02 - Nutrigenomics Detox (2).pdf

Naturopathic Nutrition Year 2 Detoxification and Nutrigenomics 1 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  Learning Outcomes In this lecture, you will learn about: Nutrigenomic...

Naturopathic Nutrition Year 2 Detoxification and Nutrigenomics 1 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  Learning Outcomes In this lecture, you will learn about: Nutrigenomics. Methylation. Toxins Liver detoxification: Phase I, II, III. Oestrogen metabolism. Optimising elimination. Detoxification in clinical practice. 2 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  Nutrigenomics Nutrigenomics = the study of the interaction of nutrition and genes, especially with regard to the prevention or treatment of disease. As a nutritional therapist you can test for key inherited genetic differences that affect how well certain aspects of physiology work. Testing involves a swab from inside the cheek ― often in an ‘at-home kit’. nutri meaning nutrition. This can be used to formulate genomics = study of genes. personalised nutrition and lifestyle gene from Greek genea ‘generation’ ― sequence of plans to optimise health. DNA coding for a protein. 3 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  gene from Greek genea Nutrigenomics ‘generation’ ― a sequence of DNA coding for a protein What we have learnt about genetics so far ― why include in clinic? Year: Identified: Genetics today can answer key clinical questions such as: 1933 DNA found in chromosomes. Why can someone be deficient 1941 Genes code for proteins found. in vitamin A despite eating a Discovery of double helix diet rich in beta-carotene? 1953 structure of DNA. Why might someone be suffering Development of how to map from oestrogen dominance? 1980 the structure DNA. Why might someone’s liver 1990 to detoxification pathways be Human Genome Project. 2003 impaired? And more… 4 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  pheno- from Greek for Nutrigenomics 'showing’ — referring to physical expression. To understand nutrigenomics, review these definitions: Gene ― made up of DNA, our physical unit of heredity. allele from Greek allel ― Trait ― an inherited characteristic such as shyness. ’one another’ Allele ― a variant form of a gene responsible for the variation in which a trait can be expressed, e.g., eye colour. Phenotype ― how genetic and environmental influences come together to create physical appearance and behaviour. Genomics ― the study of genes. Determines how they interact and influence biological pathways, networks, and physiology. (Jones, 2010) 5 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  Nutrigenomics A, T, C, G = all amino acids Every cell nucleus contains 23 pairs Nucleotide chain of chromosomes, made up of DNA. DNA contains our genetic 1 Nucleotide information and is made of two paired ‘nucleotide’ chains (the ‘double helix’). Each nucleotide contains a deoxyribose (sugar), a phosphate group, and one of four bases ― A (adenine), C (cytosine), T (thymine) or a G (guanine). DNA is ‘transcribed ‘into RNA which is translated into a protein from amino acids. This process determines property, function and shape of the resulting protein. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 6  U = ‘uracil’ ― the amino Nutrigenomics acid found in RNA (replacing thymine) Nucleotides are organised into codons – a sequence of 3 nucleotides that ’code for’ a specific amino acid. Codons make up ’genes’, which relate to specific functions. The codon ‘AUG’ codes for the amino acid methionine. However, if translation is not coded correctly (e.g., to ‘AUC’) because of an inherited alteration (next slide) in the DNA sequence, isoleucine is produced instead. This is relevant as methionine is required for methylation, which is needed for switching genes on and off. Low methionine increases the risk of cancerous cell changes. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 7  polymorphism = Nutrigenomics variation of a particular DNA sequence. Pronounced ‘snips’ Single nucleotide polymorphisms (SNPs): Differences in single bases in the sequence of a gene (a genetic variation in humans). SNPs are a normal occurrence (roughly 4–5 million SNPs in one person’s genome). Many SNPs have very little effect. Some however, can change enzyme or protein function leading to differences in phenotype. Key: Example: A SNP on genes for oestrogen metabolism can result SNP in oestrogen dominance and increase the risk of breast cancer. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 8  Nutrigenomics SNPs (cont.): Each gene is identified by an rs (‘reference SNP’) number. e.g., rs1801133 is the MTHFR gene. Each SNP is further classified, by base change and position along from start of the gene e.g., rs1801133 C677T. C represents cytosine, changed to T (thymine) ― potentially changing the resulting amino acid and insufficient conversion of folate into methylfolate. Variants can be described as ‘wild type’ — usually ‘normal / stable’, ‘heterozygous’ — 1 chromosomal variant, usually indicating some potential change of function, or ‘homozygous’ — variants in both chromosomes, with greater change of function. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 9  Nutrigenomics SNP clinical example ― vitamin C: How might a vitamin C The ‘SLC23A1’ gene codes for the production deficiency of a transporter which supports vitamin C present in absorption and distribution in the body. clinic? A SNP of this gene is, therefore, associated with a higher demand for vitamin C. The recommendation would be to optimise dietary intake (e.g., with fresh raw fruit and vegetables, esp. peppers, kiwi fruit, papaya, currants, berries, citrus, tomatoes, crucifers) and consider supplementation. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 10  Nutrigenomics Areas where genetic information is especially useful for clinic: Methylation (e.g., production of glutathione and homocysteine regulation). Detoxification (each phase and the genes involved. e.g., caffeine / alcohol detoxification). Neurotransmitter / hormone synthesis and metabolism (e.g., in relation to conditions of oestrogen excess). Vitamin conversion / receptor function (e.g., vitamin D conversion effect on bone density risk, vitamin A (e.g., reduced conversion of beta-carotene to vitamin A). © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 11  Nutrigenomics Nutrigenomics in clinic: There are many DNA tests available. Your client may even come to you with their results. e.g., LifeCode Gx, Nordic DNA Life, My DNA Health. Consider the ethics of genetic testing. Remember — genes only tell us potential for physiological difference. Always establish their significance if expressed, resulting in any impact. SNPs are not deterministic. 12 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  Nutrigenomics Nutrigenomics in clinic (cont.): Genetic testing does not replace the case history, considering the whole person, symptoms and concerns, and the way the system functions collectively. The body is highly intelligent, designed to keep you alive, no matter how many SNPs you may have! Other testing may be required to also build a clinical picture. Never treat by SNP or look at SNPs in isolation. Yet, genetic information used properly can be empowering in terms of understanding potential strengths and weaknesses. The solutions will always be lifestyle or dietary support to enable the person to reach their potential. 