Decreased nuclear receptor activity and epigenetic modulation associates with down‐regulation of hepatic drug‐metabolizing enzymes in chronic kidney disease
Bibliographic record
Abstract
Patients with chronic kidney disease (CKD) require many medications. CYP2C and CYP3A drug‐metabolizing enzymes play a critical role in determining the pharmacokinetics of the majority of prescribed medications. These enzymes are transcriptionally regulated by the nuclear receptors pregnane X receptor (PXR) and hepatic nuclear factor 4α (HNF4α). Expression of CYP2C and CYP3A is decreased in CKD; however, the mechanisms by which this occurs is unknown. We induced CKD in rats by 5/6 nephrectomy and used chromatin immunoprecipitation (ChIP) to determine nuclear receptor‐ and epigenetic alteration‐mediated differences in the promoter region of the CYP2C and CYP3A genes. RNA polymerase II and HNF‐4α binding was decreased 76 and 57% in the CYP2C11 promotor and 71 and 77% in the CYP3A2 promoter, respectively ( P <0.05). ChIP also revealed a 57% decrease in PXR binding to the CYP3A2 promoter in CKD rats ( P <0.05). The decrease in PXR and HNF‐4α binding was accompanied by diminished histone 4 acetylation in the CYP3A2 promoter (48%) and histone 3 acetylation in the CYP2C11 (77%) and CYP3A2 (77%) promoter loci for nuclear receptor activation ( P <0.05). This study suggests that decreased nuclear receptor binding and histone acetylation may contribute to the mechanism of drug‐metabolizing enzyme down‐regulation and altered pharmacokinetics in CKD.–Velenosi, T. J., Feere, D. A., Sohi, G., Hardy, D. B., Urquhart, B. L. Decreased nuclear receptor activity and epigenetic modulation associates with down‐regulation of hepatic drug‐metabolizing enzymes in chronic kidney disease. FASEB J. 28, 5388–5397 (2014). www.fasebj.org
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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 | 0.000 |
| 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 | 0.001 |
| 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".