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IFM Study > Environmental Health APM > Flashcards

Environmental Health APM Flashcards

1
Q

What is required for optimal biotransformation?

A
  1. Nutritional support - phase 1 - macronutrients, broad spectrum micronutrient support; phase 2 - cofactors for conjugation
  2. Antioxidants to neutralize the free radicals made by phase 1
  3. Phytonutrient inducers of phase 2 enzymatic reactions
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2
Q

What happens when you have imbalanced detoxification?

A

Damage to DNA, RNA, proteins and reactive oxygen species which lead to chronic disease

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3
Q

What enzymes and cofactors help body to protect itself from Reactive Oxygen Species(ROS)?

A

Catalase - Fe
Superoxide dismutase(SOD) - Zn, Cu, Mn
Glutathione peroxidase and reductase - Se

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4
Q

What dietary antioxidants are needed to help the body protect itself from ROS?

A

Vitamin C for aqueous compartments
Vitamin E for lipid compartments
Carotenoids, flavonoids, etc

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5
Q

What endogenous antioxidants are needed to help the body protect itself from ROS?

A

Glutathione, cysteine, CoQ10, Lipoic acid, uric acid and cholesterol

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6
Q

What carotenoids help protect body from ROS?

A

Provitamin A from alpha/beta carotene, B cryptoxanthin
Lycopene
Xanthopylls - lutein, zeaxanthin, astaxanthin, B-cryptoxanthin, canthaxanthin

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7
Q

What phytochemicals help body to protect itself from ROS?

A

pomegrante, green tea, curcumin, milk thistle, etc

Thiol foods - cruciferous family, onion, garlic

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8
Q

What are the Phase 2 detoxification pathways?

A

Glucoronidation, Sulfonation, Methylation(3 most important) Glutathione Conjugation, Amino Acid conjugation and Acetylation

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9
Q

Where do you find the Phase 3 antiporters proteins?

A

Small intestinal villi, hepatocytes, proximal renal tubules and capillary endothelium on BBB

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10
Q

What does Phase 3 detoxification do?

A

It reduces load of phase 1(first pass metabolism) and clears out phase 2 hydrophillic metabolites after conjugation

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11
Q

What modulates phase 3 transporters?

A

Phytochemicals modulate by 2 mechanism:

1) signaling pathways, including mitogen activated protein kinases, phosphoinositide 3 kinase and protein kinase- resveratrol, liquiritigenin(licorice), Curcuminoids
2) Direct gene expression - Piperine(black pepper), capsacin(Chili), sesamin(sesame), daidzein and genistein(soy), curcuminoids and taurine

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12
Q

What are the 3 steps to form Glucuronide Conjugate?

A
  1. Coupling of D-glucose phosphate to UTP to give UDP glucose
  2. Oxidation of primary alcohol yields the coenzyme UDP glucuronic acid
  3. Conjugation with the substrate to yield glucuronide
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13
Q

What are some substrates of Glucuronidation?

A

Carcinogens(insecticides, herbicides, heterocyclic amines)
Plastics - BPA, phthalates
Pharm drugs - sulfonamides, naproxen, ibuprofen, tylenol, fibrates, etc)
Tobacco and recreational drugs
Mycotoxins
Dopamine, Serotonin

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14
Q

Which phase 2 detox pathway handles most of phase 2 interactions?

A

Glucuronidation

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15
Q

What endogenous substances go thru Glucuronidation?

A

Bile, bile acids, steroids, thyroid hormones, retinoids, PGE,

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16
Q

What substances go thru Glucorinidation?

A

Endogenous compounds, dietary polyphenols, large number of lipophillic xenobiotics

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17
Q

What is a common snp of Glucuronidation?

A

UGT1A1*28

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18
Q

Gilberts Syndrome has defect in which phase 2 pathway?

A

Glucuronidation.

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19
Q

How does citrus affect the UGT1A1*28 snp?

A

Women with 7/7n genotype who consumed 0.5 servings daily of citrus has 30% lower serum bili then those of same genotype who didn’t.

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20
Q

What type of cancer do UGT1A1*28 snp have a higher risk for and why?

A

Breast cancer due to increased circulating estradiol associated with reduced UGT1A1 activity.

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21
Q

What is UGT?

A

UDP Glucoronosyl Transferase

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22
Q

What phytonutrient can upregulate UGT1A1?

A

Quercetin

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23
Q

Quercetin reduces exposures to what compounds through increased glucuronidation?

A

Hydroxylated PCBs

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24
Q

What flavonoids upregulate UGT?

A

Luteolin and chrysin

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25
Q

What are the highest luteolin and chrysin sources?

A

Honey, propolis, broccoli, chili peppers, celery, rosemary, parsley,

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26
Q

How does honey reduce DNA damage?

A

It extracts inhibited pesticide induced mitochondriaROS(mtROS) thru upregulating phase 2 and also by upregulating DNA repair thru NRF2

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27
Q

Which food enhanced DNA repair in residents chronically exposed to pesticides resulting in marked reduction in pesticide-induced DNA lesions?

A

Honey

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28
Q

What botanicals induces UGT?

A 
Milk thistle
Gingko Biloba
Grape Seed extract
Hawthorn
Noni
St John's wort
Valerian
Cranberry
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29
Q

How does resveratrol affect UGT1A1?