13 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  Common SNPs Nutrients (vitamin A): Gene: BCO1 gene (beta-carotene oxygenase 1) ― codes for the enzyme that converts beta-carotene to retinol. SNPs: Many SNPs affect its activity: ‒ BCO1 A379V TT alleles (= 32% reduction in enzyme activity). ‒ BCO1 R267S AT or TT plus BCO1 A379V CT or TT variant alleles (= 69% lower beta-carotene conversion). Vitamin A deficiency symptoms: Impaired night vision, frequent infections, skin conditions (e.g., acne). SNP recommendations: Increase preformed vitamin A from food (e.g., liver, fish oils) or supplements, especially if plant-based. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 14  Common SNPs Nutrients (vitamin D): Gene: VDR gene ― codes for the vitamin D receptor. SNPs: At rs1544410, the A allele is associated with reduced bone density while the G allele is associated with a decreased risk of osteoporosis. Vitamin D deficiency symptoms: Rickets and osteomalacia, osteoporosis, immune dysfunction (↑ infections, autoimmunity, allergies, asthma). Recommendations: Ensure optimal vitamin D levels with regular testing, sun exposure, food sources (e.g., mushrooms, oily fish, eggs) and supplementation. 15 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  Common SNPs Nutrients (essential fatty acids): Genes: Fatty acid desaturases are involved in EFA conversion. FADS 1 codes for Delta 5 Desaturase and FADS2 Delta 6 Desaturase. There are complex relationships between SNPs and type of fat consumed. FADS1 rs174537 GG genotype may increase conversion of high dietary omega-6 to inflammatory AA, more so in African Americans. FADS2 rs174570 T allele is associated with lower GLA, AA, and EPA levels. Consider EPA / DHA / ALA from fish oils / algae / flaxseed oils. 16 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  TNF = tumour Common SNPs necrosis factor (TNF) Other types of SNPs ― inflammation: Gene example: The TNF gene codes for the production of the pro-inflammatory cytokine (protein). SNP: At rs1800629 the A allele is associated with ↑ TNF and is associated with an ↑ risk of asthma, RA, psoriasis and cancer. Recommendations: ‒ Extra focus on ↓ pro-inflammatory foods (e.g., sugar, dairy, fried foods, high omega-6 foods), processed meats, alcohol. ‒ Increase anti-inflammatory foods / herbs ― turmeric, catechins (green tea), echinacea, omega-3 rich foods (‘SMASH’, flax). 17 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  Case Example Jane, 19-year-old female. Full time (stressful). Smoker. Presents with: Fatigue, irritability, recurrent infections. Food intake: Eats 95% plant-based, with eggs once a week. Cereals (e.g. Rice Krispies with milk) or toast with marmite. Leftover dinners for lunch or skips lunch. Pasta or curry with veg., Chinese takeaways. Beverages: 4 cups of coffee per day to keep her going. 25 units of alcohol most weekends. Observation: Pale skin and conjunctiva. Blood tests: Low ferritin, haemoglobin and vitamin D (16 nmol / L). Additional: Applies high-factor sun cream heavily in the summer. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 18  Case Example Nutrigenomics testing ― Jane: Revealed: SNPs on her vitamin D receptor and vitamin C transporter (‘SLC23A1’ gene). Subsequent recommendations: – Increase vitamin C and D-rich foods due to the SNP implications. – Supplementation of vitamin D3 and possibly C is needed. – Reduce alcohol and stop smoking (25 mg of vitamin C is lost with every cigarette smoked) and focus on stress management (stress increases vitamin C release into the blood). – Consider that the vitamin C SNP could also impair iron absorption (reducing conversion from the Fe3+ to Fe2+ state). © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 19  methyl group = Methylation 1 carbon bound to 3 hydrogen Process of adding a methyl group (CH3) to a substrate: It is involved in almost every metabolic process in the body and contributes to crucial functions, including: – Gene regulation (turning genes on and off) – DNA RNA synthesis (e.g., growth, repair, cancer prevention. – Detoxification (e.g., hormones such as oestrogen). – Energy production (CoQ10, carnitine and ATP). – Myelination and neurotransmitter production (e.g., dopamine and serotonin à melatonin). – Immune function (e.g., immune cell synthesis, inflammation) © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 20  TMG = Methylation trimethylglycine Dietary co-factors for methylation: Folate, B12, B6, B2, choline, betaine (TMG) and zinc. The ‘methyl’ (CH3) group: CH3 is provided to the body by the methyl donor known as SAMe (S-adenosylmethionine). SAMe is formed from the amino acid methionine. The system that produces SAMe is reliant on the active form of folate ― methylfolate. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 21  Methylation Disruptors: Insufficient substrates (folate, methionine). Lack of essential co-factors (B2, B12, B6, zinc) / malabsorption. SNPs affecting enzyme activity (involved in methylation). Specific nutrients depleting methyl groups (niacin). Drugs (e.g., contraceptive pill, metformin = ↓ B vits). Increased demand on processes described previously e.g., stress, imbalanced hormones, inflammation, need for repair etc. Toxin exposure ― aflatoxin (fungi on crops), air pollution, BPA (e.g., food packaging), phthalates (e.g., beauty products), heavy metals etc. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 22  Methylation Impaired methylation can contribute to: Cardiovascular disease. Cancer (e.g., breast cancer). Infertility and unexplained miscarriages. Chronic fatigue and mood disorders. Neurological disease (e.g., MS, Alzheimer’s). How to assess for indicators of poor methylation: Genetic testing ― for methylation SNPs. Homocysteine testing ― if methylation is poor, homocysteine levels generally rise. Ideal levels: 5–8 µmol / L. SAMe / SAH ratio in some tests may be more accurate. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 23  Methylation Cycles and Links UREA BH2 FOLATE Key Outputs / Functions Urea Cycle Biopterin Cycle Folate Cycle B12 Methionine SAMe Synthesis of SAMe, the Cycle Master Methyl donor. e.g., COMT, PEMT, DNA methylation etc. Via recycling, reduces NOS BH4 5-MTHF Homocysteine homocysteine. Transsulphuration Key Outputs / Key Outputs / Key Outputs / Functions Functions Functions Key Outputs / Conversion of ammonia Tetrahydrobiopterin DNA synthesis / repair Cysteine Functions to urea. AND arginine to key co-factor conversion and formation of 5- Phase 2 sulphation the vasodilator nitric of amino acids (e.g., Methyltetrahydrofolate Glutathione synthesis – oxide (CV health). tryptophan) to the (5-MTHF) master antioxidant and neurotransmitters glutathione conjugation. dopamine, serotonin and Production of sulphite / melatonin ammonia 24 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  transsulphuration = Methylation refers to the transfer of a sulphur atom Folate Cycle Methionine Cycle Folic acid Folate Methionine B3 DHFR FOLH1 MAT1 DHF Chief DNA (thymidine) SAMe methyl DHFR B12 donor! replication and repair) THF MTR (S) SAH MTHFD1.. 5,10 Methylene THF AHCY Biopterin MTRR Homocysteine (synthesis of B2, B3 MTHFR (remethylates 5-HTP, L- 5-MTHF B12) dopa) Transsulphuration sulphur detox, glutathione! 25 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  Methylation Folate cycle (MTHFR): Gene: MTHFR codes for the enzyme ‘methylenetetrahydrofolate reductase’ ― converting folate into a methylated form. Key SNP: The C667T (cytosine replaced by thymine) SNP at rs1801133 is associated with reduced activity of MTHFR. Recommendations: ‒ Optimise dietary folate. ‒ Consider a methylated folate supplement. ‒ Optimise vitamin B2 (riboflavin) ― supporting the MTHFR gene. ‒ Note: The drug methotrexate is a folate antagonist. