Topic 2: Clinical Connection To Estrogen Metabolism Gene Variants | Nutrition Genome

Clinical Case Study: Connecting the Dots to Cancer 

Imagine a 34-year-old female that consumes grain-based foods fortified with folic acid and non-organic coffee daily for breakfast, and eats out for lunch and dinner due to long work hours. This would potentially increase the ingestion of vegetable oils, hormones, xenoestrogens, sugar, and polycyclic aromatic hydrocarbons (PAH) based on average restaurant options. Your patient is also on oral contraceptives, chronically stressed, drinking multiple cups of *coffee, green tea or other caffeinated drinks to get through the day and two glasses of red wine from **California at night.

* Eighty-nine percent of U.S. women from 18-34 years of age consume the caffeine equivalent of 1.5 to two cups of coffee a day. Interesting enough, an NIH study found that Asian women had higher estrogen levels from coffee intake while Caucasian women had lower estrogen levels, but caffeinated soda or green tea caused elevated estrogen levels in Asians, Caucasians, and African-American women. Coffee and wine contain caffeic acid and chlorogenic acid that inhibits the enzyme COMT, and therefore the COMT genotype would give further individual response data.

**In California, conventionally-grown wine grapes received more pesticides than almonds, table grapes, tomatoes or strawberries. Residual concentrations of many different pesticides have been detected in bottled wine were similar to initial concentrations on the grapes. Glyphosate (Round-Up) even shows up even in organic U.S. wines, and 76 additives are approved to be used by the FDA. Along with the U.S., France also appears to be a heavier user of pesticides. Italy and Argentina have been found to have the lowest detected levels of pesticides and heavy metals in their wine. 

Analyzing the Genetic Results

You look at her genetic report and see variants in SHBG, DHFR, COMT, and CYP1B1 (from the detoxification section).

SHBG: Sex Hormone Binding Globulin (SHBG) is synthesized in the liver, and in the blood, it transports and regulates the access of sex steroids to sex hormone receptors throughout your body. Research has found that isolated fructose has the most negative effect on SHBG levels, while also being connected to cancer growth by enhancing protein synthesis and promoting a more aggressive cancer phenotype.

The results for the SHBG gene variants have different nutrigenomic solutions based on whether your patient is male or female. For women, if estrogen is high and progesterone is low, these patients require a higher fiber intake, magnesium, vitamin A, C, E, B6, selenium, and L-arginine.

For men, if testosterone is low (variants in SHBG rs6258), increased magnesium, zinc, vitamin D, omega-3’s, boron and a higher healthy fat intake (if testosterone is low and depending on the fat genes) may be required along with weight lifting. 

DHFR: Folic acid from fortified grains and supplementation slows down the DHFR gene and potentially blocks folate receptors, increasing cancer risk.

COMT:  Oral contraceptives deplete folate, vitamins B2, B6, B12, vitamin C and E, magnesium, selenium, and zinc while slowing down COMT. Stress and the catechols from the coffee or green tea and red wine slow COMT further, causing disrupted sleep and increased anxiety/stress hormones. One study found K-Ras gene mutations – common in many cancers – were 4 times higher in coffee drinkers due to the chemical load of the organochlorines (non-organic coffee beans are one of the highest sprayed crops). The wine compounds the chemical load. A poor diet and magnesium deficiency has lead to struggles with disrupted gut flora and constipation, clogging up her liver with genotoxic estrogen.

CYP1B1: A higher activation rate of catechol estrogens may be occurring, causing more DNA damage and cancer risk.

Case Study Summary 

Here you can see a blueprint of how hormone-based cancer can develop based on a combination of gene variants, diet, and lifestyle. Explaining this visual can help a patient become more compliant and empowered to make changes. Avoiding vegetable oils, isolated fructose, lowering grain consumption/avoiding folic acid, reducing or eliminating caffeine/coffee/wine based on the individual, increasing magnesium and fiber, and increasing foods high in resveratrol and the flavonoids quercetin, apigenin, and myricetin all provide solutions to enhance gene expression and lower the risk of cancerous growth for this genetic and epigenetic profile.

