Oxidations of 17β-estradiol and estrone and their interconversions catalyzed by liver, mammary gland and mammary tumor after acute and chronic treatment of rats with indole-3-carbinol or β-naphthoflavone
Bibliographic record
Abstract
Altered cytochrome P450-catalyzed metabolism of 17β-estradiol (E2) and estrone (E1) in the liver and (or) extrahepatic tissues may affect estrogen-sensitive tumorigenesis. We examined the effects of oral treatments of (i) indole-3-carbinol (I3C) at 250 or 500 mg/kg or β-naphthoflavone (β-NF) at 40 mg/kg of body weight (bw)/day from 51 to 54 days of age (acute regimen), and (ii) I3C at 250 mg/kg or β-NF at 20 mg/kg bw given 3x/week from 10 to 22 weeks of age (chronic regimen) in female Sprague-Dawley rats. We determined the effects of these treatments on the P450 content and P450 (CYP)-specific activities in the liver, P450-dependent metabolism of E2 and E1 by the liver and mammary gland, and interconversion of E1 and E2 catalyzed by 17β-hydroxysteroid dehydrogenase (17β-HSD) in these tissues and malignant mammary tumors. I3C at the two levels of acute regimen elicited similar responses. Acute and chronic treatments with I3C, but not β-NF, increased P450 content ~2-fold. I3C, and to a lesser extent β-NF, increased CYP1A1 and CYP1A2 probe activities in liver up to 117- and 27- fold, respectively, and after acute regimens, that of CYP3A by ~1.8-fold. I3C also increased activity of CYP2B up to 100-fold. Overall hepatic metabolism of E2 and E1, which was ~2-fold greater at 55 than 155 days of age, was increased (~2.8-fold) by I3C with 2-, 4-, 16α-, 6α-, 6β-, and 15α-hydroxy (OH) comprising [Formula: see text]54, 3, 2, ~2, ~5, 7, and 2%, respectively, of E1 and E2 metabolites. Acute regimens of β-NF increased 2- and 15α-OH-E2 (62 and 5% of total) from E2 and 2-, 4-, and 6α-OH-E1 + 6β-OH-E1 (32, 13, and 4% of total) from E1. Mammary gland metabolized E2 to E1 and small amounts of 15α-, 4-, 16α-, 6β-, and 6α-OH-E2. After the acute IC3 regimen, E2 was also converted to 2-OH-E2. 17β-HSD-catalyzed oxidation of E2 was favored in the liver and reduction of E1 was favored in mammary gland and tumor (= 1% of hepatic activity). An increased (~2-fold) ratio of reductive to oxidative activities in malignant mammary tumors by chronic I3C regimen may stimulate tumor growth. This is the first report showing that after chronic oral regimens, the I3C-, but not β-NF-, induced changes in CYP complement led to elevated E2 and E1 metabolism. The persistent effects of increased putative carcinogenic and estrogenic 4- and 16α-OH as well as 6α- and 6β-OH-E2 and 6β-OH-E1 might counteract those of the less estrogenic 2-OH metabolites, thus accounting for the lack of suppression of mammary tumorigenesis by I3C in our previous study.Key words: estrogen metabolism, P450, 17β-hydroxysteroid dehydrogenase, indole-3-carbinol, β-naphthoflavone.
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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 | 0.000 |
| 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 | 0.000 |
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".