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 26  Methylation Methionine cycle (MTR / MTRR): Genes: MTR / MTRR = code for the enzyme methionine synthase (MS), which ↑ the conversion of homocysteine to methionine. MTR SNP: The A allele of rs1805087 in the MTR gene is associated with decreased MS activity. MTRR SNP: The A66G SNP at rs1801394 = ↓ conversion of vitamin B12 to its methylated form. Recommendations: Vitamin B12 and folate foods are co-factors in the conversion of homocysteine to methionine. Consider supplementation of their methylated forms. Ensure no mercury / lead toxicity ― these can hinder the process. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 27  CBS = cystathionine Transsulphuration beta-synthase Homocysteine Another ‘output route’ for homocysteine that provides CBS B6 a substrate for glutathione Cystathionine CTH synthesis and the key phase 2 NAC detoxification processes of Cysteine Ammonia sulphation and glutathione conjugation. Cysteine sulphate Glutathione Urea For peroxidase Sulphite and transferase Mo SUOX Sulphate Sulphation © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 28  Transsulphuration Transsulphuration cycle (CBS): Genes: CBS converts homocysteine to cystathionine. SNP: C669T SNP at rs234706 ↑ CBS activity = less homocysteine to recycle and potential ↓ SAMe. Faster conversion to ammonia (pressure on urea cycle) increasing the need for glutathione. Recommendations: Increase zinc, choline and TMG (e.g., beetroot). Neutralise the ammonia (↓ animal protein, probiotics to ↓ bacterial production, supplement activated charcoal. Limit sulphur-containing foods, e.g., eggs. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 29  Neurotransmitters COMT = catechol-O- methyltransferase Genes: MTHFR essential for 5-MTHF, thus biopterin and synthesis of serotonin, dopamine, adrenaline etc. SAMe-dependent COMT breaks down dopamine, adrenaline and noradrenaline. COMT also converts active oestrogen to less active oestrogen. SNPs: rs4680 ― the A allele is associated with ↓ COMT activity: ‒ AA = excessive catecholamines ― also associated ↑ oestrogen (and hence breast cancer, etc.). ‒ GG = fast metabolism of catecholamines. Recommendations: Choline, betaine, folate and B12-rich foods support the production of SAMe. Avoid exogenous oestrogens (e.g., avoid plastic, anti-perspirants, dairy products, etc.). © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 30  eNOS = endothelium- Methylation derived nitric oxide synthase Urea cycle (eNOS): Genes: eNOS is responsible for generating nitric oxide from arginine, which plays a key role as a vasodilator. SNPs: At rs1799983 the T allele is associated with ↓ eNOS activity and nitric oxide linked to slower ammonia detoxification, ↑ free radical levels and an ↑ risk of cardiovascular disease. Recommendations: – Increase antioxidants (‘rainbow of colour’). – Moderate intake of ammonia-generating foods (↓ animal protein). – Support NO production with L-arginine and beetroot juice. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 31  Case Study Mark, 59 years old, full time lorry driver, sedentary: Presents with: Osteoarthritis (bilateral knee and hip pain). Psoriasis (mostly on elbows) with on / off use of methotrexate. Diet diary: Revealed a high intake of ‘white carbs’, alcohol, caffeine and processed meats. Often eats microwaved meals. Family history: Cardiovascular disease. SNPs identified: MTHFR (C667T), TNF (at rs1800629) and eNOS (at rs1799983). Based on this information and the genetic SNPs, give dietary advice to Mark and explain the rationale for your recommendations. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 32  Detoxification Increased exposure to environmental toxins is a key factor to the continued rise in chronic disease worldwide, in both older and younger population groups: A key strategy in managing the rise in illness and chronic disease is ensuring efficient detoxification and elimination. This requires consideration of the individual’s: ‒ Exposure to various toxins (toxic load). ‒ Antioxidant and nutritional status. ‒ Liver function and elimination capacity, particularly via the GIT, urinary tract and skin. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 33  xenobiotics = a chemical Detoxification found in an organism that is not expected to be present Detoxification = the process of transforming fat-soluble toxins and xenobiotics into water-soluble compounds that can be eliminated via the urine or bile: Detoxification is carried out by a variety of cells, but takes place primarily in hepatocytes (functional liver cells). In clinic, to support detoxification: – Minimise the toxic load. – Support elimination pathways (before promoting liver detoxification). – Support detoxification pathways. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 34  Toxin from Latin Toxins toxicum ’poison’ What are toxins? Classical definition: A poison produced in organisms that is active at low concentrations e.g., aflatoxins from moulds. More modern broader definition: Any agent (biological or otherwise) that disturbs physiology and can be harmful to the body. Toxicant / xenobiotic: Foreign substances (typically synthetic) found in the body that are not derived from a normal diet or produced endogenously e.g., pesticides, food additives, heavy metals, pharmaceutical drugs, industrial chemicals. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 35  endogenous = Toxins those produced within the body Endogenous toxins include: Inefficient detoxification GI microbes: generates more toxins. ‒ Toxic compounds such as aldehydes, alcohols and indoles released from undesirable bacteria and fungi. ‒ Fragments of dysbiotic bacteria called lipopolysaccharides (endotoxins) can enter the bloodstream (esp. if ↑ intestinal permeability) causing excessive immune reactions. Waste products from normal metabolic processes e.g., urea if not properly metabolised in the liver. Poorly detoxified / eliminated hormones (e.g., chronic constipation à ↓ oestrogen elimination). © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 36  exogenous = arise externally Toxins OCPs = organochlorine pesticides Exogenous chemical toxins: Chemical toxin: Sources: Associated with: Bisphenols: Tinned and Type 2 diabetes, E.g., bisphenol A plastic infertility, oestrogen (BPA) packaging. disruption. Pesticides and Chemically-grown Alzheimer’s, herbicides: E.g., food, water infertility, erectile glyphosate + (contamination). dysfunction, RA, OCPs SLE, cancer. Phthalates: Plastic products Infertility, Type 2 beauty products. diabetes, allergies. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 37  Toxins Exogenous chemical toxins (cont.): Chemical toxin: Sources: Associated with: Polybrominated Flame Insulin resistance, child diphenyl ethers retardants, behavioural problems. (PBDEs): farmed fish. Polycyclic aromatic Air pollution / Type 2 diabetes, ADHD, hydrocarbons vehicle exhaust Alzheimer’s, atopic (PAHs): (diesel = worst). conditions, COPD. Solvents: Vehicle Alzheimer’s, infertility, E.g., benzene, exhausts, MS, RA, ↑ autism risk. toluene, styrene. smoking, foods. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 38  UK children have Toxins the highest dietary aluminium exposure in the world. Exogenous metal toxins include: Metal toxin: Sources: Associated with: Aluminium: Foil (and food), anti- Mitochondrial damage, perspirants, vaccines. Alzheimer’s. Mercury: Amalgams, fish (esp. Chronic fatigue, neurological larger fish), water, damage, Hashimoto’s, vaccines, air pollution. ADHD, infertility, SLE Arsenic: Water, rice, chicken, Type 2 diabetes, cancer, gout, fish, smoking. peripheral neuropathy. AS3MT SNPs ― associated with ↑ toxic reactions (i.e., in those with ↓ arsenic exposure). © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 39  Toxins Living toxin free: Eat organic and wash food where needed; avoid farmed and large fish; avoid plastic packaging as much as possible and replace with glass containers, beeswax wraps etc. Use an air purifier and / or air purifying plants (e.g., peace lily, snake plant, English ivy), especially if in a polluted area. Take off shoes before entering the house. Use a good-quality water filter (e.g., reverse osmosis). Carefully select non-chemically ridden beauty products, cleaning products and kitchenware. Avoid the toxins mentioned, alcohol, smoking and drugs. