Expression of the Human <i>UGT1</i> Locus in Transgenic Mice by WY‐14643 and Implications on Drug Metabolism Through Peroxisome Proliferator‐Activated Receptor (PPAR) α Activation
Bibliographic record
Abstract
Transgenic mice carrying the human UDP‐glucuronosyltransferase‐1 locus (Tg‐ UGT1 ) was recently created and shown to express the nine UGT1A genes in a pattern that resembles their expression in human tissues. In the present study, UGT1A1, 1A3, 1A4, and 1A6 have been identified as targets of PPARα in human hepatocytes and Tg‐ UGT1 mice. Oral administration of WY‐14643 to Tg‐ UGT1 mice led to inductionof these proteins in either the liver, gastrointestinal tract, or kidney. With UGT1A3 previously identified as the major human enzyme involved in human C24‐glucuronidation of lithocholic acid (LCA), the dramatic induction of liver UGT1A3 RNA in Tg‐ UGT1 mice was consistent with the formation of LCA‐24G in plasma. Furthermore, PPAR‐responsive elements were identified flanking the UGT1A1 , UGT1A3, and UGT1A6 genes by a combination of site‐directed mutagenesis, specific binding to the PPARα receptor, and functional response in HepG2 cells overexpressing PPARα. In conclusion, these results suggest that oral fibrate treatment in humans will induce the UGT1A family of proteins in the gastrointestinal tract and liver, influencing first‐pass metabolism of other drugs that are taken concurrently with hypolipidemic therapy. (Supported by USPHS grants ES10337 and GM49135).
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".