Environmental Health APM Flashcards
1
Q
What is required for optimal biotransformation?
A
- Nutritional support - phase 1 - macronutrients, broad spectrum micronutrient support; phase 2 - cofactors for conjugation
- Antioxidants to neutralize the free radicals made by phase 1
- Phytonutrient inducers of phase 2 enzymatic reactions
2
Q
What happens when you have imbalanced detoxification?
A
Damage to DNA, RNA, proteins and reactive oxygen species which lead to chronic disease
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
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
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
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
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
8
Q
What are the Phase 2 detoxification pathways?
A
Glucoronidation, Sulfonation, Methylation(3 most important) Glutathione Conjugation, Amino Acid conjugation and Acetylation
9
Q
Where do you find the Phase 3 antiporters proteins?
A
Small intestinal villi, hepatocytes, proximal renal tubules and capillary endothelium on BBB
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
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
12
Q
What are the 3 steps to form Glucuronide Conjugate?
A
- Coupling of D-glucose phosphate to UTP to give UDP glucose
- Oxidation of primary alcohol yields the coenzyme UDP glucuronic acid
- Conjugation with the substrate to yield glucuronide
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
14
Q
Which phase 2 detox pathway handles most of phase 2 interactions?
A
Glucuronidation
15
Q
What endogenous substances go thru Glucuronidation?
A
Bile, bile acids, steroids, thyroid hormones, retinoids, PGE,
16
Q
What substances go thru Glucorinidation?
A
Endogenous compounds, dietary polyphenols, large number of lipophillic xenobiotics
17
Q
What is a common snp of Glucuronidation?
A
UGT1A1*28
18
Q
Gilberts Syndrome has defect in which phase 2 pathway?
A
Glucuronidation.
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.
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.
21
Q
What is UGT?
A
UDP Glucoronosyl Transferase
22
Q
What phytonutrient can upregulate UGT1A1?
A
Quercetin
23
Q
Quercetin reduces exposures to what compounds through increased glucuronidation?
A
Hydroxylated PCBs
24
Q
What flavonoids upregulate UGT?
A
Luteolin and chrysin
25
What are the highest luteolin and chrysin sources?
Honey, propolis, broccoli, chili peppers, celery, rosemary, parsley,
26
How does honey reduce DNA damage?
It extracts inhibited pesticide induced mitochondriaROS(mtROS) thru upregulating phase 2 and also by upregulating DNA repair thru NRF2
27
Which food enhanced DNA repair in residents chronically exposed to pesticides resulting in marked reduction in pesticide-induced DNA lesions?
Honey
28
What botanicals induces UGT?
```
Milk thistle
Gingko Biloba
Grape Seed extract
Hawthorn
Noni
St John's wort
Valerian
Cranberry
```
29
How does resveratrol affect UGT1A1?
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.
30
How does Glucosinolates upregulate Glucuronidation?
Watercress increases urinary glucuronides in smokers
| Gardencress has chemoprotective effect thru enhancement of detoxification of IQ by UDPGT
31
What is the relationship to Beta Glucuronidase and certain foods?
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.
32
What are some beta glucuronidase inhibitors?
Silymarin(milk thistle), strawberry, black currant, reishi(ganoderma lucidum), licorice, lactic acid probiotics, prebiotics such as inulin, caloric restriction, lactoveg diets, calcium d glucarate,
33
What cancers do calcium d glucarate reduce?
breast, colon, lung, liver, skin
34
How does d glucarates reduce cancer risk?
Suppresses cell proliferation and inflammation but also induces apoptosis.
35
What veggies contain highest amount D glucarates?
Highest in Cruciferous veggies
36
How does thyroid hormone affect glucuronidation?
involved in expression of UGT1A1(bilirubin glucuronidation) and UGT1A6(xenobiotics)
37
Which vitamin influences T3 effect on UGT expression?
Vitamin A retinol
38
How does Vitamin A deficiency affect glucuronidation?
