Adrenalectomy and Glucocorticoid Effects on the Rat Hepatic Aryl Hydrocarbon Receptor Pathway and the Response to Aromatic Hydrocarbons
Bibliographic record
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the effects of aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene (MC); the prototypical response is induction of drug-metabolizing enzymes. Factors that regulate AHR levels in vivo are poorly understood. It is also not clear how AHR levels affect MC responsiveness. I hypothesize that glucocorticoids enhance hepatic AHR based on previous findings of decreased hepatic AHR protein in hypophysectomised rats and increased AHR levels following glucocorticoid treatment in rodent hepatoma cells. To study this, adrenalectomized (ADX) or SHAM-ADX rats were treated with dexamethasone or vehicle. AHR protein was decreased by 50–60% at 4 days after ADX, but was not altered by dexamethasone. Dexamethasone induced hepatic AHR nuclear translocator (ARNT) mRNA by up to 9-fold, with no corresponding change in ARNT protein. AHR target gene expression was measured in MC-treated ADX rats to assess MC responsiveness given the decrease in AHR protein following ADX. MC-induced hepatic CYP1B1 mRNA was reduced by 50% in ADX rats relative to SHAM. AHR mRNA was increased 4-fold, 6 h after MC in SHAM rats, but no induction was observed in ADX rats. MC-induced 7-ethoxyresorufin O-deethylation activity in ADX rats was 35% of the activity \n\nin the MC-treated SHAM group at 6 h. To assess the capacity for hepatic P450-mediated metabolism, NADPH-cytochrome P450 oxidoreductase (POR) was measured. POR activity was decreased by 50-65% following ADX. DEX induced hepatic POR mRNA by up to 7-fold, 6 h after treatment in SHAM, ADX and intact rats. Putative glucocorticoid responsive elements in the rat Por gene were identified, but recruitment of the glucocorticoid receptor to these elements was not detected using chromatin immunoprecipitation. In rat H-4-II-E hepatoma cells, dexamethasone induced POR, but not ARNT, mRNA. I have shown that ADX decreases hepatic AHR protein and subsequently, MC responsiveness is suppressed for some AHR-mediated responses. Decreased POR activity following ADX might contribute to a decreased capacity for P450-dependent metabolism. The novel findings with respect to glucocorticoid regulation of ARNT and POR demonstrate the complexity of AHR-glucocorticoid cross-talk and the need for further study.
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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".