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Detoxification Pathways

Theory and Application to Practice

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Detoxification Pathways Failure to detoxify Accumulation of Toxins Detoxification mechanism Importance to practitioner Phase 1 Biotransformation Phase 2 Conjugation Phase 3 Elimination Summary Application to practice

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Failure to Detoxify symptoms Headache Muscle and joint pain Fatigue Irritability, Depression Mental confusion Flu like symptoms Allergic reactions (Hileman 1991) Gastrointestinal tract irregularities Cardiovascular irregularities

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Failure to Detoxify conditions

Inflammatory conditions (Rooney 1990)

Rheumatoid Arthritis (Smith 1985) Parkinsons (Steventon et al 1990) Alzheimers (Steventon et al 1989) Cancer (Heerdt et al 1995) CFS / ME (Racciatti et al 2001)

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Accumulation of Toxins

TOXIC BURDEN depends on

Genetics Age Lifestyle diet, exercise, stress Environment

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EXOTOXINS

Drugs recreational, pharmaceutical Pesticides Industrial chemicals Food additives Environmental pollutants

Cigarette smoke, car exhaust, barbecue fumes

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ENDOTOXINS

Intestinal bacteria Products of normal metabolism Free radicals

Many substances become more harmful to the body as they pass through the detoxification process

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The Process of Detoxification

Natural Barriers Skin, Lungs, Gastrointestinal tract

Rooney et al (1990) associate leaky gut syndrome with inflammatory joint disease

Allison et al (1992) cite increased permeability to be due to imbalance of intestinal flora, use of NSAIDs, asprin

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Processing and Eliminating Waste

Liver Most intensive site of detoxification

Intestines Second most intensive site

Kidneys

Blood and Bile

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Importance of Detoxification

Increasing exposure to foreign chemicals

Increasing Stress Use of processed and nutrient poor

foods Increasing access to and use of

pharmaceutical drugs

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Three Phases of Detoxification

Phase 1 Biotransformation Introduces oxygen to form a reactive site

Phase 2 Conjugation Adds water soluble group to reactive site

Phase 3 Elimination Actively eliminates conjugates from the cell

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Phase 1 Bioactivation

Oxidation: substrates are amines, alcohols, aldehydes

Hydroxylation: major pathway for cholesterol and endogenous estrogens

Reduction: substrates are aldehydes and ketones

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Phase 1 Bioactivation

Introduction of oxygen into molecule by Cytochromes P 450

Enzymes / oxidases which are present in the liver, intestines, skin, lymphocytes, placenta and which catalyse reactions

Over ten groups of CYP450 are present in humans

Each enzyme may transform up to 20 toxins

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Phase 1 BioactivationActivity induced / accelerated by: Medications (e.g. epilepsy drugs) Xenobiotics pesticides, organophosphates,

paint fumes Alcohol Tobacco, charcoaled meat both are active

inducers of phase 1, with no phase 2 stimulation Natural substances hypericin, indole 3 carbinol

(brassicas)

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Phase 1 BioactivationActivity inhibited by: Grapefruit juice (quercitin) Seville orange Turmeric (curcumin) Pomegranate (ellagic acid) Green tea (catechins) Milk thistle (silymarin) Watercress Hypothyroidism

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Phase 1 Bioactivation

Dietary co factors to support Phase 1 Niacin and other B Vitamins Antioxidants Vitamin C (Anderson & Kappas 1991) Bioflavanoids Zinc, Magnesium, Copper Molybdenum (Anderson & Kappas 1991)

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Phase 2 Conjugation

35 genes control production of enzymes Glutathione conjugation Glucoronidation Methylation Sulfation Acetylation Amino acid conjugation

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Glutathione conjugation (Phase2)

Substrates: Benzopyrene (car exhaust, smoke, barbecue) Penicillin Paracetamol Heavy metals Bacterial toxins Fatty peroxides Alcohol Steroids

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Glutathione conjugation (Phase 2)

Inducers, co factors, conjugation moitetes: Glutamine, glutamate, glycine Cysteine, Methionine Indole 3 carbinol (flavanoid rosemary) Curcumin, ellagic acid Sulforophane (brassicas and horseradish) Vitamins B2,3,6,12, Se, Zn, Mg, CuInhibitors Co factor deficiencies

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Glucoronidation (Phase 2)

Substrates: Asprin, paracetamol Propranalol, benzodiazapenes Nitrosomes Carcinogens (Amdur et al 1991) Steroid hormones Serum estrogen (Heerdt et al 1995)

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Glucoronidation (Phase 2)Inducers, co factors: Glutamine Fe, Mg, Vits B3, B6 D Limonene (esp lemon) Cynarin (globe artichoke) Fish oil Calcium D Glucarate S-adenosyl methionine

(SAM) Obesity

Inhibitors: Silymarin Fast (lack of glucose) Oxidative stress Hypothyroidism Gilberts syndrome

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Other Phase 2 pathways MethylationSubstrates: Estrogens, heavy metals Inducers: Choline, inositol, methionineCo factors: SAM, magnesium, B vitamins SulfationSubstrates: Paracetamol, estrogenInducers: Sulpher amino acids Co factors: Vitamin A, protein, sulphates

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Amino acid conjugation (Phase 2)

IMPORTANT AMINO ACIDS Glycine Taurine Glutamine Cysteine Arginine Ornithine

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Phase 2 ConjugationSupportive: Watercress Green tea Phytoestrogens D Limonene Magnesium B Vitamins Carnitine (ATP) Complex carbohydrates

Inhibitive: Alcohol High fructose intake Smoking Fasting Simple sugars Deficiency of co factors

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Application for the Practitioner Individuality of Client Need for cell energy (ATP) Improve gut barrier Minimise exposure to toxins Support Cytochrome P450 activity (phase 1) Protect cell membranes against

damage Stabilise blood sugar levels Co factors for phase 2 Elimination from cell and body

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References Allison MC et al 1992 gastrointestinal damage associated with the use of non

steroidal and anti inflammatory drugs N Eng J of Med327:749-54 Amdur MO et al 1991 The basic science of poisons N.Y. McGraw -Hill Anderson KE and Kappas A 1991 Dietary regulation of cytochrome P450 Annu Rev

Nutr:11:141-67 Heerdt AS, Young CW, Borgen PI. Calcium glucarate as a chemopreventative agent

in breast cancer Israel Journal of Medical Sciences. 1995 31(2-3),101-5 Hileman B Multiple Chemical Sensitivity C&EN July 22, 1991; 26-42 Racciatti D et al 2001 Chronic fatigue syndrome following a toxic exposure

Sci Total Environ 270(1-3) 27-31 Rooney PJ 1990 A short review of the relationship between intestinal permeability

and inflammatory joint disease Clinical and Experimental Rheumatology 12:299-305 Smith MD 1985 Abnormal bowel permeability in ankylosing spondylitis and

rheumatoid arthritis J Rheumatol 12:299-305 Steventon GB et al 1989 Xenobiotic metabolism in Parkinsons disease

Neurology39:883-87 Steventon GB et al 1990 Xenobiotic metabolism in Alzheimers disease

Neurology40:1095-98

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Bibliography

Hall DC 2001 Nutritional influences on estrogen metabolism Applied Nutritional Science Reports Advanced Met451 1/01 Nutrition Publications Inc

Seeley RS, Stephens TD, Tate P 2006 Anatomy and Physiology New York, McGraw - Hill