It inhibits UGT 1A1 and 1A6 expression.
39
What are high quercetin foods?
Apple, onion, cherry, kale, red wine, EVOO, beans, broccoli and tea
40
What are high chrysin foods?
Honey, celery, parsley, chili pepper, broccoli, rosemary, propolis
41
What foods inhibit beta glucuronidase?
Strawberry, black currant, milk thistle, Reishi, licorice, probiotics, inulin, citrus, watercress(cruciferous) and tumeric
42
How do EFA affect glucuronidation?
Needed as glucuronidation occurs on smooth endoplasmic reticulum;
43
What are some supportive factors of glucuronidation?
EFA, magnesium, flavonoids, glucosinolates, catechin
44
What are some inhibitors of glucuronidation?
Smoking, fasting, high fructose diet
45
What are the steps in Sulfate Conjugation?
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.
46
What is PAPS?
Coenzyme in sulfonation - 3 phosphoadenosine 5 phosphosulfate that participates in sulfotransferase phase 2 reactions(liver, kidney, intestine).
47
What does sulfonation detoxify?
Many rx drugs, endogenous hormones(estrogen) and amines
48
What is PEITC?
glucosinolate found in cabbage and watercress that supports glucuronidation and sulfonation.
49
What induces SULT expression?
Genistein isoflavone, PEITC, vitamin E, Vitamin A(retinol), selenium and caffeine induce SULT to biotransform xenobiotics esp xenoestrogens.
50
What is sulfite oxidase?
catalyzes the transformation of sulfite to sulfate, a reaction necessary for the metabolism of sulfur-containing amino acids(methionine and cysteine)
51
What are sulfite oxidase(SO) cofactors?
B6 and Molybdenum
52
What are sources of Molybdenum?
Adzuki beans, other legumes, grains, nuts
53
What is dose of Molybdenum?
100-200 mcg; Toxicity is >1500 mcg
54
What are the sulfur amino acids?
Methionine, cysteine, cystine, homocysteine, glutathione, taurine
55
What substances is sulfur needed for synthesis of?
Lipoic acid, Coenzyme A, biotin, mucopolysaccharides chondroitin and glucosamine sulfate
56
What substances are sulfur a component of?
insulin, metallothionein, heparin and collagen
57
What are chronic diseases associated with sulfation impairment?(SULT snps)
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)
58
How does insulin and DM affect Transsulfuration?
It downregulates CBS(Cystathionine B synthase)
59
What amino acid gets converted to glutathione via sulfonation?
Cysteine
60
What is CBS?
Enzyme that makes glutathione from amino acid.
61
How do you diagnose or get a clue of sulfonation issues?
Blood sulfate,
Sulfur amino acids:plasma methionine, cystathionine, cysteine
Transulforation: CBS gene SNP(b6 is coenzyme)
SULT gene SNPs
62
How can you supplement with sulfur?
```
High sulfur foods - primarily seafood
Sodium sulfate (100-1500 mg)
Sulfur amino acids(methionine, NAC and Taurine)
MSM 2-6 gm
Vitamin B6
```
63
What is the highest plant methionine source?
Corn
64
What are plant cysteine sources?
Oats, Corn
65
What are some plant methionine sources:
Corn(highest), sunflower seeds, oats, chocolate, cashew, walnuts, almonds, sesame seeds(lowest)
66
What key factors do methyltransferases donate a methyl group from SAMe?
DNA protection
Phosphatidylcholine Synthesis
Neurotransmitter metabolism(epi, norepi, dopamine, anxiety/dep, insomnia, mania, learning disabilities)
67
Define susceptibility to toxins.
The ability of an individual to biotransform, detoxify and eliminate exogenous and endogenous compounds.
68
What is the breakdown product of glyphosate?
AMPA
69
How long can it take for a chemical to be on the market before it is found to be toxic?
10-20 years
70
How has lead level acceptibility changed over the years?
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.
