ds, evidence was found of multiple sites of side-chain hydroxylation consistent with the generation of more than one active form. The potential involvement of CYP27A and other putative 25-hydroxylases in 1alpha-OH-D activation was also shown, as well as the potential for CYP24 activation and inactivation. In the case of calcipotriol, the respective roles of non-vitamin D-related CYPs and CYP24 in the catabolism of this anti-psoriatic drug were dissected out using cell lines with or without CYP24 expression, allowing us to demonstrate the potential contribution of CYP24 to "vitamin D resistance". The implications of hepatic metabolism in the context of other facets thought to play a role in the mechanism of action of anticancer and antiproliferative vitamin D analogs are discussed.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".