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 40  Detoxification Symptoms and signs of ‘sluggish’ liver detoxification: Poor appetite and fatigue. Waking between 1 and 3 am. Nausea, esp. in the morning. Yellowing of the whites of eyes. Difficulty digesting fatty foods. Dark circles under the eyes. Gallstones. Hormone imbalances. Pale, fatty stools that float. Mood changes. Intolerance to alcohol. ↓ concentration Dry skin and itching. and brain fog. Halitosis and a bitter taste. Headaches Offensive body odour. Tongue: Esp. thick coatings on A feeling of overheating. the tongue, e.g., a yellow coat. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 41  Detoxification Testing for detoxification (e.g. via Regenerus, Genova) include: Hair analysis of toxic elements. Urine heavy metals (e.g. ‘GPL-TOX’ ― screens for 172 environmental pollutants). Blood metals panel. Stool panel. Genetic profiling e.g., LifeCode GX Detox Panel. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 42  Detoxification: Antioxidants Phase I detoxification generates free radicals. An adequate antioxidant defence is crucial to avoid tissue damage. Antioxidants = play a central role in detoxification by converting free radicals / ROS to stable, non-toxic molecules. They can be divided into three main groups: 1. Antioxidant enzymes. 2. Chain-breaking antioxidants ― the chain of ROS can be broken when a molecule can accept or donate an electron without needing to rectify its gain or loss. 3. Transition metal-binding proteins. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 43  Detoxification: Antioxidants 1. Antioxidant Description: Nutrients enzymes: needed: Superoxide A group of enzymes that convert superoxide Zinc, dismutase to hydrogen peroxide. copper, (SOD): Hydrogen peroxide (also a ROS) manganese. must then be detoxified by catalase or glutathione peroxidase. Catalase: Converts hydrogen peroxide to H2O and O2. Iron. Glutathione Same as for catalase. Note: Mercury can Selenium. peroxidase: suppress selenium activity in the body. Glutathione Regenerates glutathione that has been Vitamin reductase: oxidised. B3. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 44  Detoxification: Antioxidants 2. Chain-breaking Description: antioxidants: Vitamin E: Sunflower seeds, almonds, pine nuts, olive oil, avocado, sweet potato, spinach. Vitamin C: Peppers, kiwi fruit, papaya, currants, berries, citrus, crucifers, mangoes, tomatoes. Flavonoids: E.g., quercetin (red onions, apples), anthocyanins (red grapes), catechins (green tea), kaempferol (kale, spinach) Carotenoids: Yellow, orange, and red fruits and vegetables. Green vegetables. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 45  Detoxification: Antioxidants 3. Transition metal Description: binding protein: Metallothionein MTs are cysteine-rich proteins that bind essential (MT): and toxic heavy metals (e.g., cadmium). They are important for zinc and copper homeostasis, and also to reduce oxidative stress. Require adequate levels of cysteine (e.g., in legumes, sunflower seeds, eggs, chicken) zinc, copper, and selenium. Exercise: Write breakfast and dinner ideas that would support the activity of these key antioxidants covered. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 46  Detoxification (Phase Zero) The liver is the primary site for detoxification because it filters blood coming directly from the GIT and spleen via the portal vein. Phase zero = the entry of the toxin into the cell (primarily hepatocytes) or exit of the unmetabolised Drug toxin from storage inside cells such as adipocytes: SLC Fat-soluble toxins diffuse through the cell membrane. Water-soluble or charged toxins need to access or leave the cell through a transporter. Drug The main transporter families used for phase transport zero are (both with many different transporters): – Solute carriers (SLC) and ATP binding cassette carriers. (Alexander et al., 2019) © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 47  lipophilic = ‘fat- Detoxification (Phase I) loving’ (or soluble) Phase I = primarily involves transformation enzymes collectively known as cytochrome P450 (CYP450) in the liver: Most toxins that arrive inside the hepatocytes are lipophilic and have to undergo phase I detoxification. The CYP450 + toxin / hormone reaction creates an active binding site on the toxin (often exposing an –OH / alcohol group). This makes them more water-soluble, but also more reactive in order for conjugation to occur (phase II). Therefore, in phase I, intermediates are formed which are very bioactive. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 48  Detoxification (Phase I) CYP450 = involves 50 to 100 enzymes, each Endogenous compounds such of which is best able to detoxify certain as steroids compounds, but has broad specificity: hormones are also This means the liver can accommodate a metabolised by CYP450 enzymes. wide range of chemical exposure. However: ‒ Many of the enzymes are produced in response to increased exposure to a certain toxin by producing more of the enzyme that degrades it. This can happen at the expense of other toxin biotransformation. ‒ Induction of phase I enzymes without co-induction of phase II can = increased reactive intermediates, ↑ oxidative stress. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 49  Detoxification (Phase I) Phase I to phase II key considerations: Smoking, The progression of metabolites from alcohol, caffeine phase I through to phase II must happen and chargrilled in quick succession to minimise damaging food increase phase I activity effects of intermediary products. Genetic variations (SNPs), diet and availability of nutrient co-factors can influence an individual’s ability to metabolise toxins. Phase II enzymes are generally less inducible than phase I. Typically, phase I will be upregulated due to toxic load, while phase II will be slow due to overwhelm from heightened phase I activity and / or lack of co-factors (e.g., a poor, nutrient-depleted diet). © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 50  Detoxification (Phase I) Supporting phase I detoxification: Reduce the toxic load to slow phase I: 1. Go organic to minimise intake of pesticides and other xenobiotics from the food chain. 2. Minimise exposure of xenobiotics in toiletries and household products. 3. Stop smoking and avoid caffeine. 4. Avoid chargrilled and smoked foods. 5. Reduce or ideally eliminate alcohol. 6. Avoid unnecessary medications. 7. Avoid use of plastics in contact with food. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 51  Detoxification (Phase I) Ensure adequate co-factors to support phase I detoxification: The B complex vitamins are vital co-factors for the action of the cytochrome P450 enzymes and other phase I enzyme families. Alcohol depletes B vitamins and so should be avoided to optimise an individual’s B vitamin status. B vitamin-rich foods include whole grains, legumes, mushrooms, sunflower seeds, pistachios, wild fish, eggs, sea vegetables. Adequate amounts of the branched chain amino acids (BCAAs) leucine, isoleucine and valine are also necessary to support phase I activity. Sources include quinoa, fish, eggs and meat. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 52  Detoxification (Phase I SNPs) CYP450 genes code for CYP450 enzymes. There are many genes involved in phase I. Examples include: CYP2E1 ― ethanol CYP17A1 ― pregnenolone CYP1A2 ― caffeine CYP19A1 ― testosterone CYP2C9 ― warfarin CYP1A1 ― oestrogen SNPs can influence enzyme activity ― either turning it up (↑ metabolism) or down (↓ metabolism). It has the potential to increase toxicity by speeding up conversion of compounds to reactive intermediary products or by causing an accumulation of unmetabolised toxins. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 53  Detoxification (Phase I SNPs) Phase I SNPs of most clinical relevance: CYP1A1: Gene: CYP1A1 gene codes for the phase I enzyme CYP1A1 which is responsible for: – Deactivating oestrogen. An SNP of this gene increases the risk of oestrogen dominance. – Detoxifying many toxins including polycyclic aromatic hydrocarbons (PAHs) and solvents. PAHs damage DNA increasing cancer risk. They are formed in chargrilled meat, smoked foods and cigarettes. SNP: A G2453T SNP at Rs1799814 is associated with reduced activity of CYP1A1. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 54  Detoxification (Phase I SNPs) CYP1A1 SNP recommendations: Avoid (more crucial for these people): Chargrilled meats and smoked food. Smoking and exposure to second-hand smoke. Industrial pollutants and synthetic oestrogens (e.g., parabens in beauty products, plastic). Focus on plant foods (minimal animal protein), rich in colour (phytonutrients) including polyphenols (green tea, berries, apples, etc.). Also rosemary. Sulphur-rich foods, especially cruciferous vegetables (e.g., broccoli sprouts for the high I3C content) and allium vegetables). Consider supplementation with Indole-3-carbinol. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 55  Detoxification (Phase I SNPs) Phase I SNPs of most clinical relevance: CYP1A2: Gene: CYP1A2 gene encodes a member of the CYP450 family of enzymes, which metabolise nutrients and drugs, including caffeine. SNP: The SNP at rs762551 impacts CYP1A2 activity. Individuals with the CC genotype, also known as CYP1A2*1C, are ‘slow’ caffeine metabolisers. ‒ Caffeine intake > 300 mg / day can be damaging to the brain, heart, liver and kidneys. SNP recommendations: Avoid all caffeine intake from coffee, tea and foods such as chocolate. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 56  Detoxification (Phase II) Phase II = a variety of chemical reactions which add functional groups to reactive toxins to make them safe to be released into the blood or bile for excretion via the kidneys or bowel: There are six primary phase II detoxification pathways, which are all highly dependent on the necessary substrates to carry out their function. Amino acids are of central importance. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 57  Detoxification (Phase II) Summary of phase II reactions: Reaction: Enzymes: What happens: Glucuronidation UDP- Glucuronic acid is added to the Glucuronosyltransferases phase I metabolite. Sulphation Sulphotransferases Sulphate is added to the phase I (SULT) metabolite. Glutathione Glutathione S- Reactive phase I metabolites are conjugation transferases (GST) reacted with glutathione. Amino acid Amino acid transferases An amino acid (mostly glycine) is conjugation added to the phase I metabolite. Acetylation N-acetyl transferases An acetyl group is added to the (NAT) phase I metabolite. Methylation Methyltransferases e.g., A methyl group (-CH3) is added COMT to the phase I metabolite. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 58  Detoxification (Phase II) 1. Glucuronidation: Detoxifies: Oestrogens, NSAIDs, morphine, hydrocarbons. Inhibited by: Aspirin, smoking, contraceptive pill, fluoride. Requires: Glucuronic acid (e.g., from apples, alfalfa, broccoli). Enhanced by: Citrus peel, brassica vegetables, turmeric. 2. Sulphation: Detoxifies: Steroid hormones (e.g., oestrogen), food additives, industrial chemicals. Inhibited by: NSAIDs, tartrazine, molybdenum deficiency. Requires: Sulphur-containing amino acids (esp. cysteine and methionine, Sulphur-rich foods (brassica veg; onion, garlic). Molybdenum (legumes, leafy veg, whole grains). © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 59  Detoxification (Phase II) 3. Acetylation Detoxifies: Smoke, HAAs, halides, histamine, sulphonamides Inhibited by: Vitamin B and C deficiency. Enhanced by: Vitamins B1, B5, vitamin C, butyric acid (SCFA). 4. Methylation Detoxifies: Steroid hormones incl. oestrogens, dopamine, adrenaline, noradrenaline. Arsenic and urea. Inhibited B12 and folate deficiency; a high sucrose by: diet can inhibit enzymes such as COMT. Enhanced Methionine, betaine, choline, vitamins B2, by: B6, B12, folate, magnesium. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 60  Detoxification (Phase II) 5. Amino acid conjugation Detoxifies: Xenobiotics, drugs (e.g., aspirin and statins). Inhibited by: Low protein diet. Enhanced by: Glycine primarily (legumes, seaweed, cauliflower, bone broth, meat, fish, eggs), taurine, glutamine, arginine. 6. Glutathione conjugation Detoxifies: Xenobiotics, paracetamol, heavy metals (esp. mercury). Requires: Glycine, glutamine and cysteine for formation of glutathione. Inhibited by: Selenium, B6, zinc, glutathione deficiency. Enhanced by: Brassica veg (especially broccoli sprouts), turmeric, citrus peel, alpha-lipoic acid. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 61  Detoxification (Phase II) Supporting phase II (increasing Nrf2 gene expression): In addition to the nutrients outlined for each of the six pathways, there are some general strategies for supporting phase II. The transcription factor, Nrf2 (nuclear factor erythroid 2) is key to regulating the body's detoxification and antioxidant system: – Induction of Nrf2 increases endogenous antioxidants to protect against reactive intermediates, and promotes phase II pathways. – Nrf2 induction is considered protective against various oxidative stress-related conditions such as cancer, kidney dysfunction, neurological disease, and cardiovascular disease. (Hodges & Minich, 2015) © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 62  Detoxification (Phase II) Supporting phase II (increasing Nrf2 gene expression) (cont.): Phytonutrients not only scavenge ROS (acting as direct antioxidants), but also regulate Nrf2 activity. Phytochemicals / foods that can regulate Nrf2 activity: ‒ Curcumin (turmeric), broccoli constituents, garlic, epicatechins (e.g., green tea), lycopene (tomatoes), resveratrol (e.g., red grapes), isoflavones (legumes, alfalfa sprouts), rosemary, blueberry, pomegranate, naringenin (grapefruit). ‒ The effects of whole foods / herbs versus isolated bioactive compounds appear greater. (Hodges & Minich, 2015) © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 63  Glutathione Glutathione = a crucial antioxidant that protects against reactive metabolites from phase I and is essential for glutathione conjugation in phase II: Cysteine is the rate-limiting amino acid for glutathione synthesis (sources include legumes, sunflower seeds, eggs, chicken). Glutathione is critical to mitochondrial protection. Low levels of glutathione have been associated with neurodegenerative diseases, autoimmunity, CVD, liver diseases, and pulmonary diseases such as COPD. Glutathione binds and transports mercury out of cells and out of the brain across the blood-brain barrier. