EFFECTS OF EPIGENETICS ON DETOXIFICATION OF HORMONES. Jennifer Landa, MD ABAARM

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1 EFFECTS OF EPIGENETICS ON DETOXIFICATION OF HORMONES Jennifer Landa, MD ABAARM

2 OBJECTIVES Learn main metabolites of estrogens and how they relate to your patient s risk of breast and/or prostate cancer Be familiar with urinary testing of estrogen metabolites Know how to help patients improve their estrogen metabolism and reduce their risk of breast and/or prostate cancer Understand recent scientific literature on influence of genetics and environment on estrogen metabolism

3 DETOXIFICATION 101 Detoxification is the concept that xenobiotics (chemicals foreign to the biologic system) after consumption by the animal are transformed into nontoxic metabolites that can be excreted into urine or feces

4 TOXIC BURDEN INCREASING Toxic burden is ever increasing EPA estimates in 1994 over 2.2 billion lbs of toxic chemicals released into environment in the US alone For 2002, estimates were 4.7 billion lbs

5 DETOXIFICATION CONTINUED Detoxification is extremely complex and individualized Our understanding of detox is ever evolving Inability to detoxify has been proposed as the etiology in a vast array of disorders from cancer (asbestos) to neurologic dysfunction (PD) to puzzling entities such as chronic fatigue, multiple chemical sensitivity syndromes Pic from website of

6 BIOTRANSFORMATION Conversion of toxic into non-toxic Make more water-soluble compounds 2 major sites Liver Intestinal mucosal wall To a lesser extent in the tissues 2 phases Phase I uses oxygen to form a reactive site Phase II conjugation adds a water soluble group to the reactive site to assist in excretion

7 TWO PHASES OF DETOX

8 TOXINS Xenobiotics are initially lipophillic and cannot be excreted Xenobiotics in this category include: Metabolic end products Micro-organisms Contaminants/pollutants Insecticides/pesticides Food additives Drugs, alcohol Hormones and hormone disruptors

9 Where Do Toxins Come From? Lifestyle Toxins Nicotine Alcohol Caffeine Recreational drugs Prescription drugs Over-the-counter drugs Artificial food additives, colorings and preservatives Meats that contain hormones and antibiotics Refined foods and sugars Dietary choices (fast foods, fried foods)

10 Where Do Toxins Come From? Internal Toxins Bacterial, yeast, fungal overgrowth By-products of metabolic reactions (such as carbon dioxide, ammonia, hormones) Undigested food Stress Unresolved trauma or abuse (experienced as a child or as an adult) Unhappy relationships (with a relative, a spouse, a significant other, a boss, a co-worker, a neighbor, etc.)

11 TOXINS ARE EVERYWHERE AND WE ALL HAVE THEM 2009 EWG study of cord blood samples 232 toxic chemicals detected in newborn cord blood 2009 CDC 4 th report on human exposure to environmental chemicals Looked at blood, serum and urine of 2500 NHANES participants Showed widespread exposure to some industrial chemicals, including BPA and others

12 TOTAL TOXIC LOAD Toxic load or burden can determine how influential individuals toxins will be must look at the whole picture Xenobiotics (insecticides, herbicides, drugs, solvents, metals) Infections (strep, pseudomonas, parasites) Toxins (aflatoxin, ergot toxins) Biologic inhalants (mold, algae, pollen ) Physical phenomena (EMF, ionizing radiation) Lifestyle (drinking, smoking) Mechanical problems (nasal or intestinal obstruction) Hormonal imbalance Psychosocial factors (stress, coping skills, belief systems)

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14 Liver Detox Pathways

15 PHASE 1 DETOXIFICATION Reactions include: Oxidation Reduction Hydrolysis Hydration Dehalogenation Actions by mainly cytochrome p450 enzymes Main desired result = production of ROS *Intermediary metabolites

16 PHASE 1 DETOX CONTINUED Required nutrients for phase 1 Vit B2 (Riboflavin) Vit B3 (Niacin) Vit B6 (Pyridosine) Folic Acid Vitamin B12 Glutathione Branched-chain amino acids Flavonoids Phospholipids

