Phase 1, 2 And 3 Estrogen Detoxification: Reducing Symptoms .

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Medical Disclaimer:The medical information in this lecture is provided as an information resource onlyand is not to be used or relied on for any diagnostic or treatment purposes. Thislecture contains general information about medical conditions and treatments. Theinformation is not advice and should not be treated as such. This information is notintended to be patient education, does not create any patient-physician relationship,and should not be used as a substitute for professional diagnosis and treatment.The medical information in this lecture is provided “as is” without any representations orwarranties, express or implied. Precision Analytical Inc. (DUTCH) or Dr. Carrie Jones makesno representations or warranties in relation to the medical information in this lecture.All rights reserved 2019 Precision Analytical Inc.

DUTCH Testing OptionsDUTCH CompleteAll rights reserved 2019 Precision Analytical Inc.DUTCH Plus

DUTCH Testing OptionsDUTCH Cycle MappingAll rights reserved 2019 Precision Analytical Inc.

D.U.T.C.H. Serum(blood) EstrogenEstrogen Estrogen (metabolism)Estrogen (methylation) Testosterone (total/free) Testosterone (available)Testosterone (metabolism) DHEA or DHEA-S DHEADHEA (metabolites) ProgesteroneProgesteroneCortisol/cortisone (free pattern) Cortisol/cortisone (metabolism) Cortisol (total, no diurnal pattern)Cortisol Awakening Response (CAR)B6, B12, Glutathione deficiency Neurotransmitter balanceOxidative stress Melatonin (production) Cycle Mapping – all monthAll rights reserved 2019 Precision Analytical Inc.SalivaEstrogenTestosterone (available)DHEA or DHEA-SProgesteroneCortisol (free pattern)Cortisol (CAR)MelatoninMonth long estrogen/progesterone

Dried urinein theliteratureAll rights reserved 2019 Precision Analytical Inc.

Which Estrogen Detox We’ll Discuss:1.Through the liver Phase 1 detoxification via hydroxylation to 2, 4 and 16-OH Phase 2 detoxification via methylation and COMT Phase 2.5 detoxification via transporters to the kidney/bile2.Through Phase 3 in the GI Tract (glucuronidation) Looking at Beta-glucuronidaseAll rights reserved 2019 Precision Analytical Inc.

Let’s Start With the Liver:Phase 1 and Phase 2 DetoxificationAll rights reserved 2019 Precision Analytical Inc.

Why is Estrogen Metabolism Important?12UnderstandUnderstand/try to reducecancer riskestrogen dominancein men and womenAll rights reserved 2019 Precision Analytical Inc.

Dr. Jones’ Estrogen Metabolism ExpandedEstrone (E1)17bHSDEstradiol hione QuinoneEstriol (E3)GSTCYP1B1QuinoneReductaseQuinone formDepurinating adductson e adductAll rights reserved 2019 Precision Analytical Inc.2MethoxyE1IncreasedMutationCancer risk

A Little About Each Metabolite:The phase-1 estrogen metabolites are considered free radicals in theirsemi-quinone or quinone states2-OH (Phase-1) CYP activity primarily in the liver, small amountextra-hepatically Considered the “less carcinogenic” metabolitebecause it binds to estrogen receptors with lessaffinity/not as tightly Forms ‘stable’ adducts with DNA Weak carcinogenic activity – can form semi-Q andQuinones but stableAll rights reserved 2019 Precision Analytical Inc.

A Little About Each Metabolite:The phase-1 estrogen metabolites are considered free radicals in theirsemi-quinone or quinone states2-methoxy (Phase-2) Methylated via COMT Considered anti-proliferative through microtubledisruption, apoptosis induction and angiogenesisinhibition Considered to have anti-aromatase activity Not thought to bind to the estrogen receptor(much) Weak carcinogenic activity – can form semi-Q and2-OH (Phase-1) CYP activity primarily in the liver, small amountextra-hepatically Considered the “less carcinogenic” metabolitebecause it binds to estrogen receptors with lessaffinity/not as tightly Forms ‘stable’ adducts with DNAQuinones but stableAll rights reserved 2019 Precision Analytical Inc.