71
What products have BPA?
plastic water bottles, cash, receipts, canned food and drinks; over 100 tons released into atmosphere yearly
72
How is BPA absorbed in humans?
Thru gut mucosa and skin
73
How does BPA affect us?
It is an endocrine disruptor. Mimics estrogen and other hormones and interrupts cellular signaling even at low levels.
74
What diseases are BPA linked to?
Diabetes, obesity, heart disease and liver inflammation. Cancer, thyroid d/o and infertility.
75
What product increases the absorption of BPA?
Hand sanitizer
76
Explain study of BPA serum concentration on men
Increasing serum BPA is significantly associated with decreased testosterone and androstenedione levels. Decreased sperm count and impaired sexual function.
77
What age is the most sensitive window of exposure to endocrine disrupting chemicals(EDC)?
during critcal periods of development, such as fetal development and puberty
78
What hormones do EDCs act on?
Estrogen, androgens and thyroid. But may interact with multiple hormone receptors at same time.
79
What are possible obesogens?
Organochlorines(POP), Organotins,
Phthalates, BPA, Perfluorooctanoic acids(PFOA), Polybrominated diphenylethers(PBDE), Nonylphenol(alkylphenol), Atrazine, air pollutants, HighFructose Syrup, Diethylstilbestrol, atypical antipsychotics, thiazolidinediones
80
What is a xenobiotic?
Chemical substances that are foreign to life that are detected in the body
81
What is the exposome?
Combined exposures of all sources that reach the body's internal chemical environment
82
What is disease risk?
Lifetime exposure x toxic potency x susceptibility
83
Total toxic load results from
Total toxic exposure minus ability to biotransform and excrete toxins
84
Biotransformation is
- 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
85
All tissues have biotransformation activity. True of False.
True.
86
What organs/tissues have the highest amount of biotransformation?
Skin, liver, lungs, gut, kidney, BBB
87
In general terms, what does phase 1 reactions do?
Introduce or expose a functional group on parent compound, making it more polar; May also activate inert compounds(prodrugs or procarcinogens).
88
What does it mean that a compound is polar?
Has a positive and negative charge and so body can then do something with it.
89
What happens when you have inhibition of CYP450?
= 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
90
What are some CYP450 inhibitors?
```
Berberine
Antifungals
Grapefruit juice
Green tea catechins
Garlic
SSRI
Star juice
Cimetidine
```
91
What are some commonly induced Phase 1 enzymes?
CYP1A, CYP1B1, CYP2E1
92
How does phase 1 get induced?
By upregulating transcription
93
Why does Phase 2 take so much energy?
Much of the energy is used to make enzymes and they are large globular proteins
94
What qualities do phase 2 resulting conjugates have?
highly polar, inactive and rapidly excreted
95
What pathway is phase 2 activity substantially increased by?
Genetic induction via NRF2/ARE pathway
96
What otc medicine bypasses phase 1?
Tylenol
97
If phase 2 enzymes get overloaded then which phase 1 CYP450 enzyme does tylenol go thru?
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
98
What is NAC?
N-acetylcysteine, rate limiting precursor to glutathione, Essential nutrient for detoxification regimens
Used for tylenol toxicity
Potent antioxidant
99
What are some reasons some people retain more or more sensitive to toxins?
```
High sugar, low protein diet
Oxidative stress
Poor elimination
Polymorphisms
Chronic inflammation
Overwhelming toxic load
Intestinal dysbiosis
Nutrient deficiencies
Stress, emotional trauma
```
100
What is GGT representative of in evaluating for toxicity?
Glutathione activity
101
What triggers would you look at to assess toxicity?
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
102
What mediators would you look at to assess toxicity?
Essential fatty acid profile
Oxidative stress markers
Extra and intra cellular antiox level - vitamin A and E
103
What are functional medicine principles for detoxification?
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
104
Which fish have the highest mercury content?
Tuna, swordfish, shark, king mackerel, tilefish, oysters downstream from wastewater
105
What are the 5R for detoxification?
