Week 6-7 Alcohol + Vitamins Flashcards
1
Q
Non-Dietary Consequences
A
1800 die of alcohol causes/600,000 injured
> 40% College students, 4+ (women) and 5+ (men)
> Acute intoxication and death
> Absorbed in stomach (20%) and SI (80%) directly into blood
> 0.6 oz (14g) pure ethanol
2
Q
Ethanol Metabolism
A
Alcohol –(alcohol dehydrogenase; NAD+ to NADH)–> Acetaldehyde
> Rate-limiting
Acetaldehyde –(aldehyde dehydrogenase; NAD+ to NADH)–> Acetate –> Acetyl CoA –> TCA (Energy) or FA synthesis (Fatty Liver)
3
Q
XX are more affected by alcohol
A
- Less body mass
- Less water (more fat: lean muscle is 75% water, fat tissue is 15% water)
- Less ADH in stomach lining (10% ethanol consumed vs 30% in men)
4
Q
ALDH Variants
A
ALDH2 (mito) and ALDH1 (cytosol)
> Variant of ALDH2 (Glu504 to Lys) –> Low activity enzyme in East Asian (dominant)
> Flushing and hangover due to acetaldehyde buildup
> Treatment: ALDH2 inhibitor (Antabuse/difulfiram convert acetaldehyde to acetic acid; NADH made)
5
Q
Microsomal Ethanol Oxidizing System (Cyt P450)
A
In times of high doses of alcohol (ADH cannot keep up)
> NADPH to NADP+ via MEOS, converting ethanol to acetaldehyde
> More alcohol, more active the MEOS –> tolerance
> Metabolize drugs and xenobiotics
6
Q
Pharmacokinetics: [drug] over time
A
- Cmax: maximum concentration of drugs + side effects
- AUC: overall drug exposure
- t1/2: [drug] half-life
- Cmin: trough [drug] + anti-HIV effectiveness
7
Q
Alcohol-Drug Metabolism
A
- Block metabolism:
> Drug + EtOH = competitive inhibitors (sedative detoxification) - Enhance metabolism:
> Increase P450 level: either reduce drug effect or increase toxic effect
> Acetaminophen –> toxic metabolites
8
Q
Alcohol and Brain
A
- Cerebral cortex: more talkative and confident
- Hippocampus: ST-memories don’t become LT-memories; exaggerated emotions
- Cerebellum: cannot walk in straight line
- Brain Stem: Impaired breathing and HR
9
Q
Excessive Drinking
A
- Binge/heavy drinking, pregnant and underage drinking
> Women: 8+ /week
> Men: 15+ /week - Too many empty calories and few nutrients
> Less absorption, metabolism and retention of micronutrients
> Block gluconeogenesis (NADH-mediated pyruvate loss)
> Diuretic –> dehydration
10
Q
Nutritional Effect on Physiology
A
- Liver:
> Fatty liver disease (steatosis)
> Non-alcoholic Steatohepatitis
> Alcoholic hepatitis: chronic inflammation
> Alcoholic cirrhosis: ALD that makes liver stiff, swollen and non-functional - Heart Failure: fat buildup –> enlargement
> *** 1 drink/day can reduce incidence of heart disease by 20-40% (red wine has antioxidants) - Brain damage: toxicity –> impaired function
- Cancer:
> Breast: 50% from 3+ drinks/day
> Liver, stomach, colon
> Oropharyngeal: smoking and 30+ drinks/ week
11
Q
Fetal Alcohol Syndrome (FAS)
A
Alcohol is potent teratogen (birth defects)
> Mental delay, imparied immune function, low nasal bridge, flattened face (leading cause of mental disability in the West)
12
Q
Casimir Funk
A
Discovered 4 substances to be healthy (first was beri-beri)
> B1 (thiamine), B2 (Riboflavin), C (ascorbic acid) and D (cholecalciferol)
13
Q
Vitamin (Overview)