Citations: Hersey RM, Lloyd T, MacLusky NJ, Weisz J. The catechol estrogen, 2-hydroxyestradiol17 alpha, is formed from estradiol-17 alpha by hypothalamic tissue in vitro and inhibitstyrosine hydroxylase. Endocrinology. 1982; 111(5):1734-6. [pubmed] Lakhani NJ, Sarkar MA, Venitz J, Figg WD. 2-Methoxyestradiol, a promising anticanceragent. Pharmacotherapy. 2003; 23(2):165-72. [pubmed] Purohit A, Singh A, Ghilchik MW, Reed MJ. Inhibition of tumor necrosis factor alphastimulated aromatase activity by microtubule-stabilizing agents, paclitaxel and 2methoxyestradiol. Biochemical and biophysical research communications. 1999;261(1):214-7. [pubmed]All rights reserved 2019 Precision Analytical Inc.

A Little About Each Metabolite:The phase-1 estrogen metabolites are considered free radicals in theirsemi-quinone or quinone states4-OH (Phase-1) CYP activity primarily in the breast, ovary, uterus, lung and kidney, minorlyin the liver Much more carcinogenic because they form ‘unstable’ or ‘depurinating’adducts Binds to the estrogen receptor with higher and tighter affinity than 2-OH E2 can increase CYP1B1 higher 4-OHTsuchiya Y, Nakajima M, Kyo S, Kanaya T, Inoue M, Yokoi T. Human CYP1B1 is regulated by estradiol via estrogen receptor. Cancer research. 2004; 64(9):3119-25. [pubmed]All rights reserved 2019 Precision Analytical Inc.

How MightEstrogenMetabolites“Cause”Breast Cancer?Cavalieri EL, Rogan EG. Depurinating estrogen-DNA adducts, generators of cancer initiation: their minimization leads to cancer prevention. Clinical andtranslational medicine. 2016; 5(1):12. [pubmed]All rights reserved 2019 Precision Analytical Inc.

Stable adducts remain in DNA unlessremoved by repair –much more ideal, no holes, less risk mutationAll rights reserved 2019 Precision Analytical Inc.

Depurinating (unstable) adducts break off from theDNA leaving a DNA with apurinic sites primarilyat the N3 and N7 of Adenine and N7 of Guanine.Poor repair of these sites can causemutations that lead to cancer.All rights reserved 2019 Precision Analytical Inc.

Breast Cancer,Estrogen-DNA AdductsCavalieri E and Rogan E. Depurinating estrogen–DNA adducts in the etiology and prevention of breast and other human cancers. Future Oncol. 2015;6(1):75-91.All rights reserved 2019 Precision Analytical Inc.

Detox Analogy: Picture a claw foot tubPhase 1 is the water filling up the tub Is the right type of water filling up the tub? How fast or slow is it filling up?Phase 2 is the drain How open or closed is the drain? Is it open wide enough?Phase 3 is the sewer line out Is this dysfunctional causing backup?All rights reserved 2019 Precision Analytical Inc.

Estrogen DetoxificationLearn it as phase 1 2 (2.5) 3Address it as phase 3 (2.5) 2 1All rights reserved 2019 Precision Analytical Inc.

How Do You EvaluatePhases 1 and 2All rights reserved 2019 Precision Analytical Inc.

Phase 1 Detoxification of EstrogenAll rights reserved 2019 Precision Analytical Inc.

What Affects Your CYP1 Family? Iron – CYP are heme dependent Environmental toxicants – PAHs, PCBs, xenoestrogens(phthalates, BPA) Smoking Charred meats (BBQ) Grapefruit juiceAll rights reserved 2019 Precision Analytical Inc.

Before and After DIM (Phase 1)Protective PathwayProtective PathwayAll rights reserved 2019 Precision Analytical Inc.Much better!

Phase 1: Estrogen Optimization Strategies:DIM/I3CDi-indole-methane or Indole-3-CarbinolAll rights reserved 2019 Precision Analytical Inc.

