Environmental Flashcards
What does “PURE” stand for in the context of detox?
Pattern recognition
Undernourished
Reduce exposures
Ensure a safe detox
How is Total Toxic Load determined?
Total toxic exposure MINUS ability to biotransform + excrete toxins
(TTL=total of body burdens of exogenous chemicals, heavy metals, and toxic endogenous compounds)
What are the phase 1 (CYP P450) detox reactions?
Oxidation, reduction, hydrolysis
introduce or expose a functional group to render the compound more polar
What are the phase II detox reactions?
Glutathione conjugation (glutathione-S-transferase) - mostly into bile
Amino acid conjugation (taurine, glycine, arginine, glutamine)
Methylation (methyltransferase/eg COMT)
Sulfation (sulfonyltransferase) - excreted into urine (low substrate concentrations)
Acetylation (N-acetyltransferase)
Glucuronidation (UGT enzymes)
What are the Neuro & psych manifestations of poor detox?
Concentration and memory issues ADHD, autism Chronic headaches, insomnia Peripheral neuropathies, tremor Autonomic dysfunction Neurodegenerative disease - ALS, Parkinsons, AD MS Mood disorders Pain
What are the immune manifestations of poor detox?
Atopy
Autoimmune disease - Hashimoto’s, IBD, RA, SLE, psoriasis, Sjogrens
Chronic inflammatory disease
Recurrent/chronic infections
Chronic dermatitis
Adverse food reactions
Multiple chemical sensitivities (MCS): TILT
What are the mitochondrial and metabolic manifestations of poor detox?
Obesity and abnormal weight gain Metabolic syndrome & type 2 DM Atherosclerosis Fatigue, CFS Fibromyalgia, muscle aches, weakness Osteoporosis
What are the endocrine manifestations of poor detox?
Hormonal and HPA axis imbalances Thyroid issues Met Sx & Type 2 DM Females: premature puberty, PMS, PCOS, infertility, endometriosis, fibroids Males: oligospermia, sperm dysmotility
What are nutrients and foods which support phase 1 detoxification?
Riboflavin (soy, spinach, cremini, eggs, asparagus, almonds, turkey)
Niacin (fish, meat, brown rice)
Pyridoxine (meat, fish, sweet potatoes, potatoes, sunflower seeds, spinach, banana)
Folic acid (legumes, broccoli, turnip greens)
B12 (fish, meat)
Glutathione (undenatured whey protein, asparagus, curcumin, broccoli, avocado, spinach, garlic, citrus, Brazil nuts)
BCAAs (whey protein, fish, chicken, eggs)
Flavonoids
Phospholipids (soy, sunflower seeds, eggs)
Mg, Zn, Cu, Fe, molybdenum
What are nutrients which protect against overproduction of toxic phase I metabolites?
Carotenes/vitamin A
Vitamin C
Vitamin E (sunflower seeds, almonds, spinach, chard, avocado, asparagus)
Selenium (Brazil nuts, fish, meat)
Copper (sesame seeds, cashews, soy, mushrooms, walnuts, lentils, lima beans)
Zinc (meat, pumpkin seeds, lentils, quinoa)
Manganese (cloves, oats, brown rice, beans, pineapple, pumpkin seeds)
CoQ10 (meat, fish)
Thiols (garlic, leeks, onions, chives)
Flavonoids
Silymarin (milk thistle, artichokes)
Pycnogenol (skins of grapes, blueberries, cherries, plums)
What are nutrients and foods which can support phase II detox?
Glycine - beef, chicken, lamb
Taurine - fish, meat
Glutamine - beef, chicken, fish, eggs, cabbage, beets, beans, spinach, parsley
N-acetyl cysteine - meat, garlic, crucifers
Cysteine - meat, fish
Methionine - eggs, sesame, Brazil nuts, soy, chicken, tuna, legumes, almonds, brown rice
What are lab measures of antioxidant capacity?
Whole blood GSH (reflects tissue levels and correlated with NK function)
Glutathione peroxidase (Se dependent)
SOD (Cu/Zn cytosol and Mn mitochondria)
CoQ10
What are biomarkers of toxic susceptibility in the stool?
Dysbiosis and reduced diversity
beta-glucuronidase
Intestinal permeability (ie low lactulose or mannitol recovery)
Malabsorption markers:
List some oxidative stress tests
oxLDL
8-OH-dG - DNA damage (note: minimally affected by chemical antioxidants - A,C,E, beta-carotene)
Thiobarbituric acid reactive substances (TBARS)
Oxygen radical absorbance capacity (ORAC) - measures antioxidants in blood
Lipid peroxides
F2-Isoprostanes - formed from free radical attack of AAs, GLA & formed from COX
How can body burden be assessed?
Biomonitoring:
Measurement of exogenous agents in blood, stool, urine, hair, nail & adipose tissue
Measure markers that indicate presence or effects of toxin
What metals can be measured in hair?