A
- Essential growth substances needed in trace quantities
> No energy yield, but facilitate reactions
> Metabolism, development and immunity
> Absent in diet –> deficiency (exception :D)
> NOT inorganic (minerals)
> Water-soluble: excreted faster, low toxicity (filtered via kidney, small storage (1-4 weeks), C (diet –> storage –> biochem defects –> symptoms (20-40 days before); except B12 in liver)
> Fat-soluble: large storage pool (1 yr supply of A), can be toxic; uptake in SI
14
Q
Total Parenteral Nutrition (TPN)
A
Medicine administered by means other than oral or rectal intake (intravenous or injection)
> Typical test of complete nutrition
15
Q
Vitamin A: Carotinoids
High diet lowers risk of Lung CA
A
- High quantities in orange fruits and veggies and leafy greens
> B-carotene can be converted to A by cleavage at center via B-carotene dioxygenase into 2 retinal molecules in SI
> Vision: Light strikes rods/cones in retina –> interacts with rhodopsin (opsin + cis-retinal form visual pigment) –> cis-retinal converted to trans-retinal (polyene chain straightening activates opsin)
16
Q
Rhodopsin-retinal Visual Cycle
A
- Rhodopsin absorbs light
- II-cis retinal –> all-trans retinal
- All-trans retinal separate from opsin
- Opsin –> cascade that sends signals to brain
- All-trans retinal converted back to II-cis retinal
- Opsin + II-cis retinal combined to reform rhodopsin
17
Q
Genetic Deficiency in RPE65
A
Blood circulation –> trans retinol –> trans retinyl esters –> RPE65 –> cis retinol –> cis retinal –> Rhodopsin –> trans retinal OR electrical stimulation in brain
Visual Gene Therapy: LUXTURNA introduces functional RPE65 to compensate for mutation
18
Q
Retinoic Acid
A
- Vitamin A carried by retinol-binding protein and transthyretin
- Released and enters target cell; binds to nuclear-retinoid receptors (RAR/RXR)
- Complex binds to DNA –> Gene transcription –> mRNA to protein –> cellular responses
Function:
- Hormone/signal –> GE
- Immune in GI tract (Low Vit A kids can get diarrhea)
- Structural integrity of epithelial tissues (rounded, moist, and mucus-secreting cells and cilia)
19
Q
Vitamin A deficiency and Overdose Symptoms
A
DEFICIENCY 1. Eye and vision: > Night blindness (little retinal, little rhodopsin) > Xeropthalmia: no mucus --> dry eye --> cornea off 2. Infection: > Poor GI tract immunity 3. Skin dysfunction: > Rough skin (follicular hyperkeratosis)
OVERDOSE
- Acute: GI upsets, muscle uncoordination
- Chronic: liver damage, hair loss, appetite loss
- Teratogenic: fetal malformation, spontaneous abortion
20
Q
Source of Vitamin A: RAE (retinol activity equivalents)
A
RDA: 900 ug (M), 700 (F)
> 3000 IU (M), 2333 (F)
> Sweet Potato (960), Spinach (500), Mango (400)
UL: 3000 RAE/day or 10,000 IU
Greatest risk of toxicity if 2x-4x the RDA (shows up 3-6 months later)
21
Q
CARET (B-Carotene and Retinol Efficacy Trial)
A
Tested effect of daily b-carotene (30 mg) and retinyl palmitate (25,000 IU) on lung CA risk patients
> 28% increase in lung CA incidence, 17% increase in death and higher rate of CVD mortality
22
Q
Vitamin D3: Cholecalciferol
Fish, fortified milk, soy, almond milk