DIM/I3C Phase 1 Metabolism Primarily I3C needs stomach acid to then convert into 15 compounds, of which themost predominant is DIM 10-60% of I3C converts to DIM DIM: An acid catalyzed dimer of I3C DIM increases in brassica family if the food is chopped or mildly heated Out of the body within about 24hrs DIM increases the conversion of E1/E2 into 2-OH-E1 via CYP1A DIM binds to aryl hydrocarbon receptor (AhR) Nrf2 Dosage in research: 100-300mg/dayThomson CA, Ho E, Strom MB. Chemopreventive properties of 3,3'-diindolylmethane in breast cancer: evidence from experimental and human studies. Nutrition reviews. 2016; 74(7):432-43.]All rights reserved 2019 Precision Analytical Inc.

Please Keep in Mind 1.2.3.4.5.2-OH is not healthy per se – just ‘less carcinogenic’2-OH can still form adductsThe goal is to make 2-methoxy quicklyRemember treatment is 3 2 1 don’t put everyone on DIMCYP1A1 is not only for estrogen – be aware if you upregulate it.All rights reserved 2019 Precision Analytical Inc.

Can’t I just Eat the Brassica Family Foods?“On average, 100 g of cruciferous vegetablescontains up to 30 mg of glucobrassicin,which is estimated to convert to approximately 2 mg of DIM.However, the variation in DIM content between differentcruciferous vegetables is considerable, with differences rangingfrom 5- to 8-fold. To achieve a biologically relevant exposure,it is suggested that intake would need to be upwards of 600 g/dand sustained for several years to achieve an anticancer benefit.An intake this high is difficult to attainor maintain through diet alone.”Thomson CA, Ho E, Strom MB. Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies.Nutrition Reviews. 2016;74(7):432-443. doi:10.1093/nutrit/nuw010.All rights reserved 2019 Precision Analytical Inc.

600g/day 2.5 cups/dayAll rights reserved 2019 Precision Analytical Inc.

Lower Risk/Reduce Symptoms: NAC Phase 1(ish) and 2 Metabolism N-Acetyl-Cysteine Prevent damage to DNA by inhibiting formation of catechol quinones and/orreacting with themo Can also reduce the E2-3,4semiquinone back into 4-OH-E2o NAC inhibited adduct formation by 60% or more by reacting with quinoneitself in in vitro studies Hydrolysis of NAC in the liver and gut cysteine to make glutathioneAll rights reserved 2019 Precision Analytical Inc.

NAC SupplementationLowers DNA AdductsNo NACLots of NAChttp://www.academia.edu/8408986/Inhibition of Depurinating Estrogen DNA Adduct Formation by Natural CompoundsAll rights reserved 2019 Precision Analytical Inc.

Lower Risk/Reduce Symptoms:Suforaphane/Glucoraphanin Phase 1(ish), 2 and 3 Metabolism Compound in isothiocyanate group from cruciferous veggies Made when the enzyme Myrosinase is released from chopping/chewing andcombines with Glucoraphanin Sulforaphane Broccoli sprouts have highest concentration as do cauliflower and mustard sprouts Once absorbed, reacts with glutathione via GST Activates the Nrf2/ARE pathways to induce phase II enzymes Helps phase 3 detox see slides Activates Quinone reductase to convert quinones back to catechol estrogens (2and 4-OH)All rights reserved 2019 Precision Analytical Inc.

Lower Risk/Reduce Symptoms: Resveratrol Phase 1(ish), 2 and 3 Metabolism In grapes, peanuts, wine: Cabernet Franc wine supposed to be best wine toraise Quinone reductase but it’s still alcohol. Reduces estrogen semi-quinones back into catechol estrogens and inducesQuinone Reductase Non-competitive inhibitor of CYP1B1 (to prevent E1/E2 4-OH-E1) It reduces E2-3,4-semiquinone back into 4-OH-E2 instead Induces Nrf2 Not very bioavailable, unfortunately, so much study is done invitro as levels aren’t highenough in humans to make much impact with supplementation or dietAll rights reserved 2019 Precision Analytical Inc.

Sulforaphane/Resveratrol & Nrf2Requires a lotAll rights reserved 2019 Precision Analytical Inc.