```
Remove pathogens
Replace enzymes and HCL
Repair damaged intestinal mucosa
Reinoculate with probiotics/prebiotics
Rebalance
```
106
What are some agents that repair gut lining?
```
Probiotics
Plant fibers
L-glutamine
Arabinogalactan(Western Larch bark)
Aloe vera mucopolysaccharides
Licorice Root,
Bovine Colostrum
```
107
What are some agents that enhance excreting toxins?
Activated charcoal(don't use with other supplements)
Bile acid sequestrants(choleystyramine)
Olestra(sucrose polyesters)
D Glucaric acid
108
What are some CYP450 Xenobiotic Metabolizers?
1A1, 1A2, 1B1 - PAH, food mutagens, aflatoxins
2E1 - etoh, nitrosamines, food mutagens, ketones
3A4 - aflatoxin, food mutagens
109
Elevated levels of B-glucoronidase are found with:
Dysbiosis
| Exposure to xenobiotics(smoke, PAH, nitrosamines)
110
What does B-glucoronidase do?
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.
111
What foods contain D glucaric acid?
```
Cruciferous veggies
Citrus
Apples
Apricots
Bean sprouts
Cherries
```
112
What are some functions of D-glucaric acid?
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
113
What are some things you can do/eat to help remove toxins?
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)
114
What are some polysaccharides from algae and seaweed that help remove toxins?
Chlorella pyrenoidosa - removes mercury, dioxin
Fucus(bladderwrack)
Laminaria(kelp)
115
How do cholagogues and Cholerectics work to reduce toxins?
Enhance secretion of toxins by increasing bile flow.
116
What are some cholagogues and cholerectics?
```
Berberine
Coffee
Tumeric
Milk thistle
Globe Artichoke
Greater Celandine
Dandelion
Taurine
```
117
Which antioxidant nutrients may minimize endothelial cell damage mediated by POPs?
Vitamin E
Dietary Flavonoids
High ratio of Omega 3:6 ratio
118
What are some antioxidants used for detox?
```
Rosemary
Cucurmin
Flavonoids
Carotenoids
Tocopherols(esp gamma and alpha)
NAC/Glutathione
Alpha lipoic acid
CoQ10
```
119
What is the primary intracellular non-enzymatic antioxidant present in all living cells?
Glutathione
120
Where are high concentrations of glutathione found?
Brain parenchyma and liver
121
What is substrates does glutathione conjugate?
Heavy metals
External toxicants
Carcinogens
Pharmaceuticals
122
What supplements can optimize reduced glutathione levels?
```
Vitamin C
NAC
Lipoic acid
Cucurmin
Milk thistle
Whey protein concentrates
```
123
What nutritional and phytochemical support do you need for biotransformation?
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
What are some phase 2 inducers?
```
Glucosinolates
Flavonoids
Organosulphur compounds
Curcuminoids
Milk Thistle
Articoke
Rosemary
Monoterpenes
```
125
What is a potent transcription inducer of Phase 2 detoxification and antioxidant enzymes?
Sulforaphane
126
What are the effects of Curcumin on detoxification?
```
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
How does Ellagic Acid affect detoxification?
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
What are effects of Green Tea on detoxification?
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
What are the effects of Milk Thistle on detoxification?
Hepatoprotectant
May inhibit 2E1
Increases serum and hepatic glutathione and glutathione production
Induces Glutathione transferases
No deleterious effects on drug metabolism
130
What 2 main classes of organosulphates does garlic have?
- Gamma glutamylcysteines(water soluble) - metabolized to S-allycysteine which is found in aged garlic
- Cysteine sulfoxides(fat soluble)
131
What CYP450 enzyme does garlic oil, diallyl disulfide, trisulfide inhibit?
CYP2E1
132
How does garlic oil, diallyl disulfide, trisulfide induce Phase 2 enzymes?
by activation of antioxidant response element(ARE) genes
Induces - glutathione S-transferase and Quinone reductase
133
What are some methylators that support phase 2 conjugation?