A
Synthesis
> D2 (food) + UV –> D3 (skin) –> hydroxy-D3 (25-OH, calcidiol, liver) –> dihydroxy-D3/calcitriol (1, 25-OH2; active; kidney)
Calcidiol stable for weeks in blood (normally 12-24 hours)
*UV step is less efficient in older people and people with dark skin, smogged areas
23
Q
Vitamin D Function, Deficiency and Requirements
A
Function:
- Bone growth in young: increase Ca2+ absorption by intestine; Ca2+ release from bone
- Differentiation of skin cells
- Inhibit breast, colon and prostate CA/ increase infection resistance
Deficiency: Rickets (lack of Ca and P to mineralize bone; large rib cage and head enlargement)
Overdose: Depletes bone Ca2+ and increase Ca2+ in soft tissues –> bone malformation + kidney stones
RDA (varies), so AI: > 600 IU/day for <70 yo (15 ug) > 800 IU/day for >70 yo (20 ug) UL: 4000 IU/day 1000-10000 can improve functions more
24
Q
Vitamin D Trends
A
Breast CA: higher serum Vit D (calcidiol) –> higher survival
General Decline: >30 ng to <10 ng/mL from 1990 to 2000 (African Americans suffering the most)
25
Vitamin E: a-tocopherol
Hydrophobic: antioxidant for lipids and membranes
RDA: 15 mg/day
UL: 1000 mg/day
Deficiency: hemolysis and RBC sensitivity to ROS (7 years to show deficiency)
> Infants exposed to lots of O2 + smokers --> blindness
Overdose: hemorrhaging
26
ROS
Produced via respiration, toxins and IS (can be used to kill pathogens, apoptosis and signaling)
> Release chemical signals (histamine) to tissue injury --> dilation and more leakiness of blood vessels --> phagocytes migrate and consume bacteria
O2 --> O2- --> H2O2 --> OH radical (superoxide anion and hydroxyl radical) --> TOXIC
27
Host of Anti-oxidants
| Tocopherols, carotenoids, ascorbic acid, glutathione
```
1. Superroxide dismutase
2O2- --> H2O2 + O2
2. Catalase
2H2O2 --> 2H2O + O2
3. Peroxidase
H2O2 --> 2H2O
```
28
```
Vitamin K (Quinone)
> Inhibited by Warfarin (Coumadin) by inactivating vitamin K-dependent proteins
```
Phylloquinone (K1) and Menaquinone (K2, colon)
> Fish oils and meats
> AI: 120 ug (M), 90 ug (F)
> DV: 80 ug
Glutamate alpha-carboxylation
> AA-Glutamic Acid-AA (Preprothrombin) --(K)--> AA-Gla-AA (Prothrombin) --> Calcium --> Prothrombin activating factor for coagulation (Fibrin)
Glu --> Gla [glutamate --(gamma-glutamyl carboxylase)--> gamma-carboxyglutamic acid
(CO2+O2 --> H2O+H+)
(KO --> KH2)
29
Vitamin B1: Thiamin --> Thiamin Pyrophosphate (TPP)
RDA: 1.0-1.5 mg/day
UL: N/A
AI: 1.2-2/0 mg/day
Primarily decarboxylation / carbonyl activation
> Pyruvate + CoA + NAD+ --(Pyruvate DHG)--> Ac-CoA + NADH + CO2
> Reactive group is thiazole ring
Deficiency: Beri-beri
> Impairs organ function with high energy consumption (CNS, GI tract, muscles; appear in 1-2 weeks)
> From refined grains (80% calories)
> Alcohol inhibits B1 Abs: Wernicke-Korsakoff (Thiamin deficiency with staggering gait, derangement and eye trouble)
30
Vitamin B2: Riblflavin --> FAD, FMN
RDA： 1.2-1.8 mg/day
UL: N/A
Redox reactions and Co-substrate
> dehydrogenation reactions (TCA, b-oxidation)
Deficiency: 2 months after deprivation (throat/tongue/mouth inflammation; anemia, fatigue)
31
Vitamin B3: Niacin --> NAD, NADP