Citations:1.Anand David AV, Arulmoli R, and Parasuraman S. Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid. PharmacognRev. 2016 Jul-Dec;10(20):84-89. 62/#!po 10.41672. Cavalieri E and Rogan E. The Molecular Etiology and Prevention of Estrogen-Initiated Cancers. Mol Aspects Med. 2014 Apr; 0: d-glucarate/3. Examine.com. Calcium d-Glucarate. Retrieved on July 7, 2017 from4. Hwang ES and Jeffery EH. Induction of quinone reductase by sulforaphane and sulforaphane N-acetylcysteine conjugate in murinehepatoma cells. J Med Food. 2005 Summer;8(2):198-203.5. Linus Pauling Institute, Oregon State University. (2017). Resveratrol. Retrieved on January 26, 2017 /phytochemicals/resveratrol6. Marques M, Laflamme L and Gaudreau L. Low levels of 3,3′-diindolylmethane activate estrogen receptor α and induce proliferation ofbreast cancer cells in the absence of estradiol. BMJ. 2014;14:524-534. 25/pdf/14712407-14-524.pdf7. Montano MM, Chaplin LJ, Deng H, Mesia-Vela S, Gaikwad N, Zahid M, and Rogan E. Protective roles of quinone reductase and tamoxifenagainst estrogen-induced mammary tumorigenesis. Oncogene (2007) 26, 3587–3590.8. Parvaresh A, Razavi R, Rafie N, Ghiasvand R, Pourmasoumi M, Miraghajani M. Quercetin and ovarian cancer: An evaluation based on asystematic review. J Res Med Sci. 2016 May 9;21:34. 22/9. Tarozzi A, Angeloni C, Malaguti M, Morroni F, Hrelia S, and Hrelia P. Suforaphane as a potential protective phytochemical againstneurodegenerative diseases. Oxidative Medicine and Cellular Longevity. 13/415078/abs/10. Uda Y, Price KR, Williamson G, Rhodes MJ. Induction of the anticarcinogenic marker enzyme, quinone reductase, in murine hepatomacells in vitro by flavonoids. Cancer Lett. 1997 Dec 9;120(2):213-6.11. Yang J and Liu RH. Induction of phase II enzyme, quinone reductase, in murine hepatoma cells in vitro by grape extracts and selectedphytochemicals. Food Chemistry. 2009;114(3):898-904.All rights reserved 2019 Precision Analytical Inc.

Phase 2 Detoxification of EstrogenAll rights reserved 2019 Precision Analytical Inc.

Estrogen Dominant Symptoms(Male or Female) Phase-2 – Why?3-4-fold decreasedCOMT activityAll rights reserved 2019 Precision Analytical Inc.

With permission: Dr. Ben Lynch/StrateGene: www.drbenlynch.comAll rights reserved 2019 Precision Analytical Inc.

Phase-2 Detox RequiresCOMT and Methyl DonorsExamples: Magnesium SAMe Tri-methyl-glycine Methionine Choline Methylated B vitamins ZincAll rights reserved 2019 Precision Analytical Inc.

What Slows Down/Affects COMT? COMT mutation ( / ) Being estrogen dominant Even elevated estrogencatechols Gut infections Phenols from gut bacteria Certain Phenols fromfoods/supplements Green tea, quercetinAll rights reserved 2019 Precision Analytical Inc. High levels of SAH (blocksmethyltransferases) Consider Sam/SAH ratio Bisphenol and PCB exposure Serotonin can competitivelyblock SAM receptors in COMT COMT inhibitors Medications Really anything that affectsthe methionine cycle

Citations: Cavalieri EL, Rogan EG. Is bisphenol A a weak carcinogen like the natural estrogens anddiethylstilbestrol? IUBMB life. 2010; 62(10):746-51. [pubmed] Tsao D, Wieskopf JS, Rashid N, et al. Serotonin-induced hypersensitivity via inhibition of catecholO-methyltransferase activity. Molecular pain. 2012; 8:25. [pubmed] van Duursen MB, Sanderson JT, de Jong PC, Kraaij M, van den Berg M. Phytochemicals inhibitcatechol-O-methyltransferase activity in cytosolic fractions from healthy human mammary tissues:implications for catechol estrogen-induced DNA damage. Toxicological sciences : an official journalof the Society of Toxicology. 2004; 81(2):316-24. [pubmed] Wang P, Heber D, Henning SM. Quercetin increased bioavailability and decreased methylation ofgreen tea polyphenols in vitro and in vivo. Food & function. 2012; 3(6):635-42. [pubmed]All rights reserved 2019 Precision Analytical Inc.