```
Methylfolate
Methylcobalamin
Trimethylglycine
SAMe
Phosphatidylcholine
Glycine
Taurine
Glutamine
Sodium Sulphate
Pantothetic acid
Magnesium
```
134
Which patients should you consider detoxification in?
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
What CYP450 does berberine inhibit?
2D6, 3A4, 2C9
136
What CYP450 does Green tea inhibit?
1A1, 1A2, 1B1
137
What CYP450 does garlic inhibit?
2E1
138
What CYP450 does star fruit inhibit?
2A6, 1A2, 3A4
139
What CYP450 does Grapefruit juice(furanocoumarins) inhibit?
3A4
140
What is enzyme used in Methylation?
Methyltransferase
141
Which substrates require a transfer from methyl groups from SAMe via methylation?
nucleic acids, proteins, lipids and secondary metabolites
142
Describe process of methylation
SAMe will donate its methyl group to other substances to form SAH(s-adenosyl homocysteine).
143
NASH is a problem from which phase 2 reaction?
Methylation - low SAMe leads to elevated homocysteine
144
What increases SAMe?
Trimethylglycine(Betaine)
145
What supplement helps NASH and why?
Trimethylglycine as it increases SAMe and reduces hepatic enzymes, steatosis and fibrosis associated with NASH
146
What combination of supplements was shown to help lower homocysteine by 39%?
B12 and fish oil
147
What is associated with decreased arsenic methylation?
Skin cancers
148
What donates methyl groups to arsenic during methylation process?
SAMe and choline to produce monmethylarsinic acid and dimethylarsinic acid
149
What amino acid is needed for arsenic methylation?
Methionine
150
What substances increased arsenic methylation in vitro?
Methylcobalamin, Glutathione and Selenium
151
High arsenic exposure let to 57% reduction in which antioxidant?
Glutathione
152
What is inversely related to whole blood Arsenic and its methylated forms MMA, DMA?
Glutathione
153
What low nutrient level correlated with lower ability to methylate Arsenic in Tawainese exposed arsenic related ischemic heart disease?
low serum Alpha and beta carotene
154
Poor vibratory sense and impaired light touch is associated with defect in which phase 2 reaction?
Methylation
155
What can you check for methylation diagnosis?
Methionine metabolism
MMA
Gene SNP(tells of potential impairment)
Serum b12, folate, pyridoxine less helpful
156
What are some labs to tell you about methionine metabolism?
```
Plasma homocysteine
Plasma SAMe
Plasma SAH
SAMe/SAH ratio - index of methylation potential
Plasma methionine and cysteine
```
157
What are the 3 common causes of Neuropathy in Adults?
1. DM, IR
2. Etoh
3. Toxic metals - PB, Hg, Cd, As, xenobiotics
158
What 3 amino acids are GSH composed of?
Glutamine(glutamic acid), glycine, cysteine
159
How does GSH be the primary free radical cell protector?
by maintaining mitochondrial redox potential and cell membrane stability
160
What is mercapturic acid?
Glutathione conjugate which is excreted in urine
161
What is GSH used in conjugation with to form Leukotrienes?
Arachodonic acid
162
What are some common diseases that are associated with low Glutathione levels?
Heart disease, HTN, arthritis and MSK diseases, Diabetes, Leukemia, hearing loss, macular degeneration, autism
163
What foods contain GSH?
F/V - contribute over 50% dietary GSH
| Meats - contribute to less than 25%
164
What is associated with decreased risk of oral cancer?
Increased dietary intake of GSH from F/V and subsequently higher blood GSH levels
165
What supplement can increase NK cell cytotoxicity?
GSH
166
What is a rate limiting step for glutathione synthesis?
Cysteine(NAC)
167
What supplement can boost GSH levels?
NAC
168
True of False. Cognitive improvements were seen following NAC treatment.
