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//Today's Show //
Eleanor Rogan, PhD has been studying chemical carcinogens for over 30 years. Today she explores how improperly metabolized estrogens can cause cancer; specifically when they're metabolized to the Catechol estrogen quinone.
01:34 In Nebraska, fracking is an issue as is the Keystone Pipeline. The route has been shifted to the sand hills. A spill would likely go into the Ogallala aquifer which provides water to multiple states.
06:18 Estrone is E1. Estradiol is E2. They convert back and forth. Both were studied.
06:55 Catechol estrogens can be methylated. They travel in the blood as methylated estrogens. If the body needs the methyl group, it is taken off and it becomes an estrogen.
07:18 Catechol estrogens are an endogenous carcinogen. If they are further oxidized into catechol estrogen quinones, they are highly reactive with DNA in specific ways which start the process leading to cancer, peptides and proteins. They react with glutathione.
08:32 P450 1B1 is dangerous in the number 4 position in the molecule. It creates a quinone and is highly reactive with DNA. In estrone or estradiol, cytochrome P450 1A usually puts the extra hydroxyl group onto the 2 position in the molecule.
10:40 A study looked at women with and without ovarian cancer. Women with ovarian cancer have higher levels of estrogen DNA adducts than women who do not have ovarian cancer.
11:03 They looked at the polymorphic variations in 2 enzymes. One was a variant that made cytokine P450 1B1 more active. The other was a variant that made catechol-o-methyltransferase, a protective enzyme, less active.
11:38 The research found that women with 2 copies of the less active catechol-o- methyltransferase, plus one or two copies of the more active cytokine P450 1B1, were 3 times more likely to have ovarian cancer.
12:10 The women who had 2 copies of the more active P450 1B1 and 2 copies of the less active catechol-o-methyltransferase, they were six times more likely to have ovarian cancer.
12:55 If you have a SNP, you have it in every cell in your body. This means it can be measured in any of them.
13:27 When our COMT is functioning normally, we make the catechol estrogen and put a methyl group on it. It cannot from a quinone. Lower levels of quinones means you have lower levels of adducts.
13:50 If your catechol-o-methyltransferase is not working well, your catechol estrogen can go on to become a quinone and react with DNA.
16:18 Dopamine is the only other molecule that goes through this kind of metabolism; however, it is pH dependent.
18:03 It would cost a few $100,000 to determine if researching dopamine quinones in Parkinson’s was the right track for something useful. Funding is not available.
19:25 Dopamine quinones make analogous DNA adducts, depurinating adducts that form only on the purine basis.
20:36 Adducts are analogous to taking a step off the DNA ladder. They cause a space with no message. When DNA replicates, any base can go in the gap. Sometimes it is the right base, sometimes it is incorrect, but causes no effect and sometimes it is a change producing base.
27:02 Men with prostate cancer have high levels of estrogen DNA adducts. It may be that prostate cancer is initiated by estrogens and promoted by testosterone. Do they have the adducts because they had cancer, or do they have cancer because they have adducts?
32:22 Hormone replacement therapy has evolved into lower and less frequent doses. Studies of HRT show evidence is that the problem is not with the estrogen, but with the synthetic progestin. In Europe, they are more likely to use progesterone. Progesterone use has not been linked to breast cancer, but progestin has.
35:25 Dr. Rogan’s research with sulforaphane showed it not to be as effective as it was hoped.
36:08 A study of resveratrol and n-acetylcystine taken twice a day, showed that after 3 months, adduct levels were lowered significantly statistically.
43:20 Dr. Rogan is studying Fuch’s eye dystrophy, where the corneal cells become misshapen and eventually you can go blind. The only treatment is a corneal transplant. These cells make many estrogen DNA adducts and may be why they misfunction. There is evidence that cytokine P450 1B1 is involved.
48:46 The formation of estrogen adducts may be a fundamental mechanism of disease. It is probably involved in a variety of things besides cancer.
54:57 Promising research on estrogen carcinogenesis is not funded/supported, and therefore not completed.
01:00:22 Initiation of cancer by estrogens does not require the estrogen receptor. The estrogen receptor, however, may be important when the cells that have mutated into a detectible tumor.