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 64  Glutathione How to increase glutathione levels: Decrease depletion (decrease oxidative stress): Decrease toxic load, optimise melatonin (sleep hygiene, vitamin B6 etc.), alpha-lipoic acid. Milk thistle (silymarin). NAC (also binds to methyl Hg) — 300–1000 mg x 2 daily. Liposomal glutathione. Resveratrol (e.g., red grapes, berries). Cruciferous vegetables (glucosinolates boost glutathione). Cordyceps mushroom. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 65  Detoxification (Phase II SNPs) Glutathione (GSTM1): Genes: GSTM1 is the most active member of the GST family and is responsible for the removal of xenobiotics, carcinogens and products of oxidative stress. SNPs: An ‘absent’ gene is common, resulting in reduced capacity for liver detoxification. Recommendations: – Focus on minimising toxic load, e.g., stop smoking, eat organic. – ↑ antioxidants (‘rainbow of colour’). – ↑ cruciferous vegetables (for the sulforaphane) and alliums. – Milk thistle, NAC, alpha-lipoic acid, selenium. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 66  Detoxification (Phase III) Phase III = the removal and excretion phase where detoxified products are pumped into blood or bile for elimination: This involves over 350 antiporter proteins (ATP- dependent pumps) that work on specific substrates. How to induce phase III metabolism: ‒ Fasting (e.g., intermittent / vegetable broth). ‒ Being in a lipolytic state allows toxins stored in fat cells to be mobilised and eliminated. ‒ Fasts and calorie restriction should be short term (5–10 days) and toxin elimination should be supported with practices such as saunas. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 67  choleretics = ↑ bile production Detoxification (Phase III) cholagogues = ↑ bile release from the gallbladder Supporting phase III (cont.): Certain very high dose isolated phytonutrients appear to inhibit phase III — notably curcumin and epicatechins (in green tea). – However, turmeric and green tea are highly valuable to detoxification and antioxidant processes. – Focus on dietary inclusion and use of whole plant preparations. Good hydration is essential, helping with elimination. Bile production and flow can be supported with choleretic and cholagogue herbs. Dandelion root and globe artichoke leaf provide both actions and are also mild diuretics. Burdock root (e.g., tea) is a cholagogue. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 68  Detoxification (Phase III) A proportion of conjugated metabolites from the liver are pumped into bile and travel to the intestinal lumen for excretion: Efficiency of excretion is dependent on different factors, particularly influences from the diet and microflora. Fibre binds conjugated xenobiotics, decreases stool transit time and reduces the amount of deconjugating enzymes in the stool. Dysbiosis — undesirable bacteria can produce enzymes such as beta-glucuronidase that deconjugate phase II compounds, ↓ elimination. Deconjugated xenobiotics re-enter the blood and are sent back to the liver for processing. (Claus et al., 2016; © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. Liska, 1998) 69  Overview of Detoxification B2, B3, B6, Folate, B12, glutathione, BCAAs, flavonoids, phospholipids Toxins Phase I Phase II (Non-polar, CYP450 Intermediate Conjugation lipid soluble) enzymes metabolites Endogenous (Oxidation, reduction, (more polar, less lipid hydrolysis, hydration, soluble) exogenous Glutathione Glucuron- Amino acid dehalogenation Methylation Sulphation Acetylation conjugation idation conjugation Methionine, Glucuronic acid Superoxide Cysteine, Cysteine, Glycine, ROS B6, B12, Mo glutathione e.g.,apple, B5 taurine radicals folate alfalfa, broccoli Antioxidants SOD Phase III Cu, Zn, Mn Glutathione Transport / excretion via bile and kidneys GPX Hydrogen Peroxide Catalase © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 70  Hepatoprotection hepato = liver Milk thistle (Silybum marianum): A liver tonic that has strong antioxidant properties and has been shown to help protect the liver from the damaging effects of phase I metabolites. It is suitable for hepatoprotection e.g., high alcohol intake, pharmaceutical drugs and hepatitis. However, milk thistle at high doses can inhibit phase III. Mycotherapy: Shiitake and maitake are hepatoprotective. Cordyceps — hepatoprotective and supports detoxification by increasing glutathione (phase II). (Das & Vasudevan, 2006; McCord, 2008) © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 71  Oestrogen Metabolism Key oestrogen liver genes: DIM / I3C from cruciferous veg stimulate CYP1A1 CYP1A1 is crucial because it converts oestrogens into 2OH oestrogens, which are neutral or even beneficial for the body. CYP1B1 converts oestrogens to 4OH oestrogens and can promote the synthesis of harmful molecules called quinones, which damage DNA and potentially initiate cancer. Variations on CYP1B1 are associated with increased production of 4OH oestrogens. COMT is involved in the methylation of 2OH and 4OH before detoxification of these oestrogens occurs. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 72  CDSA = comprehensive Oestrogen Metabolism digestive stool analysis Oestrogen elimination: Oestrogens are then detoxified by sulphation and glucuronidation. SULT / UGT SNPs increase the risk of hormone-related cancers e.g., breast cancer. Oestrogen enters the bowel (in bile), where certain gut bacteria ‘deconjugate’ it, allowing recirculation via beta-glucuronidase enzymes. Excess activity can lead to increased levels. Raised beta-glucuronidase is often due to an overgrowth of bacteria such as E. coli and Clostridium perfringens. Detected on a CDSA. To combat this: Optimise gut flora and ↑ glucuronic acid-rich foods, mung bean sprouts, orange peel (infused tea), apples, broccoli. (Thorne Research Inc. 2002) © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 73  Oestrogen Metabolism How to optimise oestrogen metabolism: Increase intake of: ‒ Cruciferous vegetables, and focus on broccoli sprouts due to the high I3C content. ‒ Fibre (elimination), organic fruit and vegetables, filtered water. Avoid: Dairy, excess alcohol and caffeine, non-organic meat and eggs, water from plastic bottles (due to BPA), anti-perspirants, hormonal contraceptives. Address dysbiosis (e.g., weed, seed, feed protocol). Calcium D-glucarate has been shown to inhibit beta-glucuronidase. (Thorne Research Inc. 2002) 74 © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH.  Case Exercise Karen, 45 years of age, owner of a gym. Karen has a significant family history of breast cancer (mum, grandma and auntie). She is concerned about this and heard about genetic testing which she would like to do through you. Symptoms: Feeling irritable and has ‘always suffered’ with painful periods. Keeps waking up between 1‒3 am. Beverages: 30 units of alcohol each weekend. Drinks 3 cups of coffee most days and feels ‘shaky’ after drinking it. What genetic SNPs would you be most interested in exploring in Karen’s case, and why? What might your recommendations include? © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 75  Optimising Elimination Support bowel elimination (‘clean up the GIT’): Remove anything damaging the GIT (e.g., alcohol, NSAIDs). Ensure good hydration. Eat foods rich in mucilage, which swells and lubricates the bowel (linseed, chia seeds, psyllium seed / husk). Always take with plenty of water. Maximise fibre intake (soluble and insoluble) to aid transit through the GIT, increase stool bulk and provide prebiotics. