NDFS 200 exam 3

Vitamin A 

visual cycle

• epithelial cell maintenance: (eg,
• xerophthalmia and follicular hyperkeratosis)

immune function / infection

growth and development

cancer prevention

Epithelial cell maintenance (retinoic acid)

Regulation of mucous formation at the level of gene expression, cell differentiation: retina, cornea, lungs, skin, GI tract, etc.

Examples

Xerophthalmia“dry eye”  (Bitot spots)

Retinoic acid required, especially for mucus formation.

Mucus lubricates the cornea, and its lack allows scratches and bacterial growth in the scratches.

 Irreversible blindness

• nFollicular
• hyperkeratosis

• nSkin
• changes, keratin protein synthesis in follicles

Abbreviations for retinoid X recepter and retinoid acid receptor

Unspecified cells that can be transformed into specialized cells.

process by which light depletes the rodopsin concentration in the eye by seperating opsin from all-trans-retinal.  This fall in rhodopsin concentration allows the eye to become adapted to bright light.

Process by which the rodopsin concentration in the eye increases in dark conditions, allowing improved vision in the dark.  

often attached to proteins that need to be cleaved off by enzymes prior to absorption.  

preformed vitamin A are divided into retinyl and retinol ester compounds.  Retinyl esters ddon't have vitamin A activity until the retinol and the fatty acid are seperated.  in the intestinal track.  This process requires bile and pancreatic lipase enzymes.  Up to 90 % of retinol is abosorbed into the cells of thte small intestine via specific carrier proteins.  After absorption, a fatty acid is attached to retinol to form a new retinyl ester.  These retinyl esters are packaged into chylomicrons before entering the lymphatic circulation.

important role in embryonic development

epitheal cells in lungs trachea, skin, and GI track as well as in many other systems. mucous forming cells in these systems.  

 

in the nucleus RXR and RAR bind to specific sites that regulate formation of messenger RNA.  making it influencial in gene expression which directs cell differenciation

The process in which stem cells develop into specialized cells with unique functions in the body.  Vitamin A is especially important in maintaining normal differenciation of the cells that make up the structural components of the eye, such as the cornea (clear lens) and the retina ( rod and cone cells).

retinal is needed in the cornea of the eye to turn visual light into nerve signals to the brain.  part of rhodopsin.  

increased incidence of infection one of the first signs of vitamin A defficiency.  this may be because of its role in maintaining the epithelium.  

• xerophthalmia 
• follicular hyperkeratosis

- condition marked by dryness of the cornea and eye membranes that result from vitamin A defficencies.

Condition  in which keratin a protein accumulates around hair follicles.  

• nRetinoids
• leave liver bound to RBP, which then binds to transthyretin, carried in blood to target cells.

Bound in cells by family of CRBP proteins

• Bound in nucleus by two sub-families of receptors, RAR and RXR.
•  RAR and RXR bind to DNA, regulating gene expression and cell differentiation (cell function, growth, immunity, etc.).

• nRationale:
• based on dietary amount to maintain adequate body pool size and stores

• n900
• RAE for men

700 RAE for women

Average intake meets RDA

Vitamin A supplements are unnecessary

No separate RDA for carotenoids

Tolerable Upper Level for Vitamin A

3000 micrograms for adults, about 4 x RDA, based on the presence of birth defects and liver toxicity

 Fatal dose - 12 g of vitamin A

Too much carotene in blood

Not harmful

• caused by ingestion of 1 very large dose of vitamin A or several taken over a few days.
• sypmtoms:
• GI upset/nausa
• headaches
• dizziness
• poor muscle coordination

very large doses can be lethal

caused - repeated doses of over 10x the RDA

• sypmtoms - 
• liver damage
• hair loss
• bone muscle/pain
• loss of appetite
• Dry skin and mucous membranes
• hemorrages
• coma
• fractures

• Acutane etc
• .  
• birth defects
• spontaneous abortion

Vitamin D

begins with a precursor of cholestrol synthesis in the skin.  during exposure to UV light 1 ring undergoes a chemical transformation, forming a more stable cholecalciferol vitamin D.  it then enters the blood stream and goes to the liver and kidneys where it undergoes conversion to its bioactive form calcitriol.   