A

Resveratrol alone or with curcumin or chysin induces UGT1A1 in the caco-2 cells(colon). Mediates 12-22 fold increase in UGT1A1 mRNA gene expression.

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30
Q

How does Glucosinolates upregulate Glucuronidation?

A

Watercress increases urinary glucuronides in smokers

Gardencress has chemoprotective effect thru enhancement of detoxification of IQ by UDPGT

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31
Q

What is the relationship to Beta Glucuronidase and certain foods?

A

Activity of B-Glu is inversely related to higher plant protein and fiber intake. Apple ingestion has same effect. Citrus, cruciferous less so.
Serum alpha and beta carotene levels are inversely associated with lowered serum B-Glu.

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32
Q

What are some beta glucuronidase inhibitors?

A

Silymarin(milk thistle), strawberry, black currant, reishi(ganoderma lucidum), licorice, lactic acid probiotics, prebiotics such as inulin, caloric restriction, lactoveg diets, calcium d glucarate,

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33
Q

What cancers do calcium d glucarate reduce?

A

breast, colon, lung, liver, skin

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34
Q

How does d glucarates reduce cancer risk?

A

Suppresses cell proliferation and inflammation but also induces apoptosis.

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35
Q

What veggies contain highest amount D glucarates?

A

Highest in Cruciferous veggies

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36
Q

How does thyroid hormone affect glucuronidation?

A

involved in expression of UGT1A1(bilirubin glucuronidation) and UGT1A6(xenobiotics)

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37
Q

Which vitamin influences T3 effect on UGT expression?

A

Vitamin A retinol

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38
Q

How does Vitamin A deficiency affect glucuronidation?

A

It inhibits UGT 1A1 and 1A6 expression.

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39
Q

What are high quercetin foods?

A

Apple, onion, cherry, kale, red wine, EVOO, beans, broccoli and tea

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40
Q

What are high chrysin foods?

A

Honey, celery, parsley, chili pepper, broccoli, rosemary, propolis

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41
Q

What foods inhibit beta glucuronidase?

A

Strawberry, black currant, milk thistle, Reishi, licorice, probiotics, inulin, citrus, watercress(cruciferous) and tumeric

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42
Q

How do EFA affect glucuronidation?

A

Needed as glucuronidation occurs on smooth endoplasmic reticulum;

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43
Q

What are some supportive factors of glucuronidation?

A

EFA, magnesium, flavonoids, glucosinolates, catechin

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44
Q

What are some inhibitors of glucuronidation?

A

Smoking, fasting, high fructose diet

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45
Q

What are the steps in Sulfate Conjugation?

A
  1. Activation of inorganic sulfate by ATP
  2. Phosphorylation of the 3’OH to generate the sulfation cofactor
  3. Conjugation with the substrate to yield the conjugate.
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46
Q

What is PAPS?

A

Coenzyme in sulfonation - 3 phosphoadenosine 5 phosphosulfate that participates in sulfotransferase phase 2 reactions(liver, kidney, intestine).

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47
Q

What does sulfonation detoxify?

A

Many rx drugs, endogenous hormones(estrogen) and amines

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48
Q

What is PEITC?

A

glucosinolate found in cabbage and watercress that supports glucuronidation and sulfonation.

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49
Q

What induces SULT expression?

A

Genistein isoflavone, PEITC, vitamin E, Vitamin A(retinol), selenium and caffeine induce SULT to biotransform xenobiotics esp xenoestrogens.

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50
Q

What is sulfite oxidase?

A

catalyzes the transformation of sulfite to sulfate, a reaction necessary for the metabolism of sulfur-containing amino acids(methionine and cysteine)

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51
Q

What are sulfite oxidase(SO) cofactors?

A

B6 and Molybdenum

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52
Q

What are sources of Molybdenum?

A

Adzuki beans, other legumes, grains, nuts

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53
Q

What is dose of Molybdenum?

A

100-200 mcg; Toxicity is >1500 mcg

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54
Q

What are the sulfur amino acids?

A

Methionine, cysteine, cystine, homocysteine, glutathione, taurine

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55
Q

What substances is sulfur needed for synthesis of?

A

Lipoic acid, Coenzyme A, biotin, mucopolysaccharides chondroitin and glucosamine sulfate

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56
Q

What substances are sulfur a component of?

A

insulin, metallothionein, heparin and collagen

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57
Q

What are chronic diseases associated with sulfation impairment?(SULT snps)

A

Environmental/chemical sensitivity
Alzheimers, Parkinsons, motor neuron dz, RA
Delayed food sensitivity(intolerance of phenol, tyramine, phenylic food constituents)
Diet responsive Autism
Acetaminophen intolerance, toxicity(starvation of SULT for sulfate substrate)

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58
Q

How does insulin and DM affect Transsulfuration?

A

It downregulates CBS(Cystathionine B synthase)

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59
Q

What amino acid gets converted to glutathione via sulfonation?

A

Cysteine

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60
Q

What is CBS?

A

Enzyme that makes glutathione from amino acid.

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61
Q

How do you diagnose or get a clue of sulfonation issues?

A

Blood sulfate,
Sulfur amino acids:plasma methionine, cystathionine, cysteine
Transulforation: CBS gene SNP(b6 is coenzyme)
SULT gene SNPs

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62
Q

How can you supplement with sulfur?