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 76  Optimising Elimination Support bowel elimination (cont.): Ensure a healthy intestinal microflora: – Eradicate pathogens / SIBO with antimicrobials, e.g., berberine. – Repopulate the flora with probiotic foods (e.g., kimchi, sauerkraut, kombucha and kefir) and / or probiotic supplements. Increase prebiotic foods (e.g., chicory, garlic, asparagus, onions). Support the intestinal mucosa, e.g., quercetin, bone broth, cabbage juice (glutamine), N-acetyl glucosamine (e.g., in shellfish). Slippery elm and / or marshmallow root (1 tsp powder in water — drink 3 x daily between meals). © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 77  Optimising Elimination Support kidney function: The kidneys play a vital role in elimination, filtering undesired products of metabolism such as uric acid, creatinine, hormone metabolites and phase II metabolites. Stop drugs that damage the kidneys, esp. NSAIDS, paracetamol. Avoid table salt and protein (esp. animal) diets as they increase the metabolic load on the kidneys. Good intake of filtered water to aid waste removal via the kidneys. Address GI dysbiosis and intestinal permeability due to the impact of circulating endotoxaemia on the kidneys. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 78  Optimising Elimination Support kidney function (cont.): Celery seed, nettle and dandelion leaf taken as herbal infusions support renal blood flow, increase urine output and encourage removal of conjugated toxins and acidic wastes. Nettle and dandelion leaf are alkalising (rich in minerals) helping the kidneys to release toxins. Beetroot juice is especially rich in organic nitrates, which are converted to nitric oxide in the body = vasodilation and improved microcirculation. 250 ml x 2 per day. Blueberries protect the kidneys from gut-derived endotoxins. (Jones et al., 2019; Pizzorno © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. & Nowicki, 2020) 79  Optimising Elimination Skin support: Toxin avoidance — especially anti-perspirants (to avoid inhibiting skin elimination). Saunas — increase the elimination of toxins (incl. heavy metals, BPA and phthalates) by promoting cutaneous vasodilation and increasing perspiration. Every 2–4 days. Wraps / poultices (i.e., rock salt, clay, mud) increase heat, which opens pores; the alkalinity absorbs acid wastes. Epsom salt / seaweed baths combine warm water (opens pores) and alkalinity (draws out acid wastes). Burdock root (tea daily) — ‘re-conditions’ the skin. (Liu et al., 2012; Pizzorno & Nowicki, 2020) © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 80  Optimising Elimination Optimise lymphatic flow: The lymphatic system plays a vital role in elimination, filtering and removing harmful substances. Exercise helps to mobilise and shift toxins and wastes. Mini trampolining is especially good! Cleaver's Dry skin brushing (gently brushing the skin from the bottom of the feet and palms of the hands toward the heart). Massage i.e., manual lymphatic drainage. Abdominal breathing exercises (promote thoracic duct drainage). Cleaver's tea (especially in the spring and summer months). © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 81  Castor Oil Packing Castor oil contains rincinoleic acid, which increases blood flow to organs such as the liver, aiding detoxification and promoting lymphatic drainage: It also acts on smooth muscle, relieving constipation and menstrual cramps. For detox support, apply the castor pack over the liver. (Arslan & Eşer, 2011) © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 82  Detoxification in Clinical Practice General detoxification support in clinic: 1. Reduce toxin burden — avoid dietary and environmental toxins. 2. Assess GI integrity — ‘weed, seed, feed’ for dysbiosis, heal gut mucosa if indicated. 3. Support eliminatory channels as outlined. 4. Regular consumption of foods that support detoxification — brassica veg, allium veg, fibre-rich foods. 5. Eat a rainbow of phytonutrients to ensure optimal antioxidant status. 6. Good quality protein to provide adequate conjugates for phase II. 7. Ensure optimal intake of B vitamins. 8. Regular saunas — ↑ toxin excretion e.g., heavy metals, PCBs. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 83  Detoxification in Clinical Practice For a deeper detox: Combine the basic liver support principles with a water fast (maximum 4 days unless supervised) or fasting mimicking diet. Water fast: Wholefoods only (mainly steamed veg) for several days prior to decrease toxin load. 2–3 litres of filtered water daily. Rest, limit exercise (gentle only). No vitamins, herbs, herbal teas. Limit medication to those needed. Reintroduce food with easy-to-digest soups and broths. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 84  Detoxification in Clinical Practice For depleted clients or highly toxic clients, a slower approach is needed: Fasting mimicking diet (5‒10 days) Low complex carbohydrate (no refined sugar). 500‒800 kcal a day. 0.8 g protein / kg body weight. 8‒10 portions of liver-supporting vegetables esp. cruciferous veg, onions and garlic, mung bean sprouts (glucuronic acid). Natural fats from plant foods. Reduced eating window — 8 hours Ensure good intake of filtered water. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 85  Case Exercise Bob, 36-year-old plumber. Smoker (approx. 6 per day). Presents with: Fatigue, trying to conceive with his partner (trying for 14 months). Observation: Bob has dry skin and a thick yellow coating on his tongue. SNPs identified on testing: MTHFR and GSTM1. Other: Has 4 mercury fillings (which he has had for between 8‒12 years). He struggles to drink alcohol as it makes him feel ‘ill for 2 days’ (vomiting). What do you make of this presentation? What might your recommendations include? © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 86  References Agusa, T. Fujihara, J. Takeshita, H. Iwata, H. (2011). ‘Individual variations in inorganic arsenic metabolism associated with AS3MT genetic polymorphisms’. Int J Mol Sci. 12(4). 2351-8. Alexander, S. Kelly, E. Mathe, A. (2019). ‘The concise guide to pharmacology 2019/20: Transporters’. The British Journal of Pharmacology. Arslan, GG. & Eşer, I. (2011). ‘An examination of the effect of castor oil packs on constipation in the elderly’. Complement Ther Clin Pract. 17(1). 58-62. Bae, S. Hong, YC. (2015). ‘Exposure to bisphenol A from drinking canned beverages increases blood pressure: randomized crossover trial.’ Hypertension. 65(2). 313-9. Baker, SM. (2008). ‘The Metaphor of Oceanic Disease’. IMCJ. 7:1. Ballatori, N. Krance, SM. Notenboom, S. Shi, S. et al. (2009). ‘Glutathione dysregulation and the etiology and progression of human diseases’. Biol Chem. 390(3).191-214. Carwile, JL. Ye, X. Zhou, X. et al. (2011 ). ‘Canned soup consumption and urinary bisphenol A: a randomized crossover trial’. JAMA. 306(20). 2218-2220. Chita, CS. Tudor, A. Christodorescu, R. Buleu, FN. et al. (2020). ‘MTHFR Gene Polymorphisms Prevalence and Cardiovascular Risk Factors Involved in Cardioembolic Stroke Type and Severity’. Brain Sci. 10(8). 476. Claus, S. Guillou, H. & Ellero-Simatos, S. (2016). ‘The gut microbiota: a major player in the toxicity of environmental pollutants?’. npj Biofilms Microbiomes. 2. 16003. Hodges, RE. & Minich, DM. (2015). ‘Modulation of metabolic detoxification pathways using foods and food-derived components: a scientific review with clinical application’. Journal of nutrition and metabolism. 2015. 760689. De Broe ME. Elseviers, MM. (2009). ‘Over-the-counter analgesic use’. J Am Soc Nephrol. 20(10).2098-103. D’Ippoliti, D. Santelli, E. De Sario, M. Scortichini, M. et al. (2015). ‘ Arsenic in Drinking Water and Mortality for Cancer and Chronic Diseases in Central Italy, 1990-2010’. PLoS One. 10(9). Doring, B. (2014). ‘Phase 0 and phase III transport in various organs: Combined concept of phases in xenobiotic transport and metabolism’. Drug Metabolism Reviews. 