RDA: 14-19 mg/day
UL: 35 mg/day (flushing)
Niacin --> nicotinamide; NAD+ --> NADH (reduction by adding H+ and 2 e-)
> NADH: catabolism (glycolysis, TCA)
> NADPH: biosynthesis (FA)
> Sources: 1/2 from food, 1/2 from Trp (protein: trp --> niacin)
Deficiency: Pellagra
> Broken skin (dementia, diarrhea; 2 months)
> US: Main food is corn/salt pork and black eye peas (corn: niacin unavailable b/c bound by protein; reversed with eggs, meat and milk/treat with alkaline)
Atherosclerosis
> Niacin is treatment: 1.5-2g decreases LDL/increase HDL (side effects: swollen tongue, GI problems, liver damage)
32
Vitamin B6 Pyridoxal --> PLP (active aldehyde)
RDA: 1.3-1.7 mg/day
UL: 100 mg/day
functions in 100+ enzymes (transaminases; acts as Schiff Base; converts homocys to cys)
Deficiency:
> Infants: convulsions
> Adults: dermatitis, anemia
> Toxicity: irreversible nerve damage
33
Folic Acid --> THF (intestine)
RDA: 400 ug/day
UL: 1000 ug/day
Additional glutamates linked to carboxyl group
> Glutamates have to be removed before absorption
> Many methylated versions: single carbon metablism; -CH2-/-CH3 transfer; nucleotide synthesis (dUMP --> dTMP); AA synthesis (gly --> ser; homocys --> Met)
Toxicity: colon CA, mask B12 deficiency
Deficiency: no DNA synthesis; megaloblastic anemia (immature and larger BM cells); spina bifida (fetal neural tube defect from spinal fluid buildup); increased CVD and homocysteine risks --> endothelial damage, cholesterol oxidation, platelet aggregation)
34
Vitamin B12 --> Cobalamin
RDA: 2.4 ug/day
AI: 4.5 (F), 6.9 (M)
UL: N/A
```
Corrin ring (Co-ion holder)
> Cofactor in covalent group transfers
> Pernicious anemia: low RBC + hemoglobin --> nerve degeneration (AI disorder with loss of gastric PC --> low B12 abs in ileum due to lack of intrinsic factor release)
```
Sources: Intestinal bacteria, meat (animal food only); richest in liver/yolk
> Plants don't make B12 (colon bacteria make them but no absorption)
> 50-90% stored in liver
Deficiency: megaloblastic anemia, fatigue, nerve degeneration (increase with age; usually 2-3 years supply)
35
Vitamin C (Ascorbic acid)
RDA: 90 mg/day (M), 75 (F)
*Smoker is higher
Min: 10 mg/day (no scurvy)
UL: 2g/day
Undergoes reversible ReDox by loss/addition of 2 H+
> C prfesent (collagen precursor) --> collagen hydroxylated (proline and hydroxyproline) --> Triple helix
> Helps strengthen connective tissue
> Proline + a-keto --(prolyl hydroxylase; ascorbate: O2 --> CO2) --> 4-hydroxyproline + Succinate
36
Vitamin C Function
Anti-Oxidant:
> Eye: radicals made by photolysis (25-32mg/100g)
> IS: ROS made in WBCs (35 mg/100g)
> Regenerate Vitamin E
> Fe absorption; hormone and NT synthesis
Deficiency (20-40 days): fatigue and hemorrhage in hair follicles
> Scurvy: no collagen made, bleeding gums and joins; slow wound healing
Intravenous HIGH C alleviates cancer in 1971, but Mayo proved wrong (used ORAL)
37
Multivitamins Pros and Cons
Overconsumed: Na, Sat FA
Underconsumed: D, K, Ca, Fe and Fiber
PROS
1. Few persons follow Dietary guidelines
2. Most adults don't get EAR/AIs of A/D/E/Mg/K/Ca
3. Reduced CVD mortality among women and CA mortality among men