A 
High sulfur foods - primarily seafood
Sodium sulfate (100-1500 mg)
Sulfur amino acids(methionine, NAC and Taurine)
MSM 2-6 gm
Vitamin B6
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63
Q

What is the highest plant methionine source?

A

Corn

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64
Q

What are plant cysteine sources?

A

Oats, Corn

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65
Q

What are some plant methionine sources:

A

Corn(highest), sunflower seeds, oats, chocolate, cashew, walnuts, almonds, sesame seeds(lowest)

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66
Q

What key factors do methyltransferases donate a methyl group from SAMe?

A

DNA protection
Phosphatidylcholine Synthesis
Neurotransmitter metabolism(epi, norepi, dopamine, anxiety/dep, insomnia, mania, learning disabilities)

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67
Q

Define susceptibility to toxins.

A

The ability of an individual to biotransform, detoxify and eliminate exogenous and endogenous compounds.

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68
Q

What is the breakdown product of glyphosate?

A

AMPA

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69
Q

How long can it take for a chemical to be on the market before it is found to be toxic?

A

10-20 years

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70
Q

How has lead level acceptibility changed over the years?

A

In 1970’s, >60 ng/ml was std for lead poisoning, now 5ng/ml is elevated and 10 ng/ml is toxicity and no amount of lead level is considered safe.

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71
Q

What products have BPA?

A

plastic water bottles, cash, receipts, canned food and drinks; over 100 tons released into atmosphere yearly

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72
Q

How is BPA absorbed in humans?

A

Thru gut mucosa and skin

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73
Q

How does BPA affect us?

A

It is an endocrine disruptor. Mimics estrogen and other hormones and interrupts cellular signaling even at low levels.

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74
Q

What diseases are BPA linked to?

A

Diabetes, obesity, heart disease and liver inflammation. Cancer, thyroid d/o and infertility.

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75
Q

What product increases the absorption of BPA?

A

Hand sanitizer

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76
Q

Explain study of BPA serum concentration on men

A

Increasing serum BPA is significantly associated with decreased testosterone and androstenedione levels. Decreased sperm count and impaired sexual function.

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77
Q

What age is the most sensitive window of exposure to endocrine disrupting chemicals(EDC)?

A

during critcal periods of development, such as fetal development and puberty

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78
Q

What hormones do EDCs act on?

A

Estrogen, androgens and thyroid. But may interact with multiple hormone receptors at same time.

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79
Q

What are possible obesogens?

A

Organochlorines(POP), Organotins,
Phthalates, BPA, Perfluorooctanoic acids(PFOA), Polybrominated diphenylethers(PBDE), Nonylphenol(alkylphenol), Atrazine, air pollutants, HighFructose Syrup, Diethylstilbestrol, atypical antipsychotics, thiazolidinediones

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80
Q

What is a xenobiotic?

A

Chemical substances that are foreign to life that are detected in the body

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81
Q

What is the exposome?

A

Combined exposures of all sources that reach the body’s internal chemical environment

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82
Q

What is disease risk?

A

Lifetime exposure x toxic potency x susceptibility

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83
Q

Total toxic load results from

A

Total toxic exposure minus ability to biotransform and excrete toxins

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84
Q

Biotransformation is

A
  • constantly active
  • ATP dependent(energy dependent)
  • Highly nutrient dependent - if nutritionally deficient, biotransformation is less effective
  • polymorphic - marked interindividual variability
  • inducible by toxicants, drugs, phytochemicals - turns on biotransformation enzymes
  • additive - affected by total load - higher levels overload enzymes
  • redundant(multiple substrates processed thru same pathways) - multiple enzymes process it
  • highly influenced by environment
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85
Q

All tissues have biotransformation activity. True of False.

A

True.

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86
Q

What organs/tissues have the highest amount of biotransformation?

A

Skin, liver, lungs, gut, kidney, BBB

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87
Q

In general terms, what does phase 1 reactions do?

A

Introduce or expose a functional group on parent compound, making it more polar; May also activate inert compounds(prodrugs or procarcinogens).

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88
Q

What does it mean that a compound is polar?

A

Has a positive and negative charge and so body can then do something with it.

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89
Q

What happens when you have inhibition of CYP450?

A

= phase 1 inhibition and can increase blood levels of drug or hormone which is a major cause of drug drug interaction and drug-phytochemical reaction

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90
Q

What are some CYP450 inhibitors?

A 
Berberine
Antifungals
Grapefruit juice
Green tea catechins
Garlic
SSRI
Star juice
Cimetidine
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91
Q

What are some commonly induced Phase 1 enzymes?

A

CYP1A, CYP1B1, CYP2E1

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92
Q

How does phase 1 get induced?

A

By upregulating transcription

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93
Q

Why does Phase 2 take so much energy?

A

Much of the energy is used to make enzymes and they are large globular proteins

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94
Q

What qualities do phase 2 resulting conjugates have?

A

highly polar, inactive and rapidly excreted

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95
Q

What pathway is phase 2 activity substantially increased by?

A

Genetic induction via NRF2/ARE pathway

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96
Q

What otc medicine bypasses phase 1?

A

Tylenol

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97
Q

If phase 2 enzymes get overloaded then which phase 1 CYP450 enzyme does tylenol go thru?

A

CYP2E1 - leads to toxic compound which liver can neutralize with glutathione. However, if not enough or if drinking etoh it depletes glutathione and get liver damage

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98
Q

What is NAC?

