Expression of Cytochrome P450 Enzymes Is Induced by Flaxseed Enterolignans
Why this work is in the frame
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Bibliographic record
Abstract
The major flaxseed lignan, secoisolariciresinol diglucoside (SDG), is metabolized to bioactive enterolignans in the intestine and liver. Once formed, enterolignans are subject to hepatic conjugation, similar to cytochrome P450 (CYP)-mediated conjugation of many drugs. CYPs also metabolize food-derived phytochemicals; therefore, adding flaxseed to the diet may promote drug-nutrient interactions affecting the potency of medications. Clinical trials have shown blood pressure-lowering effects of flaxseed in hypertensive patients; however, it is unknown if this stems from direct actions of flaxseed bioactives or indirectly from increased circulating levels of anti-hypertensive (AH) medications resulting from competition for CYP-mediated conjugation and inactivation. Our objective was to determine if enterolignans produced from flaxseed SDG affect expression or activity of CYP enzymes that metabolize metoprolol (MET), a commonly-prescribed AH medication. 3D human hepatocyte spheroids were treated with 25 μM MET or 1, 10, or 100 μM enterodiol (END) for 48 hours, after which RNA was extracted for qPCR analysis of expression of CYP2C9 and CYP3A4, two CYP isozymes involved in MET metabolism. Spheroids were also treated with the same concentrations of MET and END for 1 and 48 hours to measure MET and END metabolites using HPLC/LC-QTOF-MS analysis. Differences were tested with 1-way ANOVA with Tukey's post-hoc test. MET, 1 μM END, and 10 μM END all induced an approximate 2-fold increase in CYP2C9 expression, while 100 μM END induced a 4-fold increase (P < 0.05). CYP3A4 expression was induced 5-fold by MET, while 1 μM and 10 μM END produced only a 2-fold increase in CYP3A4 expression (P < 0.05). 100 μM END led to an almost 14-fold increase in CYP3A4 expression (P < 0.05). Compared to 1 hour of co-treatment with 25 μM MET + END, O-demethylmetoprolol in media was significantly lower after 48 hours (P < 0.05), suggesting competition between END and MET for CYP metabolism. Our initial experiments in 3D human hepatic spheroids are the first to show that metabolites of flaxseed lignans induce expression of CYP2C9 and CYP3A4. The fact that flaxseed enterolignans induce the same CYPs as MET supports the hypothesis of shared metabolism and potential metabolic competition between enterolignans and AH medications. NSERC Discovery Grant.
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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 | 0.000 | 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) | 0.000 | 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 it