Depends on skin color, age, time of day, season, location

Clothes and sunblock inhibit conversion, but not of concern except in elderly

Angle of UV light, line from LA to Atlanta.  Winter UV light not effective above 34o N.

• Blood Ca regulation
• absorption

excretion

bone resorption or deposition

Other functions

gene expression

cell differentiation

cancer cells

•   Low blood calcium is a trigger
• for parathyroid to remove Ca from bone

reduce calcium excretion by the kidneys

stimulate synthesis of D3 in kidneys  to stimulate intestinal absirotion of Ca.  

regulate immune system

• secretion of hormones
•     insulin, renin, PTH
• cell cycle regulation

Rickets, osteomalacia

Pressure distorts bones of the:

• head
• rib cage (rachitic rosary)
• legs (bowed)
• joints
• Pelvis

RDA – intake linked with blood 25OHD level associated with benefit; assumes minimal sun exposure

UL – level not associated with classic toxicity (NOAEL 10,000 IU), corrected for uncertainty (adverse outcome other than “classic toxicity” that occur at lower intakes)

Food Sources:  fortified milk, fish, fish oils

“Sensible sun, foods, supplements”

6-7 X RDA

Main symptoms

Over-absorption of Ca

Ca deposition in kidneys, heart, blood vessels

Ca toxicity to the liver

Weakness, loss of appetite, vomiting

Mental retardation in infants

Vitamin E

•The R form of the first stereoisomer is natural, and the only active form. The RRR form is the most active

•Therefore, only about ½ of synthetic vitamin E is active.

Supplement labels indicate “d” for R and “dl” for R and S

• The tocopherols
• have chromanol
• ring with a long, saturated (phytyl) side chain (Figure 6-1). α-tocopherol
• has 3 methyl groups on the chromanol ring. β-or γ-tocopherols
• have 2 methyl groups on the chromanol ring at different positions, and δ-tocopherol
• has 1 methyl group on the chromanol ring. 

• RDA
• - based on dietary intake that maintains a plasma level adequate to limit H2O2-induced hemolysis to < 12%

• 15
• mg/day for women and men
• (=22 IU of natural source or 33 IU of synthetic form)

1 mg dl-a-tocopherol = 0.45 IU (synthetic source)

1 mg d-a-tocopherol = 0.67 IU (natural sources)

n

• nAdults
• consume on average 2/3 of the RD

absorbption depends on dietary intake.  done through passive diffusion absorption rate can vary from 20-70%.  As with all fat soluble vitamins must be incorporated into the micelles of the small intestine.  A process dependent upon bile and pancreatic enzymes.  then incorporated into chylomicrons and transported through the lymph into the blood.

Chain reaction looking for electrons; lipid peroxidation

Destruction of cells and components

Need an acceptor (chain breaking antioxidant) to stop the chain reaction

Varies with the amount of polyunsaturated fatty acids (PUFA) in the diet

PUFA are electron dense, promote free radical chain reactions

Coincidentally(?), plant oils high in PUFA also high in vitamin E

Supplements of PUFA e.g. encapsulated fish oils may not have vitamin E

Supplements up to 800 IU are probably harmless

Upper Level is 1,000 mg/d of any form of supplemental alpha-tocopherol

Inhibits vitamin K metabolism and clotting, leading to hemorrhage

Disrupts balanced anticoagulant medications, leading to hemorrhage

Possible decrease in gamma-tocopherol activity, which is Potentially beneficial in reducing prostate cancer risk

Supplements up to 800 IU are probably harmless

Upper Level is 1,000 mg/d of any form of supplemental alpha-tocopherol

Inhibits vitamin K metabolism and clotting, leading to hemorrhage

Disrupts balanced anticoagulant medications, leading to hemorrhage

Possible decrease in gamma-tocopherol activity, which is potentially beneficial in reducing prostate cancer risk