Research on Estrogen Metabolism

The Nutrition Genome Report looks at multiple genes related to estrogen metabolism including SHBG, CYP1A1, CYP1B1, CYP1A2, COMT and MAO-A. While the liver is the site for the biosynthesis of estrogens, it is also where biotransformation takes place. Once estrogens are synthesized by aromatase (estrogen synthase) in peripheral tissues including the liver, they are released into circulation. In the Nutrition Genome Report, there is a food class called “aromatase inhibitors” (white button mushrooms, celery, parsley, citrus and cruciferous vegetables), that shows up on the DNA custom grocery list based on certain gene variants. These foods help reduce estrogen-dependant cancer cells from growing.

1 Estrogen Elimination in the Liver 2


Cytochrome P-450 SNPs and Estrogen Detoxification 

The major oxidative routes of estrone and estradiol are 2- and 4-hydroxylation by cytochrome P450 CYP1A1, CYP1B1, CYP1A2 and CYP3A. CYP1A1, CYP1B1 and CYP1A2 are in the detoxification section. CYP1A2 is also in the cardiovascular section for caffeine metabolism.

CYP1A1: CYP1A1 is also involved in the metabolism of benzopyrene (a polycyclic aromatic hydrocarbon) which disrupts DNA methylation and affects breast cancer growth. Variants in CYP1A1*2C is connected to lung health in Chinese, and breast and prostate health in Caucasians.

CYP1B1: The CYP1B1 polymorphism is an ultra-rapid metabolizer, and metabolizes procarcinogens such as polycyclic aromatic hydrocarbons and 17 beta-estradiol. This means that variants cause this enzyme to move too fast, creating carcinogenic activation of polycystic aromatic hydrocarbons and estrogens to genotoxic catechol estrogens – both which cause DNA mutations – with implications for breast, ovarian, colon, lung and prostate health. Inhibiting this liver enzyme with the flavonols quercetin, apigenin and myricetin helps lower the carcinogenic activity.

CYP1A2: A homozygous CYP1A2 is also a rapid metabolizer, metabolizing various environmental procarcinogens, such as heterocyclic amines, nitrosamines, aflatoxin B1 and ochratoxin A. As many of you know, aflatoxin is one of the most carcinogenic compounds known and is found in poorly stored peanuts, Brazil nuts, corn and grain-fed dairy. Ochratoxin A is a potential human carcinogen and may cause neurotoxic damage, immunosuppressive effects, and reproductive harm. 70% of oat-based cereals purchased in the U.S. were contaminated with the fungal toxin ochratoxin A. Wheat (32%) was the second highest in contamination with corn and rice having 15% each. The highest DNA toxicity of ochratoxin A in a study was found in cells where CYP1A2 was expressed.

Polycyclic Aromatic Hydrocarbons (PAH)

Polycystic Aromatic Hydrocarbons (PAH) ) are a group of over 100 different chemicals that are formed during the incomplete burning of coal, oil and gas, garbage, or other organic substances like tobacco or charbroiled meat. In our diet, carcinogenic concerns are brought up due to the consumption of smoked and barbecued meat over an open flame where these are created. However, it isn’t meat and smoked food that is the primary problem; it is our environment and the plants that are trapping these compounds in elevated amounts. It is grains and vegetables grown by freeways and vegetable oils that are the trapping the most PAH’s, and therefore our consumption of these grains, vegetable oils, and grain-fed animal fat that becomes seriously problematic (also true for aflatoxin B1 with dairy, especially with climate change).

In an analysis of PAHs in the UK diet, it was found that the major contributions came from grains (about one-third) and from vegetable oils and fats (also one-third) with fruits, vegetables, and sugars contributing to the remainder. The amount from meat, fish, milk, and beverages was comparatively minor, however, they could be higher in other climates and cultures.

Solution: Avoid vegetable oils and consume fewer grains. It has been demonstrated in studies that the metabolic hydroxylation of resveratrol by CYP1B1, results in its conversion to piceatannol, a tyrosine kinase inhibitor and a compound of known anticancer activity. The flavonols quercetin, apigenin and myricetin all support inhibition of CYP1B1 from producing carcinogenic compounds and all have impressive anti-cancer research.

The Connection of Symptomology to Low and High Estrogen

Below you can see a low and high estrogen chart, along with how imbalanced levels can affect COMT, MAO-A, and symptomology. 


2 Low and High Estrogen 4