A Novel Type of Estrogen Metabolite: Steroid Dimers of Estradiol and Estrone?
Bibliographic record
Abstract
Extensive metabolism of endogenous estrogens to polar and non-polar metabolites occurs in various tissues besides the major contribution from the liver. Novel non-polar estrogens have been noted following incubation of estradiol (E2) with human liver microsomes; two of them were identified, surprisingly, as diaryl ether dimers of E2. Furthermore, their formation was catalyzed by certain human cytochrome P450 isoforms in the presence of NADPH as co-factor. Their production in vivo and potential biological functions have not been reported, to our knowledge. In studies on estrogen metabolism in reproductive and other tissues in several species we have encountered non-polar metabolites that have remained unidentified. They were less polar than methoxyestrogens on chromatography. Using radiolabeled estrogens as substrates in mammary tissues from adult nulliparous mice, we investigated the possibility that the non-polar metabolites were estrogen dimers. Tritium-labeled E2 and estrone (E1) were used in short-term incubations (1-4h); steroids were recovered from media by solid-phase extraction, as unconjugated and conjugated fractions. Profiles for the unconjugated fractions were obtained by HPLC (acetonitrile:water). Saponification of non-polar metabolites was done with an internal standard of estradiol stearate, followed by HPLC, to eliminate any fatty-acid esters of estrogens. Major amounts of non-polar metabolites were formed in all instances with both substrates; however, saponification yielded no estrogens except from the standard, E2 stearate. Strong acid treatment similarly did not alter the retention time of the non-polar material on subsequent HPLC, suggesting the presence of a very stable metabolite. Subsequently, we have applied the above methodology in a series of examinations of radioactive estrogen metabolites formed with tissues from the reproductive system (vas deferens, cauda epididymis, seminal vesicles and prostate from the boar and stallion; bilaminar and trilaminar equine trophoblast) and non-reproductive tissues (canine skeletal muscle and bone; porcine liver). In all instances the very non-polar metabolites were major products of the incubation and had characteristics that match those of dimers of E2 or E1. The widespread occurrence of a novel form of estrogen metabolite has been raised by these findings and current studies are underway to provide definitive proof of the dimer form and to establish the full identity of these compounds. Their possible biological significance as major metabolites of E2 and E1 will then be a subject for future investigation in both reproductive and non-reproductive systems. This research was supported by NSERC (Canada). (poster)
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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 | 0.000 | 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 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".