A

N-acetylcysteine, rate limiting precursor to glutathione, Essential nutrient for detoxification regimens
Used for tylenol toxicity
Potent antioxidant

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99
Q

What are some reasons some people retain more or more sensitive to toxins?

A 
High sugar, low protein diet
Oxidative stress
Poor elimination
Polymorphisms
Chronic inflammation
Overwhelming toxic load
Intestinal dysbiosis
Nutrient deficiencies
Stress, emotional trauma
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100
Q

What is GGT representative of in evaluating for toxicity?

A

Glutathione activity

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101
Q

What triggers would you look at to assess toxicity?

A

Toxic metals(blood, urine, hair analysis pre/post DMSA challenge)
Organic toxicants (fat biopsy, blood, urine)
Stool tests
Hepatic detoxification and oxidative stress profiles
Intestinal permeability testing

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102
Q

What mediators would you look at to assess toxicity?

A

Essential fatty acid profile
Oxidative stress markers
Extra and intra cellular antiox level - vitamin A and E

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103
Q

What are functional medicine principles for detoxification?

A

Minimize exogenous toxic exposures
Insure adequate hydration and oxygenation
Optimize bowel health and excretion
Enhance antioxidant reserve
Downregulate inflammation with EFAs
Assist and balance endogenous biotransformation of toxicants
Utilize bowel rest programs and oligo antigenic medical foods when appropriate

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104
Q

Which fish have the highest mercury content?

A

Tuna, swordfish, shark, king mackerel, tilefish, oysters downstream from wastewater

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105
Q

What are the 5R for detoxification?

A 
Remove pathogens
Replace enzymes and HCL
Repair damaged intestinal mucosa
Reinoculate with probiotics/prebiotics
Rebalance
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106
Q

What are some agents that repair gut lining?

A 
Probiotics
Plant fibers
L-glutamine
Arabinogalactan(Western Larch bark)
Aloe vera mucopolysaccharides
Licorice Root, 
Bovine Colostrum
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107
Q

What are some agents that enhance excreting toxins?

A

Activated charcoal(don’t use with other supplements)
Bile acid sequestrants(choleystyramine)
Olestra(sucrose polyesters)
D Glucaric acid

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108
Q

What are some CYP450 Xenobiotic Metabolizers?

A

1A1, 1A2, 1B1 - PAH, food mutagens, aflatoxins
2E1 - etoh, nitrosamines, food mutagens, ketones
3A4 - aflatoxin, food mutagens

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109
Q

Elevated levels of B-glucoronidase are found with:

A

Dysbiosis

Exposure to xenobiotics(smoke, PAH, nitrosamines)

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110
Q

What does B-glucoronidase do?

A

Salvage enzyme that recycles conjugated compounds. Can break bond between toxin and glucuronic acid during glucoronidation, reactivating toxins effect
Found in tissues thruout the body and varies per individual
High levels associated with increased cancer risk esp breast.

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111
Q

What foods contain D glucaric acid?

A 
Cruciferous veggies
Citrus
Apples
Apricots
Bean sprouts 
Cherries
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112
Q

What are some functions of D-glucaric acid?

A

Inhibits B-glucoronidase
Regulates blood levels of bile acids and steroid hormones
Protects against cancer of the breast, prostate, lung, colon, bladder and skin in animal studies

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113
Q

What are some things you can do/eat to help remove toxins?

A

Exercise, Sauna(Sweat)
Polysaccharides from algae and seaweeds
NAC and alpha lipoic acid
Systemic chelating agents in severe cases as it can deplete Mg.(DMSA oral, DMPS IV, Oral)

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114
Q

What are some polysaccharides from algae and seaweed that help remove toxins?

A

Chlorella pyrenoidosa - removes mercury, dioxin
Fucus(bladderwrack)
Laminaria(kelp)

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115
Q

How do cholagogues and Cholerectics work to reduce toxins?

A

Enhance secretion of toxins by increasing bile flow.

116
Q

What are some cholagogues and cholerectics?

A 
Berberine
Coffee
Tumeric
Milk thistle
Globe Artichoke
Greater Celandine
Dandelion
Taurine
117
Q

Which antioxidant nutrients may minimize endothelial cell damage mediated by POPs?

A

Vitamin E
Dietary Flavonoids
High ratio of Omega 3:6 ratio

118
Q

What are some antioxidants used for detox?

A 
Rosemary
Cucurmin
Flavonoids
Carotenoids
Tocopherols(esp gamma and alpha)
NAC/Glutathione
Alpha lipoic acid
CoQ10
119
Q

What is the primary intracellular non-enzymatic antioxidant present in all living cells?

A

Glutathione

120
Q

Where are high concentrations of glutathione found?

A

Brain parenchyma and liver

121
Q

What is substrates does glutathione conjugate?

A

Heavy metals
External toxicants
Carcinogens
Pharmaceuticals

122
Q

What supplements can optimize reduced glutathione levels?

A 
Vitamin C
NAC
Lipoic acid
Cucurmin
Milk thistle
Whey protein concentrates
123
Q

What nutritional and phytochemical support do you need for biotransformation?

A

Adequate protein source for enzyme production
Conjugant precursors for phase 2 reactions
Enzymatic cofactors for phase 1 and 2
Transcription inducers of phase 2 enzymes

124
Q

What are some phase 2 inducers?