CONS
1. No clear beneficial effect on CVD, CA
2. No effect on overall cognitive performance or verbal memory
3. Food sources are preferred: B-carotene vs vegetables and lung CA risk (apple = antioxidant of 3.5 g of Vitamin C)
4. Toxicity: A-liver, Folate-colon CA, Fe-oxidant
38
Minerals (pro-/antinutrient)
Ca, P, K, S, Na, Cl, Mg
INCREASE bioavailability
> Normal Gastric acidity
> Vitamin C
> Good Vitamin D status
```
DECREASE bioavailability
> Low gastric acidity
> Phytic acid IP6 (grains/legumes): broken down by yeast from leavened bread (causes low Zn in MidEast)
> Oxalic acid (leafy veggie)
> Polyphenol (tea, coffee)
> High supplement of one mineral
```
39
Calcium
25% Abs, needs Vitamin D
RDA: 1g/d adults; 1.2-1.3g (9-18 and women >50)
UL: 2.5g/d (can develop kidney stones)
COLLARD GREENS > Dairy and Leafy greens:
Over 500mg/meal: no Zn and Fe uptake; high Blood Ca --> blood clotting
Keep lower than 500mg, and no supplements unless deficiency
Neurotransmission and muscle contraction signaling
> Major bone/teeth component: adds 20-25+ bone age and then turnover (regenerate skeleton every 7 years); osteoblast (build), osteoclast (abs/breakdown of mineral matrix)
> Hydroxyapatite: Ca-PO4-OH
Hormonal Regulation:
1. High Blood Ca --> thyroid gland releases calcitonin --> less bone Ca release + less kidney Ca retention --> HIGH calcitonin
2. Low Blood Ca --> parathyroid gland releases hormone --> more bone Ca release + intestinal Ca uptake + kidney Ca retention --> HIGH calcitriol (active VitD)
Supplements: Ca-Carbonate (cheapest), Ca-Citrate (helps with low acid in GI), natural sources (heavy metal, Pb)
> Reduces bone loss and fracture incidents
> Increases MI (30%), stroke (12-20%) and CVD risk in PMS women
40
Osteoporosis
Drug: Abaloparatide (34 AA)
> Analog of PTHrP: anabolic selective activation
Soy intake reduces 35% fracture rate
Bone mineral density 2.5 SD below peak bone mass (20 y.o.)
> Peak bone (20-25 yrs) --> net loss (faster in PMS women + eating disorder women)
> 12 million US adults (9M F and 3M M)
> 43 million low bone density
> 1/3-1/2 women have at least one fracture (vertebrae and hip)
Risk factors:
1. Long-term Low Ca/D
2. Estrogen loss
3. Inactivity (weight)
4. Aging (lose 2-6 inches)
5. High Na, Caffeine, alcohol
6. Acid reflux med (PPI)
7. Genetics: Asian > Hispanic> AA
41
Phosphorus and Magnesium
RDA: 700mg (P), 400 (M, Mg), 310 (F, Mg)
UL: 3-4g (P, bad kidney function and vascular damage); 350mg (Mg from supplements, diarrhea and kidney failure)
Bone growth, nucleic acid metabolism (ATP), Absorption enhanced by VitD + kidney Blood reg
> Usual P intake (more than RDA): 1-1.6g/day (deficiency: bone loss, poor tooth development, rickets)
> Usual Mg intake (less than RDA): 325mg (M), 225mg (F); deficiency: neuronal and cardiac problems
42
Electrolytes: K and Cl
K:
> AI: 4.7g/day
> Usual Intake: 2-3g/day
> Greatest deficiency (no appetite, muscle cramps, confusion --> heart stops)
Cl:
> AI: 2.3g/day
> Usual intake: 4-5g/d
> UL: 3.6 g/d
43
Electrolytes: Na
HTN is considered 130/80
Processed food: High Na, low K
Unprocessed: low Na, high K
