Cytochrome P450 2C11 5′‐flanking region and promoter: regulation by aromatic hydrocarbons in vitro and in vivo
Bibliographic record
Abstract
Aromatic hydrocarbons (AHs) elicit toxic and adaptive responses via the aryl hydrocarbon receptor (AHR). AHs suppress the transcription of the growth hormone‐regulated, male‐specific rat hepatic cytochrome P450 2C11 gene ( CYP2C11 ) via an unknown mechanism. We hypothesize that the in vivo suppression of CYP2C11 by AHs is mediated by the gene’s promoter and 5′‐flank. Following bioinformatic analysis of putative transcription factor (TF) binding sites, we cloned up to 10kb of the CYP2C11 5′‐flank into a promoterless luciferase plasmid. Deletion analysis of CYP2C11‐ luciferase reporter constructs showed that a region between −2.4kb and −1.3kb mediated a paradoxical induction by AHs, particularly in human HepG2 cells. In the context of a heterologous promoter, this region did not appear to possess enhancer activity. Since suppression may only occur in an environment containing an intact endocrine system and the full complement of TFs necessary for CYP2C11 regulation, our study is now focused on live rats. Preliminary in vivo studies using high‐volume tail vein injection to deliver plasmid to the liver of live rats demonstrated measurable basal luciferase activity in rat liver homogenates; AH‐induced luciferase activity was also observed using a positive control plasmid under AHR control. The effects of anesthesia and high‐volume tail vein injection on endogenous hepatic CYP2C11 and CYP1A1 mRNA levels in vehicle and AH‐treated rats were examined. Our novel CYP2C11 ‐luciferase constructs will be studied in live rats challenged with AHs to identify key regulatory sequences mediating CYP2C11 suppression. [Support: CIHR]
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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) | 0.000 | 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) | 0.001 | 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".