Why is Phase 2 Detox Important?It makes the phase 1 metabolites(that are harmful reactive oxygen species – ROS)water soluble to be excretedAll rights reserved 2019 Precision Analytical Inc.

Phase 2.5 and 3Detoxification of EstrogenAll rights reserved 2019 Precision Analytical Inc.

What the Heck is 2.5 Detox? Once estrogen metabolites are water-soluble, they have to getOUT of the cell and excreted. Cell membranes are lipophilic The phase 2 estrogen metabolites are hydrophilic This is a problemAll rights reserved 2019 Precision Analytical Inc.

Enter: The Transporter Phase 3 transporters known as: ATP-binding cassette (ABC) Main one is P-glycoprotein (multidrug resistant protein 1) They move many things out of the cell: Drugs/medications Chemicals/toxicants Hormones etc. Once out of the cell into the interstitial fluid – they move into thekidney/urine and bile/intestines There are lots of transporters at the BBB tooAll rights reserved 2019 Precision Analytical Inc.

What Slows Down Your Transporters? Inflammation Any and all inflammation (length of time might matter) Oxidative stress Being overburdened with toxicity Specific medications like azithromycin, clarithromycin, protonpump inhibitors (ie. Omeprazole) Supplements: QuercetinAll rights reserved 2019 Precision Analytical Inc.

What Supports Your Transporters? Doing everything to reduce inflammation, oxidative stressand toxicity Nrf2 activators: atechins in chocolateDIMNot quercetinand green tea Cell membrane support: Choline Healthy fats and oils (support bile)All rights reserved 2019 Precision Analytical Inc.

Citations: Iqbal M, Ho Hl, Petropoulos S, Moisiadis VG, Gibb W and Matthews S. Pro-Inflammatory CytokineRegulation of P-glycoprotein in the Developing Blood-Brain Barrier. PLoS One. 2012;7(8):e 43022. Limtrakul P, Khantamat O and Pintha K. Inhibition of P-glycoprotein function and expression bykaempferol and quercetin. J Chemother. 2005;17(1):86-95. Lin JH and Yamazaki M. Role of P-glycoprotein in pharmacokinetics: clinical implications. ClinPharmacokinet. 2003;42(1):59-98. Roberts DJ and Goralski KB. A critical overview of the influence of inflammation and infection on Pglycoprotein expression and activity in the brain. Expert Opin Drug Metab Toxicol. 2008;4(10):12451264. Jeddi F, Soozanger N, Sadeghi MR, Somi MH, et al. Nrf2 overexpression is associated with Pglycoprotein upregulation in gastric cancer. Biomedicine Pharmacotherapy. 2018;97:286-292. Jing W, Safapour Y, Zhang T, Guo P, et al. Berberine Upregulates P-Glycoprotein in Human Caco-2Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-DependentMechanisms. J Pharmacol Exp Ther. 2018;366(2):332-340. Sadeghi MR, Jeddi F, Soozangar N, Somi MH, et al. Nrf2/P-glycoprotein axis is associated withclinicopathological characteristics in colorectal cancer. Biomed Pharmacother. 2018;104:458-464.All rights reserved 2019 Precision Analytical Inc.

The Estrobolome! “ the aggregate of enteric bacterial genes whose productsare capable of metabolizing estrogens” “By modulating the enterohepatic circulation of estrogens,the estrobolome affects both the excretion and circulation ofestrogens. In turn, the composition of the estrobolome canbe shaped by factors such as antibiotics, other drugs, anddiet that modulate its functional activity.”Plottel SC, Blaser MJ. Microbiome and malignancy. Cell Host Microbe. 2011;10(4):324-335All rights reserved 2019 Precision Analytical Inc.