17 ANTIOXIDANTS TO USE Need antioxidant protection from phase 1 ROS Vitamin A (carotenes) Vit C, Vit E Se, Cu, Zn, Mn Coq 10 Thiols (in garlic, onions, cruciferous veggies) Bioflavinoids Silymarin Pycnogenol

18 PHASE 2 DETOXIFICATION Conjugation pathways Actions are carried out by Conjugation Reactions are: Sulfation Glucuronidation GSH conjugation Acetylation Amino Acid conjugation Methylation

19 PHASE 2 DETOXIFICATION CONTINUED Nutrients used Glycine Taurine Glutamine N-acetylcysteine and Glutathione Cysteine Methionine Magnesium Vit B5, Vit B12 Folic Acid

20 PHASE 2 DETOX COMPLETED End result of detox Excretory derivatives are water soluble These water-soluble derivatives are released into: Bile --- Feces Serum --- Kidneys --- Urine

21 ROLE OF INTESTINE IN DETOX Intestines are the front line for xenobiotics -Barrier function Gut microflora can induce or inhibit detox Pathogens can produce toxins and increase toxic load Enterohepatic recirculation beta glucoronidase Detox enzymes are found in gut Toxic burden heavily influenced by gut health

22 SUPPORT FOR THE DETOXIFICATION SYSTEMS Remove foods and beverages that likely contain toxins/antigens Eliminate toxins in home and/or workplace Meet basic daily nutritional needs, adequate protein Supplement co-factors or other nutrients required in detox process Hydration Consider sauna or chelation when indicated to reduce toxic load

23 ESTROGEN METABOLISM Two major competing pathways 2-OH estrone 16-OH estrone One minor pathway 4-OH estrone

24 ESTROGEN METABOLISM After menopause, the metabolism of estrogen can change. Consequently, a woman may respond differently to estrogen replacement.

25 ESTROGEN METABOLISM

26 ESTRONE METABOLISM GST = glutathione s-transferase COMT = catechol o methyl transferase

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28 2-OH ESTRONE/METHYLATION Most favorable pathway Higher 2 OH estrone has been shown in multiple studies to be protective against breast cancer 2OHE1 converts to 2MeOHE1 via COMT (methylation) Methylated 2MeOHE1has a anti-proliferative effect on breast tissue Furhman, et al. J Natl Cancer Inst. Feb 2012.

29 4-OH ESTRONE Studies show it may directly damage DNA and cause mutations. Therefore, it is proposed to enhance cancer development. Equine estrogens, such as Premarin, increase metabolism into 4-OH estrones. Is present in greater quantities when there is a deficiency of methionine and folic acid People who have uterine fibroids also may have increased levels of 4-OH estrone. Cavalieri, et al. Biochim Biophys Acta Aug;1766(1): Review. Aberrant CYP1B1 activity leading to higher 4OHE1 levels shown in multiple cancers lung, breast, ovarian, renal cell carcinoma (White, et al. Circulation, 2012.)

30 2-OH ESTRONE (2-OHE1)/16A-OH ESTRONE (16-OHE1) Studies support assessment of 2:16 ratio and encouraging higher 2- OHE1 metabolism NYU study July 2014 In ER+ breast cancer, higher 2-OHE1 levels were associated with reduced risk of ER+ breast cancer in postmenopausal women Arslan, et al. Cancer Epidemiol Biomarkers Prev Jul;23(7) B-FIT (Breast and Bone FU to the Fx Intervention Trial) Higher 2OHE1/16OHE1 associated with lower breast cancer risk Dallal, et al. Carcinogensis Feb;35(2): Long Island Breast Cancer Study Project higher 2/16 ratio is associated with reduced breast cancer risk especially with invasive ca in premenopausal women Epidemiology Jan;17(1):80-8

31 16OH ESTRONE OUTSIDE OF BREAST CANCER Controversial estrogen metabolite Promotes pulmonary artery hypertension in mice and may play a role in human PAH (White, et al. Circulation, 2012.) Associated with lower blood pressure and is potent anti-oxidant and vasodilator via increased enos expression (Patel, et al. Nutrition, 2007) RA synovial cells produce more 16alpha OHE1 than OA synovial cells and the 16alpha OHE1 did not inhibit TNF alpha whereas all other E metabolites did so high 16OHE1 is a poor prognostic indicator in synovial inflammation (Schmidt, et al. Arthritis Rheum. Oct 2009)