A 
Glucosinolates
Flavonoids
Organosulphur compounds
Curcuminoids
Milk Thistle
Articoke
Rosemary
Monoterpenes
125
Q

What is a potent transcription inducer of Phase 2 detoxification and antioxidant enzymes?

A

Sulforaphane

126
Q

What are the effects of Curcumin on detoxification?

A 
Chemoprotective
Anti inflammatory
Hepatoprotective
Anxtioxidant(decreases LDL oxidation)
Inhibits CYP 1A1/2
Increases glutathione production
Upregulates phase 2 enzymes
Inhibits p-glycoprotein pump helping to prevent multi-drug resistance
127
Q

How does Ellagic Acid affect detoxification?

A

Binds to toxic metals(nickel), promoting excretion
Hepatoprotectant against toxin-induced damage
Inhibits CYP1A1 activation of cardinogens(PAH, Innitroso)
Induces expression of phase 2 enzymes
Binds directly to some toxins such as benzopyrene

128
Q

What are effects of Green Tea on detoxification?

A

potent antioxidant - binds to phase 1 intermediates
bind to many toxic compounds
Bifunctional modulators: 1. Modulate phase 1 enzymes(selectively induces some CYP but prevents over induction by toxins). 2. Induces phase 2 enzymes - glucuronosyl transferases, glutathione S-transferases

129
Q

What are the effects of Milk Thistle on detoxification?

A

Hepatoprotectant
May inhibit 2E1
Increases serum and hepatic glutathione and glutathione production
Induces Glutathione transferases
No deleterious effects on drug metabolism

130
Q

What 2 main classes of organosulphates does garlic have?

A
  • Gamma glutamylcysteines(water soluble) - metabolized to S-allycysteine which is found in aged garlic
  • Cysteine sulfoxides(fat soluble)
131
Q

What CYP450 enzyme does garlic oil, diallyl disulfide, trisulfide inhibit?

A

CYP2E1

132
Q

How does garlic oil, diallyl disulfide, trisulfide induce Phase 2 enzymes?

A

by activation of antioxidant response element(ARE) genes

Induces - glutathione S-transferase and Quinone reductase

133
Q

What are some methylators that support phase 2 conjugation?

A 
Methylfolate
Methylcobalamin
Trimethylglycine
SAMe
Phosphatidylcholine
Glycine
Taurine
Glutamine
Sodium Sulphate
Pantothetic acid
Magnesium
134
Q

Which patients should you consider detoxification in?

A

Feels persistently unwell and fatigued
Sudden onset of autoimmune disease or chronic neuro d/o
Sensitive to all sorts of fumes
Has personal or strong family hx of cancer
has long history of constipation
Has a past medical hx of toxic exposure

135
Q

What CYP450 does berberine inhibit?

A

2D6, 3A4, 2C9

136
Q

What CYP450 does Green tea inhibit?

A

1A1, 1A2, 1B1

137
Q

What CYP450 does garlic inhibit?

A

2E1

138
Q

What CYP450 does star fruit inhibit?

A

2A6, 1A2, 3A4

139
Q

What CYP450 does Grapefruit juice(furanocoumarins) inhibit?

A

3A4

140
Q

What is enzyme used in Methylation?

A

Methyltransferase

141
Q

Which substrates require a transfer from methyl groups from SAMe via methylation?

A

nucleic acids, proteins, lipids and secondary metabolites

142
Q

Describe process of methylation

A

SAMe will donate its methyl group to other substances to form SAH(s-adenosyl homocysteine).

143
Q

NASH is a problem from which phase 2 reaction?

A

Methylation - low SAMe leads to elevated homocysteine

144
Q

What increases SAMe?

A

Trimethylglycine(Betaine)

145
Q

What supplement helps NASH and why?

A

Trimethylglycine as it increases SAMe and reduces hepatic enzymes, steatosis and fibrosis associated with NASH

146
Q

What combination of supplements was shown to help lower homocysteine by 39%?

A

B12 and fish oil

147
Q

What is associated with decreased arsenic methylation?

A

Skin cancers

148
Q

What donates methyl groups to arsenic during methylation process?

A

SAMe and choline to produce monmethylarsinic acid and dimethylarsinic acid

149
Q

What amino acid is needed for arsenic methylation?

A

Methionine

150
Q

What substances increased arsenic methylation in vitro?

A

Methylcobalamin, Glutathione and Selenium

151
Q

High arsenic exposure let to 57% reduction in which antioxidant?

A

Glutathione

152
Q

What is inversely related to whole blood Arsenic and its methylated forms MMA, DMA?

A

Glutathione

153
Q

What low nutrient level correlated with lower ability to methylate Arsenic in Tawainese exposed arsenic related ischemic heart disease?

A

low serum Alpha and beta carotene

154
Q

Poor vibratory sense and impaired light touch is associated with defect in which phase 2 reaction?

A

Methylation

155
Q

What can you check for methylation diagnosis?

A

Methionine metabolism
MMA
Gene SNP(tells of potential impairment)
Serum b12, folate, pyridoxine less helpful

156
Q

What are some labs to tell you about methionine metabolism?

A 
Plasma homocysteine
Plasma SAMe
Plasma SAH
SAMe/SAH ratio - index of methylation potential
Plasma methionine and cysteine
157
Q

What are the 3 common causes of Neuropathy in Adults?

A
  1. DM, IR
  2. Etoh
  3. Toxic metals - PB, Hg, Cd, As, xenobiotics
158
Q

What 3 amino acids are GSH composed of?