True
169
What are key factors depend on Methylation?
DNA protection
Phosphatidylcholine synthesis
Neurotransmitter metabolism
170
Which phase 2 reaction plays a role in neurotransmitter metabolism?
Methylation - people with depression/anxiety respond well to methylation therapy
171
Does NAC bind to essential minerals?
No
172
Does NAC provide chelating sites for metals?
Yes, esp with thiol groups - lead, mercury, arsenic
173
What is 5 L oxoproline?
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
What increased amino acid intake could have a beneficial role in sarcopenic elderly?
Glycine
175
Does GSH level decline or increase with age and why?
Decline, d/t decline in NrF2 mediated induction of phase 2 enzymes and lower tissue levels of cysteine, glycine
176
What supplement can help increase Nrf2 activity that declines with age?
Lipoic acid
177
What nutrient upregulates GGT gene expression in CNS astrocytes?
Vitamin D3
178
What cell plays a pivotal role in CNS detoxification pathways?
Astrocytes
179
What could be an effective controller of detox process of the brain?
Vitamin 1, 25-D3
180
What vitamin increases GSH in RBC's and lymphocytes?
Vitamin C
181
What vitamin increases GSH in plasma?
Vitamin E
182
What protein can help to increase GSH?
Whey
183
What can you look at for Glutathione issues?
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
What amino acids are involved in amino acid conjugation of Phase 2 reactions?
Glycine, Taurine, Arginine, Glutamine
185
What does amino acid conjugation metabolize?
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
What is the primary role of amino acid conjugation?
regulate systemic levels of amino acids that are also utilized as neurotransmitters in the CNS
187
What is glycine a substrate for?
```
Porphyrins(heme)
Purines
Creatine
Sarcosine
Bile Salts
```
188
Which amino acid is in collagen and elastin?
Glycine
189
Where is the concentration of Taurine the highest?
Brain and heart
190
Which is the second most amino acid in the blood?
Taurine
191
Which amino acid crosses BBB?
Taurine, protects against glutamine excitotoxicity.
192
Which metals do taurine potentiate the depletion of from blood, liver, and renal?
Lead, Arsenic
193
Animals treated with Taurine significantly reversed ____ parameters induced by ___and ____
oxidative stress
| lead and arsenic
194
What increased blood, brain SOD &GSH and decreased Tbars by lead and arsenic?
Taurine
195
What are some clinical applications of impaired Taurine?
Hyperactivity, anxiety, sleep disturbance, seizures, autism, cholestasis etc
196
What cofactors are needed to convert cysteine to taurine?
B6 and B3
197
What cofactors are needed to convert homocysteine to taurine?
betaine, serine
198
What are some applications for glutamine?
IBD, increased IP, wounds, low mucle mass, wasting syndromes, cancer patients
199
What is the 1/2 life of glutamine?
4 hours so should dose it several times a day
200
What are contraindications to high doses of Glutamine(15gm) and why?
ALS, MS, PD - glutamine conversion to glutamate in the neurons can be excitotoxic
201
What enzyme is used in Acetylation?
N-acetyltransferase
202
What does NAT enzyme do?
catalyzes the transfer of acetyl groups from acetyl CoA to arylamines.
203
Which supplement can increase NAT activity?
Quercetin
204
How do you assess for Acetylation?
Look at NAT1 and NAT2 snp
205
Who would you consider impaired detoxification?
```
Chemically sensitive
Neuro symptoms
Autoimmune
Metabolic syndrome, obesity, DM
Structural - FM, osteopenia/osteoporosis
SNP
```
206
What clinical emphasis should you have in regards to improving glucoronidation?
Carotenoids, glucuronidase support, thyroid, dysbiosis
207
What clinical emphasis should you have in regards to improving sulfonation?
Sulfur amino acids, sulfate/MSM
208
What clinical emphasis should you have in regards to improving Methylation?
Folate, B12, B6, TMG, EPA-DHA
209
What clinical emphasis should you have in regards to improving Glutathione conjugation?