Pb, Hg, Mn, Cd, As, Cr (WITH blood/urine markers)
Note:
Autism associated w/antimony, Pb, Hg, As
ADD, oppositional defiant disorder assoc w/Mn, Pb, Hg, AI
Chronic depression assoc w/Pb
What are some potential sources of oral toxicity?
Metals (Hg amalgams, crowns, titanium implants, orthodontic appliances)
Plastics (BPA, BPS, phthalates from fillings; resins in night guards)
Infections
Oral health products - triclosan, SLS, propylene glycol, titanium dioxide, fluoride
Note: mechanisms include galvanism, leaky mouth, sublingual absorption, swallowing, microbiome disruption -> leads to immune dysregulation, inflammation & oxidative stress
What are the components of safe mercury amalgam removal?
Pt pre-treatment with ingested charcoal and chlorella rinse
Nasal air supply & eye protection for the patient
Non-latex dam and nitrile gloves
Saliva ejector under dam
“Clean-up” suction devices
Auxiliary suction devices with mercury filters
Protective gowns and mercury vapor respirator masks for dental staff
How can we prevent oral toxicities?
Diet: remove food sensitivities, nutrients to support detox
Daily physical biofilm disruption
Choose safe ceramic and BPA-free dental materials
Eliminate toxic oral health products
Probiotics
What is the difference between toxin, toxicant, xenobiotic and persistent organic pollutant (POP)?
Toxin = produced by living organism (animal, plant, fungi, bacteria) Toxicant = result of human activity Xenobiotic = chemical compound foreign to the body POP = substances that persist in the environment and bioaccumulate through the food chain
Define body burden
The quantity of an exogenous substance or its metabolites that accumulates in an individual
What are population RFs which increase risk of POP burden?
Poverty, BMI, age, gender, race
Why do some people retain or are more sensitive to toxins?
Increased or ongoing exposure Nutrient deficiencies (B vitamins, antioxidants, Mg, Se, etc) High refined food intake Inadequate protein Stress, emotional trauma Intestinal dysbiosis Genetic variations in phase I/II
What are characteristics of biotransformation?
Constantly active Inducible Energy dependent Micronutrient dependent Genetically polymorphic Additive (affected by total load) Redundant
What organs & biochemical processes are involved in absorption and first pass metabolism?
Stomach (HCl) Intestines (digestive enzymes) Gut wall (CYP3A4, P-glycoprotein anti-porter pumps) Liver (P450s, transferases) Colon (bacterial metabolism, excretion)
Where are p-glycoprotein pumps located?
Intestines, BBB, kidneys, liver (biliary)
- antiporter which decreases intracellular [substances]
What medications induce p-glycoprotein?
Chemotherapy, dexamethasone, rifampin, SJW
What medications inhibit p-glycoprotein?
tamoxifen, ketoconazole, cyclosporine, erythromycin, verapamil, grapefruit juice, berberine
Which CYP enzyme has the greatest genetic variation?
CP2D6
(codeine, dextromethorphan, tamoxifen, TCAs, SSRIs)
Absent/poor: 6-10% Caucasians, >10% blacks, 1-2% Asians
Ultra-Rapid: 30% of Middle Eastern, North Africans
Which CYP enzyme is responsible for metabolism of ethanol, acetaminophen, nitrosamines, food mutagens, ketones, benzene?
CYP2E1
A genetic SNP in which enzyme would impact caffeine, aflatoxin and arylamine metabolism?
CYP1A2
Eg. Slow Metabolizer - coffee drinking increases risk of
MI
Which enzymes do cigarette smoking, charbroiled beef & dioxins induce?
CYP1A2; therefore cigarette smokers often have high caffeine tolerance
Also CYP1A1, 1B1
SNPs or chemicals that up-regulate which CYP enzyme can lead to autoimmune diseases and increased risk of prostate & breast CA?
CYP1B1
Responsible for bioactivation of pro-carcinogens, estrogen to 4-OH
Note: inhibited by DHEA, polyphenols, resveratrol, red clover
What factors can impact CYP450 phenotypic variability?
Drugs
SNPs
Age: variable in children, may decline w/age
Inflammation and liver disease reduce activity
Induced by nuclear receptors: AhR (aromatic hydrocarbon), PXR (pregnant X), CAR (constitutive androstane), VDR, PPAR (note: which in turn activate XREs - xenobiotic response elements)
Hormones (glucocorticoids, GH induce 3A4, T3 inhibit 3A4)
fasting alters many phase I enzymes
Gilbert’s Syndrome is a SNP in which detox enzyme?
UGT1A1
Impaired ability to conjugate bilirubin with glucuronic acid, therefore elevated unconjugated bilirubin after fasting
- especially noticeable with phenytoin, irinotecan
(Note UGT1A1 can be induced by suforaphane, flavonoids)
Which enzyme is inhibited by red wine anthocyanins, catechins, quercetin, genistein, red food dye, annatto and alcohol, leading to excessive monoamines?
SULT1A3 - deactivates catecholamines
SULT1A1 - deactivates xenobiotics, estrogens, phenolics, iodothyronines (therefore, PAHs which inhibit this can lead to estrogen and thyroid disruptions)