A

Glutamine(glutamic acid), glycine, cysteine

159
Q

How does GSH be the primary free radical cell protector?

A

by maintaining mitochondrial redox potential and cell membrane stability

160
Q

What is mercapturic acid?

A

Glutathione conjugate which is excreted in urine

161
Q

What is GSH used in conjugation with to form Leukotrienes?

A

Arachodonic acid

162
Q

What are some common diseases that are associated with low Glutathione levels?

A

Heart disease, HTN, arthritis and MSK diseases, Diabetes, Leukemia, hearing loss, macular degeneration, autism

163
Q

What foods contain GSH?

A

F/V - contribute over 50% dietary GSH

Meats - contribute to less than 25%

164
Q

What is associated with decreased risk of oral cancer?

A

Increased dietary intake of GSH from F/V and subsequently higher blood GSH levels

165
Q

What supplement can increase NK cell cytotoxicity?

A

GSH

166
Q

What is a rate limiting step for glutathione synthesis?

A

Cysteine(NAC)

167
Q

What supplement can boost GSH levels?

A

NAC

168
Q

True of False. Cognitive improvements were seen following NAC treatment.

A

True

169
Q

What are key factors depend on Methylation?

A

DNA protection
Phosphatidylcholine synthesis
Neurotransmitter metabolism

170
Q

Which phase 2 reaction plays a role in neurotransmitter metabolism?

A

Methylation - people with depression/anxiety respond well to methylation therapy

171
Q

Does NAC bind to essential minerals?

A

No

172
Q

Does NAC provide chelating sites for metals?

A

Yes, esp with thiol groups - lead, mercury, arsenic

173
Q

What is 5 L oxoproline?

A

When glycine is too low to sustain a normal rate of GSH synthesis, you get a rise in tissue levels of gamma glutamylcysteine which leads to an increase in urinary excretion of this alternative metabolite(seen low protein intake)

174
Q

What increased amino acid intake could have a beneficial role in sarcopenic elderly?

A

Glycine

175
Q

Does GSH level decline or increase with age and why?

A

Decline, d/t decline in NrF2 mediated induction of phase 2 enzymes and lower tissue levels of cysteine, glycine

176
Q

What supplement can help increase Nrf2 activity that declines with age?

A

Lipoic acid

177
Q

What nutrient upregulates GGT gene expression in CNS astrocytes?

A

Vitamin D3

178
Q

What cell plays a pivotal role in CNS detoxification pathways?

A

Astrocytes

179
Q

What could be an effective controller of detox process of the brain?

A

Vitamin 1, 25-D3

180
Q

What vitamin increases GSH in RBC’s and lymphocytes?

A

Vitamin C

181
Q

What vitamin increases GSH in plasma?

A

Vitamin E

182
Q

What protein can help to increase GSH?

A

Whey

183
Q

What can you look at for Glutathione issues?

A

RBC reduced glutathione
Blood glutathione peroxidase
Serum/plasma cysteine
Urine mercapturic acid - indirect way (would see low levels if not enough cysteine or glutathione)

184
Q

What amino acids are involved in amino acid conjugation of Phase 2 reactions?

A

Glycine, Taurine, Arginine, Glutamine

185
Q

What does amino acid conjugation metabolize?

A

Minor pathways for -
Endogenous molecules - bile acids, branched chain fatty acids
Environmental - some herbicides
Food preservatives - benzoates
Drugs - salicyclic acid(glycine); ibuprofen(taurine), valproic acid

186
Q

What is the primary role of amino acid conjugation?

A

regulate systemic levels of amino acids that are also utilized as neurotransmitters in the CNS

187
Q

What is glycine a substrate for?

A 
Porphyrins(heme)
Purines
Creatine
Sarcosine
Bile Salts
188
Q

Which amino acid is in collagen and elastin?

A

Glycine

189
Q

Where is the concentration of Taurine the highest?

A

Brain and heart

190
Q

Which is the second most amino acid in the blood?

A

Taurine

191
Q

Which amino acid crosses BBB?

A

Taurine, protects against glutamine excitotoxicity.

192
Q

Which metals do taurine potentiate the depletion of from blood, liver, and renal?

A

Lead, Arsenic

193
Q

Animals treated with Taurine significantly reversed ____ parameters induced by ___and ____

A

oxidative stress

lead and arsenic

194
Q

What increased blood, brain SOD &GSH and decreased Tbars by lead and arsenic?

A

Taurine

195
Q

What are some clinical applications of impaired Taurine?

A

Hyperactivity, anxiety, sleep disturbance, seizures, autism, cholestasis etc

196
Q

What cofactors are needed to convert cysteine to taurine?

A

B6 and B3

197
Q

What cofactors are needed to convert homocysteine to taurine?

A

betaine, serine

198
Q

What are some applications for glutamine?

A

IBD, increased IP, wounds, low mucle mass, wasting syndromes, cancer patients

199
Q

What is the 1/2 life of glutamine?

A

4 hours so should dose it several times a day

200
Q

What are contraindications to high doses of Glutamine(15gm) and why?

A

ALS, MS, PD - glutamine conversion to glutamate in the neurons can be excitotoxic

201
Q

What enzyme is used in Acetylation?

A

N-acetyltransferase

202
Q

What does NAT enzyme do?

A

catalyzes the transfer of acetyl groups from acetyl CoA to arylamines.