NAC, lipoate, GSH, Mg, D3, phytonutrients
210
What phase 1 snp may increase estrogen metabolites?
1A2, 1B1
211
What labs would you check if GST snp?
blood GSH and/or oxidative stress(cysteine, SOD, GSHpx, sulfate, peroxidases)
212
Which macronutrient is the most important for detox?
Protein
213
What type of patients would you consider low protein?
Decreased intake(esp seniors)
Low acid - on PPI,
Malabsorption
Increased use of proteins - chronic infections, toxin exposure, excessive exercise
214
Whats the best and worse measure of one's protein status?
Best - plasma amino acids
Worse - total protein, A/G ratio
Indirect - BIA
215
What type of diet shows low liver CYP450?
High sucrose, low Mg. It also slows bowel transit and elevates oxidative stress
216
How do toxic metals affect ATP?
They impair the reaction of pyruvate dehydrogenase complex so get decreased ATP
217
What is an optimal amount of fiber to help reduce chronic disease?
25-29 gm
218
What are benefits of fiber?
Lower CRP
Increased body/skeletal mass in elderly
Decrease in mortality from CVD and colon cancer
Better detox
219
What effect does fat free diet have on detox?
Reduces CYP450 and GST concentration and activity
220
Why do CYP450 need fats?
To make phospholipid matrix of endoplasmic reticulum
221
What was reduced with better GSH:creatine ratio from omega 3 supplementation?
Depression
222
What is a GGT >40 associated with?
POP burden
223
What does a high GGT indicate?
increased glutathione catabolism/depletion
224
Which B deficiency is associated with supporting glutathione synthesis thru its role in ATP production?
Pantothetic acid
225
Which B deficiency is associated with lower glutathione levels?
B12
226
What is the purpose of Zn in detox?
Complexes with phospholipids:block membrane oxidation
Protects sulfhydryl groups against oxidation
Displaced by Hg, Cd, Pb
Induces Metallothionein genes
SOD requires it - stabilizes
227
Which age risk of zinc deficiency?
infants, children and >65yo
228
Who has risk for zinc deficiency?
```
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
How does zinc deficiency affect immune system?
impairs development of acquired immunity - compromises b lymphocyte development and IgG ab production. Adverse effect on macrophages.
230
What are some signs of zinc deficiency?
Dermatitis, glossitis, hair loss, nail dystrophy, frequent infection
231
What tastes will be lacking in zinc deficiency?
bitter, metallic, sour
232
What type of deficiency is a low vitamin A/beta carotene deficiency associated with?
Zinc
233
What is low alk phosp associated with?
Zinc deficiency
234
How do you check for zinc deficiency?
```
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
What does Zn suppress with supplementation?
HDL, Copper
236
What type of deficiency increases intestinal absorption and body retention of lead?
Calcium
237
What deficiency causes a loss of dopaminergic neurons in PD pts?
Magnesium
238
What are magnesium functions?
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
What mineral offers neuroprotection via NMDA block?
Magnesium
240
What are some early signs of Mg deficiency?
Constipation, HA, muscle cramps, fatigue, parathesias,
241
What are some progressed signs of Mg deficiency?
```
RAD
HTN, arrythmia
loss of appetite
N/V
Seizures
Personality changes
Tremor, carpopedal spasm
```
242
What happens when Magnesium is given to asthmatics?
Increased GSH
243
What percent of tissue levels does serum Mg represent?
1% so should get RBC Mg
244
Where does selenium reside?
2/3 resides inside RBC bound to selenoproteins(90%)
| 10% reside in GSH peroxidase
245
What metals form a complex with Selenium there by decreasing selenoenzyme activity?
Pb, Hg
246
How does Selenium improve cellular stress response, protein repair, and protection against oxidative stress?
restores Hg inhibited TxR. TxR is needed for those processes.
247
What are some symptoms of Selenium deficiency?