Vitamin K

Menaquinones also from bacteria in human intestine

40%-80% of dietary vitamin K absorbed

AI - based on reported intakes in apparently healthy populations

90 ug/day for women

120 ug/day for men

RDA met by most

Excess vitamins A, E interfere with vitamin K

Toxicity unlikely; readily excreted

Menaquinones

Fish oils, meats, bacteria in intestine

Phylloquinone

Plants

Liver

Green leafy vegetables

Broccoli

Peas

Green beans

Resistant to cooking losses

Very limited vitamin K stores in the body

Long-term antibiotics bacteria

“Blood thinners” (anticoagulants) interrupt vitamin K metabolism

Supplementation of vitamin K may decrease effectiveness of anticoagulants

16 known vitamin K-dependent (VKD) proteins

11 known mouse knock-out (KO) mutants

5 KOs embryonic lethal – coagulation factors

Thiamin

Coenzyme in caarabohydrate metabolism and energy release

–Thiamin pyrophosphate (TPP)* = thiamin diphosphate (TDP)

–Decarboxylation reactions in CHO metabolism e.g. the “bridge” reaction (pyruvate decarboxylase)

–TCA cycle, nerve function (highly respirating cells)

Beriberi, weight loss, weakness, peripheral neuropathy; wernicke-korsakoff syndrome 

Thiamin defficiency disorder characterized by muscle weakness, loss of apetite, nerve degredation, and sometimes edma 

Thiamin defficiency caused by excessive alcohol consumption.  Symptoms include eye problems, difficulty walking, and deranged mental functions

pork, pork products, enriched whole grain cereals, eggs, nuts, legumes 

• – based on RBC transketolase activity (ribose for DNA syn.), urinarythiamin excretion
• •Most exceed in diet
• –Surplus rapidly lost in urine; non toxic

Riboflavin

• •RDA
• – based on RBC glutathione reductase activity coefficient, urinary excretion

•Average intake > RDA

–Toxicity not documented

Coenzyme in numerous oxidation-reduction reactions, including those of energy release.

• FAD and FMN:  Reducing equivalent carriers in Redox
• reactions
• •Pyruvate to AcCoA

•Citric Acid Cycle

•Beta-oxidation of fats

•Br Ch AA oxidation

•Electron Transport System

• ariboflavinosis; inflamation o f mouth and tongue, cracks at corner of mouth
• •Ariboflavinosis
• –rarely seen

–Glossitis, cheilosis, seborrheic dermatitis, stomatitis, eye disorder, throat disorder, nervous system disorders, confusion, headaches

•Occurs within 2 months @ < 25% RDA

milk, milk products, mushrooms, eggs, liver, enriched grains

–Sensitive to UV radiation (sunlight)

–Stored in paper, opaque plastic containers

Niacin

–Part of NADH, NADPH 200 diff. reactions in almost every major pathway, especially those producing ATP

•Glycolysis

•Beta-oxidation

•Lipogenesis (NADPH)

•Amino Acid syn. & bkdn

•Citric Acid Cycle

•ETS

• •60
• mg tryptophan ->1 mg niacin

• •RDA:
• 14 NE/day for women, 16 NE/day for men

widely distributed in foods

• niacin defficiency 
• the four "D"s

• •Dementia
• –severe, many lived lives in mental institutions

•Diarrhea

• •Dermatitis
• –mal de la rosa

•red sickness

–pelle agra

•rough skin

•Death

flushing of skin; upper level for adults is 35mg/day from supplements , based on flushing of skin.  

•1.5-3 g/ day (75 - 150 X RDA) nicotinic acid increases HDL, decreases LDL, TG

•Slow/reverse progression of atherosclerosis with diet, exercise

• •Serious side effects:
• –flushing of the skin, itching, nausea, headache, dizziness, liver damage (especially slow release), increased blood
• glucose.