46(3). Ghayda, RA. Williams, PL. Chavarro, JE. et al. (2019). ‘Urinary bisphenol S concentrations: Potential predictors of and associations with semen quality parameters among men attending a fertility center'. Environ Int. 131.105050. Hayward, D. Wong, J. & Krynitsky, A. J. (2007). ‘Polybrominated diphenyl ethers and polychlorinated biphenyls in commercially wild, caught and farm-raised fish fillets in the United States’. Environmental Research. 103(1). 46-34. Helaleh, M. Diboun, I. Al-Tamimi, N. et al. (2018). ‘Association of polybrominated diphenyl ethers in two fat compartments with increased risk of insulin resistance in obese individuals’. Chemosphere. 268-276. Jin, Z. & Liu, Y. (2018). ‘DNA methylation in human diseases’. Genes Dis. 5(1). 1-8. Jones, T. Dunn, EL. Macdonald, JH. Kubis H-P. et al. (2019). ‘The effects of beetroot juice on blood pressure, microvascular function and large-vessel endothelial function: a randomized, double-blind, placebo-controlled pilot study in healthy older adults’. Nutrients, 11(8). Kenjale, AA. Ham, K L. Stabler, T. Robbins, J L. et al. (2011). ‘Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease’. Journal of Applied Physiology. 110(6). 1582-1591. Kim, KS. Lee, YM. Lee, HW. et al. (2015). ‘Associations between organochlorine pesticides and cognition in U.S. elders: National Health and Nutrition Examination Survey 1999–2002.’ Environment International. 75. 87–92. Kode, A. Rajendrasozhan, S. Caito, S. Yang, SR. et al. (2008). ‘Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells’. Am J Physiol Lung Cell Mol Physiol. 294(3). 478-88. Liska, D. (1998). The detoxification enzyme systems. Alternative Medicine Review, 3(3). Retrieved from https://pubmed.ncbi.nlm.nih.gov/9630736/ Liu, XX. Sun, CB. Yang, TT. Li, D. et al. (2012) ‘Decreased skin-mediated detoxification contributes to oxidative stress and insulin resistance’. Experimental Diabetes Research. 2012.128694. Liu, K. Zhao, R. Shen, M. Ye, J. et al. (2015). ‘Role of genetic mutations in folate-related enzyme genes on Male Infertility’. Scientific Reports. 5. 15548. Liu, J. (2008). ‘The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: overview’. Neurochem Res. 33.194-203. Marí, M. Morales, A. Colell, A. Garcia-Ruiz, C. & Fernandez-Checa, J. (2009). ‘Mitochondrial glutathione, a key survival antioxidant’. Antioxid Redox Signal. 11(11).2685-700. McIntyre, CW. Harrison, LE. Eldehni, MT. et al. (2011). ‘Circulating endotoxemia: A novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease’. Clin J Am Soc Nephrol. 6(1).133-141. Merad-Boudia, M. Nicole, A. Santiad-Baron, D. Saille, C. et al. (1998). ‘Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: relevance to Parkinson's disease’. Biochem Pharmacol.56(5).645-55. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 87  References Mosharov, E. Cranford, MR. Baneriee, R. (2000). ‘The Quantitatively Important Relationship between Homocysteine Metabolism and Glutathione Synthesis by the Transsulfuration Pathway and Its Regulation by Redox Changes’. Biochemistry. 39. 13005-13011. Nair, AR. Masson, GS. Ebenezer, PJ. Del Piero, F. & Francis, J. (2014). ‘Role of TLR4 in lipopolysaccharide-induced acute kidney injury: Protection by blueberry’. Free Radical Biology and Medicine. 71.16-25. Nighot, M. Rawat, M. Al-Sadi, R. Castillo, E. et al. (2019). ‘Lipopolysaccharide-Induced Increase in Intestinal Permeability Is Mediated by TAK-1 Activation of IKK and MLCK/MYLK Gene’. The American Journal of Pathology. 189(4). 797-812. Nishioka, MG. Burkholder, HM. Brinkman, MC. Lewis, RG. (1999). ‘Distribution of 2,4-Dichlorophenoxyacetic Acid in Floor Dust throughout Homes Following Homeowner and Commercial Lawn Applications: Quantitative Effects of Children, Pets, and Shoes’. Environmental Science & Technology. 33(9).1359-1365. Pizzorno, J. & Nowicki, J. (2020). Detoxification. In L. Hechtman (Ed.), Advanced Clinical Naturopathic Medicine (pp. 68-84). Elsevier, Australia. Sasidharan, S. Aravindran, S. Latha, LY. Vijenthi, R. et al. (2010). ‘In vitro antioxidant activity and hepatoprotective effects of Lentinula edodes against paracetamol-induced hepatotoxicity’. Molecules. 15(6). 4478-4489. Savastano, S. Tarantino, G. D’Esposito, V. Passaretti, F. et al. (2015). ‘Bisphenol-A plasma levels are related to inflammatory markers, visceral obesity and insulin-resistance: A cross-sectional study on adult male population’. Journal of Translational Medicine. 13,169. Schecter, A. Colacino, J. Haffner, D. Patel, K. et al. (2010). ‘Perfluorinated compounds, polychlorinated biphenyls and organochlorine pesticide contamination in composite food samples from Dallas, Texas, USA’. Environmental Health Perspectives. 118(6). 796-802. Sherif, IO. Al-Shaalan, NH. Sabry, D. (2019). ‘Ginkgo Biloba Extract Alleviates Methotrexate-Induced Renal Injury: New Impact on PI3K/Akt/mTOR Signaling and MALAT1 Expression’. Biomolecules. 9(11).691. Sinha, R. Sinha, I. Calcagnotto, A. et al. (2018). ‘Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function’. Eur J Clin Nutr. 72(1).105-111. Singh, S. Nagalakshimi, D. Sharma, KK. Ravichandiran, V. (2021). ‘Natural antioxidants for neuroinflammatory disorders and possible involvement of Nrf2 pathway: A review’. Heliyon. 7(2). Siscar, R. Koenig, S. Torreblanca, A. Sole, M. (2014). ‘The role of metallothionein and selenium in metal detoxification in the liver of deep-sea fish from the NW Mediterranean Sea’. Science of the total environment. 466-467. pp898-905. Thorne Research Inc. (2002). Calcium-D-Glucarate. Monograph. Natural Medicine Review, 7(4). Retrieved from https://altmedrev.com/wp-content/uploads/2019/02/v7-4-336.pdf Van Leeuwen, SP. Van Velzen, MJ. Swart, CP. Van der Veen, I. et al. (2009). ‘Halogenated contaminants in farmed salmon, trout, tilapia, pangasius and shrimp’. Environmental Science & Technology. 43(11). 4009-4015. Vuong, AM. Yolton, K. Xie, C. et al. (2017). ‘Childhood polybrominated diphenyl ether (PBDE) exposure and neurobehavior in children at 8 years’. Environ Res. 677-684. Walker, M. Seiler, RL. Meinert, M. (2008). ‘Effectiveness of household reverse-osmosis systems in a Western U.S. region with high arsenic in groundwater’. Sci Total Environ. 389(2-3). 245-52. Wanders, D. Hobson, K. & Ji, X. (2020). ‘Methionine restriction and Cancer Biology’. Nutrients. 12(3). 684. Wang, J. Chen, C. Jiang, Z. Wang, M. et al. (2016). ‘Protective effect of Cordyceps militaris extract against bisphenol A induced reproductive damage’. Sys Biol Reprod Med. 62(4). 249-257. Whanger, PD. Oh, SH. (1979). ‘Nutritional and environmental factors affecting metallothionein levels’. Experientia Suppl. 34. 281-291. Willhite, CC. Karyakina, NA. Yokel, RA. Yenugadhati, N. et al. (2014). ‘Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts’. Crit Rev Toxicol. 44(4). 1-80. Wolverton, BC. & Johnson, A. (1989). ‘Interior landscape plants for indoor air abatement. National Aeronautics and Space Administration’. [Online] Retrieved from https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19930073077.pdf Xu, F. Yu, K. Yu, H. Wang, P. et al. (2017). ‘Lycopene relieves AFB1-induced liver injury through enhancing hepatic antioxidation and detoxification potential with Nrf2 activation’. Journal of Functional Foods. 39. 215-224. Yagi, K. (2012). ‘Liver protective effect of Lentinula edodes mycelia(LEM)’. Gan To Kagaku Ryoho. 29(7). 1099-1102. Zhang, N. (2018). ‘Role of methionine on epigenetic modification of DNA methylation and gene expression in animals’. Animal Nutrition. 4(1). 11-16. © CNM: Nutrition Year 2: Detoxification and Nutrigenomics. DC / KH. 88