- The 4-OH pathway is considered the most genotoxic as its metabolites can create reactive products that damage DNA.
- Estrone is hydroxylated through Phase 1 detox to form 4-OH-E1. In Phase 2 it is methylation to form 4-MeE1. When 4-OH-E1 is properly methylated to 4-MeE1 it is relatively benign as the 4-MeE1 is easily eliminated and risks are low.
- When it is not methylated 4-OH-E1 builds up. Then it converts to 3,4-Quinones which are carcinogenic similarly to the 16 pathway. Women with uterine fibroids may have increased levels of 4-OH-E1. High levels of estrogen across the board are associated with heavy cycles.
4-OH-E1 is referred to as the “bad” estrogen, along with 16-OH-E1.
- It is a minor pathway of estrogen metabolism.
- It may also enhance cancer development.
- It may directly damage DNA by causing breaks in the molecular strands of DNA.
Human breast cancer tissue produces much higher levels of 4-OH-E1 than 2-OH-E1, while normal breast tissue produces approximately equal amounts of the two metabolites. Women taking hormone therapy with a polymorphism in CYP1B1 had twice the risk of developing breast cancer compared to other HRT users.
Furthermore, the 4-Hydroxyestrones have the ability to convert to metabolites that react with DNA and cause mutations that can be carcinogenic. It is also present in greater quantities in patients deficient in methionine and folic acid. Women who have uterine fibroids also may have increased levels of 4-Hydroxyestrones.
- Spink BC, Fasco MJ, Gierthy JF, Spink DC. 12-O-tetradecanoylphorbol-13-acetate upregulates the Ah receptor and differentially alters CYP1B1 and CYP1A1 expression in MCF-7 breast cancer cells. J Cell Biochem. Sep 1 1998;70(3):289- 296.
- Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR. 17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proc Natl Acad Sci USA. Sep 3 1996;93(18):9776-9781.
- Yang L, Gaikwad NW, Meza J, et al. Novel biomarkers for risk of prostate cancer: results from a case-control study. Prostate. Jan 1 2009;69(1):41-48.
- Castagnetta LA, Granata OM, Traina A, et al. Tissue content of hydroxyestrogens in relation to survival of breast cancer patients. Clin Cancer Res. Oct 2002;8(10):3146-3155.
- Low levels of the “bad estrogen”
- Generally no treatment recommended
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The bad news may be that you are making too much of the 4-hydroxyestrogens and not methylating them well. The good news is that you know this is happening and can do things to change how your body metabolizes estrogens, and in doing so decrease your breast cancer risk. Nutritional intervention (e.g., foods rich in DIM or indole-3-carbinol) can be used to shift estrogens in the direction of 2-hydroxylation, which is safer. Additionally, methylation of estrogen metabolites can be supported nutritionally (e.g., methyl donors such as vitamin B12, folic acid, SAM-e, and foods such as onions, garlic and beets). And the effectiveness of this intervention can be evaluated by measuring the ratio of 2- and 4-methoxyestrone to 2- and 4-hydroxyestrone.
- Improve methylation by adding cofactors (B12, folate) or methyl donors (betaine, dimethyl glycine)
- Consider genetic testing for COMT and CYP1B1 activity, particularly if positive family history
- Reduce stress: COMT is involved in the metabolism of epinephrine, reducing availability for estrogen metabolism
- Increase inhibitors of CYP1B1 (Grapefruit, Ginseng)
- Avoidance of CYP1B1 inducers (Polycyclic aromatic hydrocarbons)
Evaluate methylation activity:
- Serum Homocysteine
- Serum B12 or methylation
- Urinary FIGLU
- Urinary xanthurenate
Other potential protective factors:
- Glutathione (reduction of estrogen quinones)
- Resveratrol (prevents estrogen quinone formation)
- Selenium, zinc, magnesium
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