“Studies of injected radioactively labeled estradiol, estrone, and estriol in womenindicate that approximately 65% of injected estradiol, 48% of injected estrone, and23% of injected estriol are recovered in bile. As approximately 10% to 15% ofinjected radiolabeled estradiol, estrone, and estriol are found in conjugated form infeces, a biologically significant proportion of estrogens are reabsorbed in thecirculation. Hepatically conjugated estrogens excreted in the bile can bedeconjugated by bacterial species with ß-glucuronidase activity in the gut, leadingto their reabsorption into the circulation.”Maryann Kwa, Claudia S. Plottel, Martin J. Blaser, Sylvia Adams; The Intestinal Microbiome and Estrogen Receptor–Positive Female Breast Cancer. J Natl CancerInst 2016; 108 (8): djw029. doi: 10.1093/jnci/djw029All rights reserved 2019 Precision Analytical Inc.

What Does Beta-GlucuronidaseDo to Estrogen? It is an enzyme in colonocytes It ‘deconjugates’ thingsEstrogen Analogy: The body puts estrogen in a box and ties it up with a bow to be excretedin the stool (glucuronidation). Beta-glucuronidase unties the bow and opens the lid allowing estrogen toescape and get reabsorbedAll rights reserved 2019 Precision Analytical Inc.

The gut microbiota regulates estrogens through secretion of β-glucuronidase, an enzyme thatdeconjugates estrogens into their active forms.The alteration in circulating estrogens may contribute to the development of conditionsdiscussed herein: obesity, metabolic syndrome, cancer, endometrial hyperplasia, endometriosis,polycystic ovary syndrome, fertility, cardiovascular disease (CVD) and cognitive function.All rights reserved 2019 Precision Analytical Inc.

1. Focus on Diet” it is now understood that diet plays a significantit is now understood that diet plays a significant role in shaping the microbiome, withrole in shaping the microbiome, with experimentsexperiments showing that dietary alterations can induce large, temporary microbialshowing that dietaryshiftsalterationswithin 24 h. can induce large,temporary microbial shifts within 24 h.”All rights reserved 2019 Precision Analytical Inc.

What IncreasesBeta-Glucuronidase? Low consumption of:o Fruits and vegetableso Fiber High consumption of:o Sugaro Processed foodso ‘Standard American Diet’o Alcoholo Toxicantso AntibioticsAll rights reserved 2019 Precision Analytical Inc.

2. Reduce Antibiotics and ToxicantExposure“ use of antibiotics reduces the capacity of intestinalmicroflora to metabolize phytochemicals intocompounds that may protect against cancer.However, antibiotic use also disruptsthe intestinal microfloral metabolism of estrogens.”All rights reserved 2019 Precision Analytical Inc.

3. Eliminate or Reduce Alcohol:Increasing Estrogen Key TJ, Appleby PN, Reeves GK, et al. for the Endogenous Hormones and Breast CancerCollaborative Group. Circulating sex hormones and breast cancer risk factors in postmenopausalwomen: reanalysis of 13 studies. Br J Cancer. 105(5):709-22, 2011. Hamajima N, Hirose K, Tajima K, et al. for the Collaborative Group on Hormonal Factors in BreastCancer. Alcohol, tobacco and breast cancer—collaborative reanalysis of individual data from 53epidemiological studies, including 58,515 women with breast cancer and 95,067 women without thedisease. Br J Cancer. 87(11):1234-45, 2002 Erol A, Ho AM, Winham SJ, Karpyak VM. Sex hormones in alcohol consumption: a systematic reviewof evidence. 2017. Addict Biol. Dec 27. doi: 10.1111/adb.12589. [Epub ahead of print] Kolak A, Kaminska M, Sygit K, Budny A, Surdyka D, Kukielka-Budny B, Burdan F. Primary andsecondary prevention of breast cancer. Annals of Agriculture and Environmental Medicine.2017;24(4):549-553.All rights reserved 2019 Precision Analytical Inc.