32 2-OH ESTRONE (2-OHE1)/16A-OH ESTRONE (16- OHE1) AND PROSTATE CANCER Several recent observational trials show an association with 2:16 ratio and risk of prostate cancer Higher 2-OHE1: 16 alpha-ohe1 associated with protective effect against prostate cancer OR 0.53 when comparing highest tertile with third tertile (Barba, et al. J Exp Clin Cancer Res. Oct 2009) Similar findings in Muti, et al. Cancer Causes Control. Dec Need more studies to verify and expand findings

33 2 GOALS WITH ESTROGEN METABOLISM 1. Raise 2OH metabolism 2. Increase methylation of 2OH and 4OH

34 GOAL 1: HOW CAN YOU RAISE 2-OH ESTRONE? Moderate exercise Cruciferous vegetables Flax Soy Kudzu Broccoli derivatives: indole-3-carbinol taken as a supplement. Daily dose is 200 to 300 mg. Other derivatives of broccoli that have been shown to be effective are DIM (diindolymethane, a breakdown product of I-3-C) and sulforaphane glucosinolate High protein diet

35 GOAL 1: HOW CAN YOU RAISE 2-OH ESTRONE? (CONT.) Omega-3-fatty acids B6, B12, and folate MTHF TMG (Betaine) Rosemary, turmeric Weight loss Avoidance of EDC s

36 ENDOCRINE DISRUPTING CHEMICALS EDCs = Endocrine Disrupting Chemicals Bind to hormone receptors May have direct actions by binding or indirect via epigenetic mechanisms Examples BPA found in 92% of US Men and Women Rat studies show BPA affects methylation and increases prostate and breast cancer risk in rats

37 RAISE 2OH E1 BY AVOIDING BPA AND OTHER EDC S BPA (bisphenol A) = EDC Long term and cumulative exposure Interferes with hormones, acts as an estrogen Higher presence of BPA increases 4-OH metabolism vs. 2- OH metabolism Higher BPA levels increase risk of breast cancer Kim, EJ, et al. Sci Total Environ. Feb 2014.

38 BPA IS A REPRODUCTIVE TOXICANT FDA categorizes BPA as safe based mainly on 2 rat studies Well over 100 studies in 2013 and 2014 show human issues with BPA BPA and reproduction Aug 2014 review of all literature through 2013 BPA affects meiosis in animals and in vitro, reduces oocyte quality in women undergoing IVF, impaired endometrial proliferation and caused implantation failure in humans BPA may cause sexual dysfunction but needs further study Authors consider BPA an ovarian toxicant, a uterine toxicant and a reproductive toxicant Peretz, et al. Environ Health Perspect. Aug 2014

39 GOAL 2: SUPPORT METHYLATION SAMe Methionine B2, B6, B12 Folic acid (also as folinic acid, 5-formyl THF, or 5- methyltetrahydrofolate--mthf) TMG (betaine) Reducing catecholamine production by decreasing stress

40 EFFECT OF MTHFR MUTATIONS

41 MTHFR MUTATIONS 2 mutations in MTHFR gene associated with reduced enzyme activity - MTHFR C677T Heterozygotes reduced by 30-40% Homozygotes reduced by 60-70% -MTHFR A1298C Homozygotes reduced by 30-40% Consequences of mutations Elevated homocysteine Increased risk of breast cancer more predictive of B/L breast cancer and combined breast and ovarian ca than BRCA ½ Gershoni-Baruch, et al. European J Ca Dec;36(18):

42 DNA METHYLATION AND EPIGENETICS Epigenetics stable alteration in gene expression potential without any change in gene sequence Methylation DNA Methylation is one of the most commonly occurring epigenetic events taking place in the mammalian genome

43 EPIGENETICS AT WORK Methylation factors supplemented to pregnant mice with agouti trait led to normal offspring Wolff, et al. FASEB J Aug;12(11):949-57

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