Physician’s Corner with Dr. Julie Kissel #1

High 4OHE1

4OHE1 is a catechol estrogen formed by aromatic hydroxylation of primary estrogens at either the C-2 or C-4 position.  4OHE1 can be oxidized to catechol estrogen quinones if it is not inactivated by COMT and/or sulfation, glucuronidation, etc. These catechol quinones can react with DNA to produce an excess of estrogen-DNA adducts with subsequent cancer-initiating mutations. This sequence of events is possibly related to uterine fibroids in addition to cancer in the breast, uterus, and prostate.

When a patient is producing too much 4OE1 catechol estrogen, there are 4 primary approaches utilized to decrease the harmful effects and potential increased cancer risk, while still being able to maintain adequate hormone replacement therapy.

1. Decrease the production of 4OHE1 by directing primary estrogen down alternative pathways.
2. Increase the production of the safer estrogen metabolite, 4-MeOE1, by supporting the methylation of 4OHE1 in addition to supporting sulfation and glucuronidation.
3. Protect against the conversion of 4OHE1 estrogens to dangerous quinones that injure DNA.
4. Support glutathione production, because glutathione can detox dangerous quinones.
   

Decrease the production of 4OHE1 by directing primary estrogen down alternative pathways.

Although low levels of 4OHE1 are likely OK, it is very important that your liver metabolizes (breaks down) hormones effectively to avoid the production of too much 4OHE1. The liver has the option of taking estrogen down 3 different pathways, only one of which ends in increased 4OHE1. CYP1B1 is the enzyme pathway in the liver that leads to 4OHE1 production.  There are genetic variants that upregulate the CYP1B1 enzyme, predisposing a person to taking estrogen down the 4OHE1 pathway. There are toxins that turn on the CYP1B1 enzyme, subsequently increasing the production of 4OHE1. There are nutrients found in foods and in supportive supplementation that preferentially turn on the alternative pathways that do not result in 4OHE1 production. Supporting liver metabolism of estrogen down more protective pathways is accomplished with a healthy diet, the avoidance of environmental toxins (including xenoestrogens), and supportive supplementation and hormone optimization.

To inhibit the 4OHE1 pathway and/or turn on the alternative pathways particularly the safer CYP-1A1 enzyme pathway that leads to the production of 2OHE1, a safer estrogen metabolite:

1. Eat a healthy diet
   1. Cruciferous vegetables contain the phytochemical indole-3-carbinol (I3C). In the body, I3C is broken down to 3.3-diindolylmethane – DIM, for short. Cruciferous vegetables include: arugula, broccoli, brussels sprouts, cabbage, cauliflower, collard greens, kale, radishes, rutabaga, turnips and watercress.
   2. Strawberries, blackberries and raspberries (sources of Ellagic acid)
   3. Purple Grapes (a source of Resveratrol)
   4. Green tea (a source of EGCG- epigallocatechin gallate)
   5. Avoidance of Caffeine
   6. Avoidance of simple sugars
   7. Avoidance of excessive omega 6 fatty acids
2. Avoid environmental toxin exposure
   1. Xenoestrogens, a group of either naturally-occurring or artificially-created compounds in the environment, show hormone-like properties: they are both imperfect, potent estrogens and endocrine disruptors. The more efficacious a Xenoestrogen, the more it disrupts the action of physiologic estrogens. In addition, the liver can only do so much. If the liver is busy metabolizing xenoestrogens from the environment, it is not going to do as well metabolizing endogenous estrogens made by the body. Important xenoestrogens to note include: plastics, pesticides, soy isolates, and products from animals raised with inappropriate hormone exposure.
   2. PAHs – (Polycyclic Aromatic Hydrocarbons). PAHs in air are produced by burning wood and fuel for homes. They are also contained in gasoline and diesel exhaust, soot, cola, and smoke from cigars and cigarettes.
   3. PCBs (Polychlorinated Biphenyls). PCBs belong to a broad family of man-made organic chemicals known as chlorinated hydrocarbons. PCBs were domestically manufactured from 1929 until manufacturing was banned in 1979. They have a range of toxicity. Although no longer commercially produced in the United States, PCBs may be present in products and materials produced before the 1979 PCB ban. Products that may contain PCBs include: transformers and capacitors, electrical equipment, oil used in motors and hydraulic systems, old electrical devices or appliances containing PCB capacitors, fluorescent light ballasts, cable insulation, thermal insulation material (including fiberglass, felt, foam, and cork), adhesives and tapes, oil-based paint, caulking, plastics, carbonless copy paper, & floor finish. PCBs can accumulate in the leaves and above-ground parts of plants and food crops. They are also taken up into the bodies of small organisms and fish. As a result, people who ingest fish may be exposed to PCBs that have bioaccumulated in the fish they are ingesting.
3. Optimize hormones
   1. Such as Thyroxine, Progesterone, DHEA
   2. Avoidance of birth control pills
4. Supplementation
   1. EstroPure
   2. Pure Balance
   3. Pure Hormone Support – F
   4. Pure Fish Oil or OmegaAvail Smoothies. Omega -3 found in fish have been shown to promote estrogen using the C-2 pathway. This is particularly true for EPA omega-3 fatty acids.

Increase the production of the safer estrogen metabolite (4-MeOE1) by supporting the methylation of 4OHE1, in addition to supporting sulfation, glucuronidation, and conjugation to glutathione.

If 4OHE1 is overproduced, it is less likely to oxidize to carcinogenic compounds.  That creates DNA adducts if it is neutralized via methylation, sulfation, glucuronidation and/or conjugation to glutathione. Methylation by the enzyme COMT converts the 4OHE1 form of estrogen to 4-MeOE1, a safer form of estrogen. Nutrients to support the COMT enzyme include: Methionine (especially important if low homocysteine), Magnesium, B2, B6, B12, Folate (folinic acid, 5-formyl THF, or 5-methyl THF), TMG (betaine), and choline. Sulfur containing amino acids support sulfation, glucuronidation, and conjugation with glutathione.

1. Supplementation to consider:
   1. Pure Methylation
   2. Homocysteine Supreme
   3. Magnesium Glycinate, Reacted Magnesium.
   4. Caution with excessive calcium supplementation
   5. Sulfur containing compounds/amino acids like: MSM (Methylsulfonlymethane), NAC (N-Acetyl Cysteine), and Methionine
2. Avoid factors that slow or inhibit COMT.
   1. Rule out Mercury toxicity as mercury inhibits the COMT activity through inhibition of S-adenosylmethionine (SAM), a coenzyme for COMT.
   2. Plastics inhibit COMT activity
   3. Chronic Stress – the COMT enzyme is involved in the metabolism of neurotransmitters, using up available nutrients for COMT optimization in the liver.

Protect against conversion of 4OHE1 estrogens to dangerous quinones that injure DNA

1. Avoid trans fats
2. Avoid heavy metal exposure
3. Supplementation:
   1. Melatonin
   2. Theanine
   3. Sulphoraphane

Support glutathione production because glutathione can detox dangerous quinones

1. Diet
   1. Sulfur-rich foods like garlic and onions to provide sulfur containing amino acids
   2. Bioactive Whey Protein, if tolerated – a great source of cysteine
2. Supplementation to boost glutathione production
   1. N-Acetyl Cysteine
   2. Glutamine
   3. Glycine
   4. Selenium
   5. Pure Energy
3. Decrease excessive use of glutathione by: avoiding excessive pharmaceuticals, decreasing heavy metal exposure, decreasing cigarette exposure and air pollution, all of which use up available glutathione.
4. Reactivate glutathione by increasing Vitamin C and Vitamin E.