Na:
> AI: 1.5g/d (51+ adults)
> UL: 2.3g/d (1.5 is high risk in AA)
> Usual intake: 3.3g/d
Elevation: chronic stress
> Kidney injury (Renal failure), oxidative stress (endothelial dysfunction, fibrosis, less vascular elasticity), Cardiac hypertrophy (DS/S), Increase arterial pressure
> HTN (140/90+ obesity+aging, 1/3 adults, 3x in 45- M, 2x in 45- F), CVD/strokes and kidney disease
> Meat: low Na, high K
> Tomato sauce: high Na, low K
44
Iron (Fe)
F>M (menstruation)
RDA: 8mg/d (M), 18 (non-pregnant F), 27 (pregnant)
AI: 17 (M), 12 (F)
UL: 45mg/day
Oxygen/CO2 transport (hemoglobin/myoglobin); metaboism (Cytochrome in Mito for e- transfer); Detoxification (cyt P450)
Global deficiency: iron, VitA, and iodine (3 bil people affected)
> Heme iron: meat (organic); 30% are readily absorbed
> Non-heme/mineral iron: Fe3+ (Ferric) or Fe2+ (ferrous): in plants/animals, 2-10% absorbed (gastric acid from PC helps with solubilization; VitC (Fe3+ --> Fe2+ + chelate; phytic/oxalic acid/tannin inhibits abs)
45
Fe Absorption and Distribution
1. Fe + mucosal protein Ferritin in intestine
2. Absorptive cells sloughed off to control Fe+ abs
3. Iron Out through ferroportin and into blood binds transferrin --> transferrin receptor to liver/muscle/BM/body tissue (hemoglobin/myoglobin)
4. Liver and spleen harvest iron from RBC (reused)
*Fe3+ --> Fe2+ by brush border and Ferroxidase --> stored as iron-ferritin complex in liver
46
Fe deficiency anemia and Toxicity
1. Low RBC --> less O2 transport
> Gradual; depletes storage pool (iron status marker) --> low blood hemoglobin
> Source: low diet intake, poor absorption, blood loss
> Heme source: clams, liver, red meat
> Mineral source: cashews, pumpkin seeds, white beans
2. Toxicity: GI distress and ROS production
> Fenton reaction --> hydroxyl radical --> inflammation/CVD/diabetes (H2O2 --> OH- + OH+ when Fe2+ becomes Fe3+)
> Poisoning for 6- kids from 200 mg
> Hemochromatosis: genetic (poor hepcidin function) --> liver disease/heart failure (**Treat with blood removal/chelation)
47
Iron Homeostasis
High Fe --> reduce uptake and transport
1. Increase ferritin in intestine absorptive cells (if trapped --> iron dies)
2. Hepcidin release from liver into blood --> degrade ferroportin --> less iron release from cell
* Hepcidin: released during infection so pathogens eat less iron (chronic infection --> anemia)
48
Zinc
RDA: 11mg/d (M), 8 (F)
Usual intake: 9-13 mg/d (lean meats, oysters)
UL: 40mg/day (Low Cu abs)
40% abs (inhibited by high Ca/phytic acid)
ADH (alcohol), carbonic andyrase (CO2 + H2O --> HCO3), Superoxide dismutase (O2 --> H2O2 + O2)
> Normal growth and sexual maturation; taste; needed by 300 enzymes
> DNA/RNA/heme/bone synthesis, immune, antioxidant defense
Deficiency: slow growth/sexual maturation; poor taste sensitivity
Pro-nutrients: allium (garlic/onion) have mineral abs compounds for Fe/Zn
49
Iodine and Thyroid Gland
RDA: 150 ug/day
Usual Intake: 190-300
UL: 1.1mg/day
TRH (Hypothalamus)--> TSH (Pituitary gland)--> T4/T3 (thyroid gland)
> Seaweed contains a lot --> no thyroid hormone
Goiter: iodine deficiency --> TSI/TSH enlarges thyroid gland