“A subgroup of alcoholics have an altered colonic microbiome (dysbiosis).The alcoholics with dysbiosis had lower median abundances ofBacteroidetes and higher ones of Proteobacteria.The observed alterations appear to correlate with high levels of serum endotoxin in a subset of the samples.Network topology analysis indicated that alcohol use is correlated with decreased connectivity of the microbialnetwork, and this alteration is seen even after an extended period of sobriety.”All rights reserved 2019 Precision Analytical Inc.

4. Prebiotics and Resistant StarchJ Transl Med. 2017; 15: 73. Published online 2017 Apr 8. doi: 10.1186/s12967-017-1175-yExamples: Artichoke, dandelion greens, jicama, chicory root etc Partially hydrolyzed guar gum PectinAll rights reserved 2019 Precision Analytical Inc.

Citations: Ghaffarzadegan T, Marungruang N, Fåk F, Nyman M. Molecular Properties of Guar Gumand Pectin Modify Cecal Bile Acids, Microbiota, and Plasma Lipopolysaccharide-BindingProtein in Rats. PloS one. 2016; 11(6):e0157427. [pubmed] Niv E, Halak A, Tiommny E, et al. Randomized clinical study: Partially hydrolyzed guargum (PHGG) versus placebo in the treatment of patients with irritable bowel syndrome.Nutrition & metabolism. 2016; 13:10. [pubmed] Vandeputte D, Falony G, Vieira-Silva S, et al. Prebiotic inulin-type fructans induce specificchanges in the human gut microbiota. Gut. 2017; 66(11):1968-1974. [pubmed] Yang X, Darko KO, Huang Y, et al. Resistant Starch Regulates Gut Microbiota: Structure,Biochemistry and Cell Signalling. Cellular physiology and biochemistry : internationaljournal of experimental cellular physiology, biochemistry, and pharmacology. 2017;42(1):306-318. [pubmed]All rights reserved 2019 Precision Analytical Inc.

4. Probiotics and Fermented Foods*Studies evaluated looked at fermented foods and taking probioticsJ Transl Med. 2017; 15: 73. Published online 2017 Apr 8. doi: 10.1186/s12967-017-1175-yAll rights reserved 2019 Precision Analytical Inc.

5. Supplement: Calcium-d-Glucarate CDG b-glucuronidase inhibitor Also known as: Calcium glucarate, Saccharic acid, Calcium-D-Saccharate, Glucaric acid Do not confuse it with: Calcium, Glutamine or SaccharinAll rights reserved 2019 Precision Analytical Inc.

5. Supplement: Calcium-d-Glucarate MOA: Keeps the glucuronide group on the hydrophobic molecule for excretion (urine/GI) It does NOT lower b-glucuronidase levels in the gut Dosing is VERY high: 1500-3000mg/day at a minimum (in animal studies, they were on much higherdoses based on mg/kg of body weight) However, it appears that every bit helps (ie. 500mg is still helpful) Foods high in CDG (but not anywhere near therapeutic doses): oranges, carrots, apples, grapefruit,and cruciferous vegetablesAll rights reserved 2019 Precision Analytical IncAll rights reserved 2019 Precision Analytical Inc.

Let’s Summarize:1. Learn it as Phase 1 2 3 but address it as 3 2 12. The creation of unstable adducts is a real problem3. If you don’t test estrogen metabolism through DUTCH testing and GItesting, you won’t know where the problem lies4. Look to the COMT, QR, and GST gene to help with proper excretion5. Don’t forget about your transporters!6.7.8.9.(Eat dark chocolate)Unhealthy bile and an unbalanced microbiome will raise hormone levelsDo stool and/or a SIBO test for further evaluationYou are what you eat/absorb eat for the liver and your microbiomeIf you have to drink alcohol, drink Cabernet Franc (apparently)All rights reserved 2019 Precision Analytical Inc.

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Dr. Jones' Estrogen Metabolism Expanded Estrone (E1) Estradiol (E2) 16OHE1 Estriol (E3) 4OHE1 2OHE1 4MethoxyE1 COMT Quinone form Depurinating adducts on DNA Increased Mutation Cancer risk GST Quinone Reductase COMT 2MethoxyE1 CYP3A4 17bHSD 17bHSD CYP1B1 CYP1A1 Glutathione Quinone Excreted Excreted Excreted CYP3A4 Stable adduct