203
Q

Which supplement can increase NAT activity?

A

Quercetin

204
Q

How do you assess for Acetylation?

A

Look at NAT1 and NAT2 snp

205
Q

Who would you consider impaired detoxification?

A 
Chemically sensitive
Neuro symptoms
Autoimmune
Metabolic syndrome, obesity, DM
Structural - FM, osteopenia/osteoporosis
SNP
206
Q

What clinical emphasis should you have in regards to improving glucoronidation?

A

Carotenoids, glucuronidase support, thyroid, dysbiosis

207
Q

What clinical emphasis should you have in regards to improving sulfonation?

A

Sulfur amino acids, sulfate/MSM

208
Q

What clinical emphasis should you have in regards to improving Methylation?

A

Folate, B12, B6, TMG, EPA-DHA

209
Q

What clinical emphasis should you have in regards to improving Glutathione conjugation?

A

NAC, lipoate, GSH, Mg, D3, phytonutrients

210
Q

What phase 1 snp may increase estrogen metabolites?

A

1A2, 1B1

211
Q

What labs would you check if GST snp?

A

blood GSH and/or oxidative stress(cysteine, SOD, GSHpx, sulfate, peroxidases)

212
Q

Which macronutrient is the most important for detox?

A

Protein

213
Q

What type of patients would you consider low protein?

A

Decreased intake(esp seniors)
Low acid - on PPI,
Malabsorption
Increased use of proteins - chronic infections, toxin exposure, excessive exercise

214
Q

Whats the best and worse measure of one’s protein status?

A

Best - plasma amino acids
Worse - total protein, A/G ratio
Indirect - BIA

215
Q

What type of diet shows low liver CYP450?

A

High sucrose, low Mg. It also slows bowel transit and elevates oxidative stress

216
Q

How do toxic metals affect ATP?

A

They impair the reaction of pyruvate dehydrogenase complex so get decreased ATP

217
Q

What is an optimal amount of fiber to help reduce chronic disease?

A

25-29 gm

218
Q

What are benefits of fiber?

A

Lower CRP
Increased body/skeletal mass in elderly
Decrease in mortality from CVD and colon cancer
Better detox

219
Q

What effect does fat free diet have on detox?

A

Reduces CYP450 and GST concentration and activity

220
Q

Why do CYP450 need fats?

A

To make phospholipid matrix of endoplasmic reticulum

221
Q

What was reduced with better GSH:creatine ratio from omega 3 supplementation?

A

Depression

222
Q

What is a GGT >40 associated with?

A

POP burden

223
Q

What does a high GGT indicate?

A

increased glutathione catabolism/depletion

224
Q

Which B deficiency is associated with supporting glutathione synthesis thru its role in ATP production?

A

Pantothetic acid

225
Q

Which B deficiency is associated with lower glutathione levels?

A

B12

226
Q

What is the purpose of Zn in detox?

A

Complexes with phospholipids:block membrane oxidation
Protects sulfhydryl groups against oxidation
Displaced by Hg, Cd, Pb
Induces Metallothionein genes
SOD requires it - stabilizes

227
Q

Which age risk of zinc deficiency?

A

infants, children and >65yo

228
Q

Who has risk for zinc deficiency?

A 
infants, children and >65 yo
Pregnant, breast feeding
Severe/persistent diarrhea
Malabsorption syndromes - celiac disease, short bowel
IBD
Strict vegetarians - high grain/legume phytate content can increase demand for zinc by 50%
Etohlic liver dz - renal losses zinc
Malnourished
229
Q

How does zinc deficiency affect immune system?

A

impairs development of acquired immunity - compromises b lymphocyte development and IgG ab production. Adverse effect on macrophages.

230
Q

What are some signs of zinc deficiency?

A

Dermatitis, glossitis, hair loss, nail dystrophy, frequent infection

231
Q

What tastes will be lacking in zinc deficiency?

A

bitter, metallic, sour

232
Q

What type of deficiency is a low vitamin A/beta carotene deficiency associated with?

A

Zinc

233
Q

What is low alk phosp associated with?

A

Zinc deficiency

234
Q

How do you check for zinc deficiency?

A 
Low RBC or plasma zinc
Low alk phos
Check for high copper
Zinc taste test - loss of bitter, metallic and sour
Low vitamin A/beta carotene ratio
235
Q

What does Zn suppress with supplementation?

A

HDL, Copper

236
Q

What type of deficiency increases intestinal absorption and body retention of lead?

A

Calcium

237
Q

What deficiency causes a loss of dopaminergic neurons in PD pts?

A

Magnesium

238
Q

What are magnesium functions?

A

Molecular synthesis - DNA, RNA, proteins(glutathione), carbs, lipids
Energy production - fat and carb metabolism for ATP
Ion transport - Na-K ATPase, calcium reg
Cell signaling - protein phosphorylation, formation of cAMP(PTH)

239
Q

What mineral offers neuroprotection via NMDA block?

A

Magnesium

240
Q

What are some early signs of Mg deficiency?

A

Constipation, HA, muscle cramps, fatigue, parathesias,

241
Q

What are some progressed signs of Mg deficiency?

A 
RAD
HTN, arrythmia
loss of appetite
N/V
Seizures
Personality changes
Tremor, carpopedal spasm
242
Q

What happens when Magnesium is given to asthmatics?