```
Muscle aches/fatigue, frequent colds/flu, brain fog
Hypothyroid(T4-T3 conversion)
Dental Caries
CV disease, thrombosis
Increased inflammatory response
```
248
What are some benefits of Selenium?
Increased Hg excretion
Decreased malondialdehyde(lipid peroxidation)
Decreased 8-OH-dG(DNA oxidation)
249
What labs can you order to check Selenium deficiency?
RBC selenium, urine selenium
250
Which mineral is required for all CYP450 enzymes?
Iron
251
What mineral impedes Zinc absorption when both are taken in the fasted state but not when taken with meals?
Iron
252
What heavy metal has increased GI absorption with iron deficiency?
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
Iron deficiency causes an increased blood level of what metal?
Lead
254
What are some high heme iron foods?
Meat, poultry, seafood
255
What concerns about iron from non-heme foods?
absorption is inhibited by phytic acid, polyphenols with low vitamin C and soy protein.
256
Do vegetarians have a higher iron requirement?
Yes, 1.8 times higher then nonveg
257
What do lipoates induce?
Phase 2 enzymes by activating Nrf2
| DNA protection against carcinogens, ROS & nitrogen species
258
What effect on metals does lipoate have?
may directly chelate Pb, Hg, Cd, As or reduce the oxidative capacity of the metal
259
What are some functions of lipoic acid?
```
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
How does lipoic acid restore intracellular GSH?
substrate for NADPH-dependent enzyme GSH reductase
261
What substances inhibit inflammatory cytokines?
Lipoic acid, Zn, Omega 3, cucurmin by blocking NFKB
262
How does lipoic acid protect membranes?
reduces oxidized forms of CoQ10, vitamin C, GSH which in turns recycles E
263
What is PON1?
Hydrolyzes organophosphates in the liver
264
What is ALDH2?
Metabolizes acetaldehyde
265
What is a surrogate for PON1?
Low HDL
266
What is more toxic metabolite of As?
Monomethylarsonic acid(MMA)
267
What is less toxic metabolite of As?
Dimethylarsinic acid(DMA)
268
What supplement can decrease toxic metabolites of As?
Folic acid
269
What are you depleting if you have high As?
SAMe as As gets methylated
270
What are some tests of Antiox capacity?
GSH, SOD, CoQ10, GPx
271
What has a linear correlation with NK cells?
GSH
272
What condition is associated with hyperabsorption?
PD
273
What are some biomarkers of effect?
WBC, RBC
LFTs(ALT, LDH, GGT)
Uric acid(PCBs, dioxin and dioxin like chemicals)
Kidney fxn(BUN, Cr, Cystatin C)
274
What toxins are assoc with persistent leukopenia?
Benzene, Strontium, As, Hexavalent Chromium
275
What can you check in regards to organophosphate exposure?
Cholinesterase
276
What ox stress marker is high in smokers?
8 OHDG also in PD and lung cancer
277
What is Tbars?
End product of lipid peroxides
278
How does BPA exert toxic effects to cause NASH?
It increases IP
It increases PAMPS leading to hepatic inflammation
Reduces SCFA
Increases LPS
Upregulated TLR4 and NFKB and increased cytokines
279
What bacteria are increased/decreased with BPA in the gut?
Proteobacteria/Akermensia
280
What has a direct proportionality to BPA exposure?
TBARS
281
What in urine showed a positive association with NASH?
As
282
What compounds increase risk of PN?
As, Pb, Hg and organophosphorous compounds
283
Who might be at risk for toxic PN?
Furniture workers(hexane), Rayon and cellophane workers(carbon disulfide) and dry cleaners, spray adhesive, optical instruments, ceramics(1 bromopropane)
284
What is presentation of toxic PN?
Numbness/parathesia in stocking glove distribution
Optic neuropathy
rhabdomyopathy
285
Exposure to 1 bromopropane may present how?
PN, muscle weakness, urinary incontinence and memory disturbance