A

Increased GSH

243
Q

What percent of tissue levels does serum Mg represent?

A

1% so should get RBC Mg

244
Q

Where does selenium reside?

A

2/3 resides inside RBC bound to selenoproteins(90%)

10% reside in GSH peroxidase

245
Q

What metals form a complex with Selenium there by decreasing selenoenzyme activity?

A

Pb, Hg

246
Q

How does Selenium improve cellular stress response, protein repair, and protection against oxidative stress?

A

restores Hg inhibited TxR. TxR is needed for those processes.

247
Q

What are some symptoms of Selenium deficiency?

A 
Muscle aches/fatigue, frequent colds/flu, brain fog
Hypothyroid(T4-T3 conversion)
Dental Caries
CV disease, thrombosis
Increased inflammatory response
248
Q

What are some benefits of Selenium?

A

Increased Hg excretion
Decreased malondialdehyde(lipid peroxidation)
Decreased 8-OH-dG(DNA oxidation)

249
Q

What labs can you order to check Selenium deficiency?

A

RBC selenium, urine selenium

250
Q

Which mineral is required for all CYP450 enzymes?

A

Iron

251
Q

What mineral impedes Zinc absorption when both are taken in the fasted state but not when taken with meals?

A

Iron

252
Q

What heavy metal has increased GI absorption with iron deficiency?

A

Cadmium; Fe deficiency is a risk factor for elevated blood and urine Cd among never smoker, premenopausal, nonpregnant women independent of age, race, poverty, bmi and parity

253
Q

Iron deficiency causes an increased blood level of what metal?

A

Lead

254
Q

What are some high heme iron foods?

A

Meat, poultry, seafood

255
Q

What concerns about iron from non-heme foods?

A

absorption is inhibited by phytic acid, polyphenols with low vitamin C and soy protein.

256
Q

Do vegetarians have a higher iron requirement?

A

Yes, 1.8 times higher then nonveg

257
Q

What do lipoates induce?

A

Phase 2 enzymes by activating Nrf2

DNA protection against carcinogens, ROS & nitrogen species

258
Q

What effect on metals does lipoate have?

A

may directly chelate Pb, Hg, Cd, As or reduce the oxidative capacity of the metal

259
Q

What are some functions of lipoic acid?

A 
Restores intracellular GSH 
DHLA regenerates Vit C better than GSH and Vit E from their oxidized form
Protects membrane
Protects against metal ox stress
Antioxidant
Inhibits inflammatory cytokines
260
Q

How does lipoic acid restore intracellular GSH?

A

substrate for NADPH-dependent enzyme GSH reductase

261
Q

What substances inhibit inflammatory cytokines?

A

Lipoic acid, Zn, Omega 3, cucurmin by blocking NFKB

262
Q

How does lipoic acid protect membranes?

A

reduces oxidized forms of CoQ10, vitamin C, GSH which in turns recycles E

263
Q

What is PON1?

A

Hydrolyzes organophosphates in the liver

264
Q

What is ALDH2?

A

Metabolizes acetaldehyde

265
Q

What is a surrogate for PON1?

A

Low HDL

266
Q

What is more toxic metabolite of As?

A

Monomethylarsonic acid(MMA)

267
Q

What is less toxic metabolite of As?

A

Dimethylarsinic acid(DMA)

268
Q

What supplement can decrease toxic metabolites of As?

A

Folic acid

269
Q

What are you depleting if you have high As?

A

SAMe as As gets methylated

270
Q

What are some tests of Antiox capacity?

A

GSH, SOD, CoQ10, GPx

271
Q

What has a linear correlation with NK cells?

A

GSH

272
Q

What condition is associated with hyperabsorption?

A

PD

273
Q

What are some biomarkers of effect?

A

WBC, RBC
LFTs(ALT, LDH, GGT)
Uric acid(PCBs, dioxin and dioxin like chemicals)
Kidney fxn(BUN, Cr, Cystatin C)

274
Q

What toxins are assoc with persistent leukopenia?

A

Benzene, Strontium, As, Hexavalent Chromium

275
Q

What can you check in regards to organophosphate exposure?

A

Cholinesterase

276
Q

What ox stress marker is high in smokers?

A

8 OHDG also in PD and lung cancer

277
Q

What is Tbars?

A

End product of lipid peroxides

278
Q

How does BPA exert toxic effects to cause NASH?

A

It increases IP
It increases PAMPS leading to hepatic inflammation
Reduces SCFA
Increases LPS
Upregulated TLR4 and NFKB and increased cytokines

279
Q

What bacteria are increased/decreased with BPA in the gut?

A

Proteobacteria/Akermensia

280
Q

What has a direct proportionality to BPA exposure?

A

TBARS

281
Q

What in urine showed a positive association with NASH?

A

As

282
Q

What compounds increase risk of PN?

A

As, Pb, Hg and organophosphorous compounds

283
Q

Who might be at risk for toxic PN?

A

Furniture workers(hexane), Rayon and cellophane workers(carbon disulfide) and dry cleaners, spray adhesive, optical instruments, ceramics(1 bromopropane)

284
Q

What is presentation of toxic PN?

A

Numbness/parathesia in stocking glove distribution
Optic neuropathy
rhabdomyopathy

285
Q

Exposure to 1 bromopropane may present how?

A

PN, muscle weakness, urinary incontinence and memory disturbance

IFM Study (10 decks)

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