Coenzyme A

Pantothenic acid

• •AI
• based on intake adequate to replace urinary excretion

–AI set at 5 mg/day (avg intake meets AI)

• •Abundantin foods (Greek pantothen = everywhere), deficiency very rare

–Acetyl CoA formation from:

–Pyruvate

–Beta-oxidation

–Amino acids

–Alcohol

–Initiate the Citric acid cycle

–Succinyl CoA in Citric acid cycle

• –Initiate
• fatty acid synthesis

• –Acetyl CoA + CO2→Malonyl
• CoA

–Part of Acyl Carrier Protein

–Increase fatty acid chain length

Deficiency very rare

• Experimentally induced: headache, burning
• foot syndrome, fatigue, nausea, tingling

Hidden among other deficiencies

biotin

•Absorption:

–Free biotin in small intestine directly

–Biocytin cleaved in small intestine by biotinidase

•Functions: carboxylations

•Fatty acid synthesis and elongation

•AcCoA + CO2→malonylCoA

•CHO metabolism

•Pyr + CO2→  oxaloacetate

•Replenish TCA

•Gluconeogenesis

•AI based on extrapolation from exclusively breast fed infants, limited estimates of intake by adults

–AI set at 30 ug/day for adults, no UL

–May be an overestimation because of extrapolation

•Food Sources:

–Cauliflower, yolk, liver, peanuts, cheese

–Intestinal synthesis of biotin

•Biotin content only available for a small number of foods

•Unsure as to bioavailablity of GI bacterially synthesized biotin

•We excrete more than we consume

•Avidin

–egg white protein

–inhibits absorption, powerful binding (one of strongest in nature)

–>12 raw egg whites/d to take effect

–cooking egg white denatures avidin

–protein-bound form of biotin in food; covalently bound to lysine.

–in small intestine cleaves this bond, makes available for absorption.

–1 in 60,000 infants have genetic defect in biotinidase production

–Deficiency in infants within months, must be treated with large doses.

•Rash, hair loss, convulsions, neurological disorders,            growth

Vitamin B6

•RDA: 1.3 mg/day for adults

–Criteria: maintain adequate plasma PLP

•Food Sources:

–Muscle of meat, fish, poultry

–Whole grains (milled not enriched with B6)

–Banana, spinach, avocado,      potato

•Coenzyme in reactions involving N-containingcompounds

– without B6 every amino acid would be essential;


–RBC (heme) synthesis, a nitrogen containing ring.

–Brain neurotransmitter synthesis: serotonin, dopamine, norepinephrine (N-containing neurotransmitters)

–CHO metabolism:  glycogenolysis requires B6, maintains blood glucose concentrations.

–Gluconeogenesis from glucogenic aa.

• –Vitamin
• metabolism: 

Functions

• AA transaminations

• neurotransmitter   synthesis

• glycogenolysis

• • homocysteine to
• methionine

•Microcytic hypochromic anemia (decreased heme synthesis)

•Convulsion, depression, confusion

•Peripheral nerve damage

•Reduced immune response

Folate

•Many relationships to B12: transfer of single carbon units (e.g. methyl groups)

•DNA and RNA synthesis (U to T)

•Cell division

•Methotrexate therapy (THFA analogue)

•Neurotransmitter synthesis

•Homocysteine to methionine

•homocysteine levels in blood

•Cells with short life span, rapid turnover affected most

•Megaloblastic anemia: low DNA/RNA synthesis

•Cardiovascular disease: homocysteine toxicity

•Neural tube defects: low DNA/RNA synthesis

•Cancer hypomethylation of DNA

•Pregnant women; alcoholics

•FDA limits nonprescription supplements to 400 mg per tablet for non-pregnant adults

•OTC prenatal supplement contains 800 mg

•Epilepsy (?)

•Skin, respiratory disorder (?)

Treating a B12 deficiency with increased folate “masks” the B12 deficiency, that will result in nerve damage, by relieving the megaloblastic anemia that results from deficiency of either.

•Chemotherapeutic agents antagonize folate, decrease DNA synthesis, inhibit rapidly growing cells (e.g. cancer cells)

•Aberrations in DNA methylation in cancer

–Methylation decreases gene expression

–Global hypomethylation

–Promoter-specific hypermethylation

– alterations of chromatin that affect gene expression without changing DNA sequence

green vegetables, liver, enriched cereal products, legumes, oranges 

B12

•Functions:  (one carbon transfers)

–Methylmalonyl CoA reductase (3C fa residue to 4C succinyl CoAàTCA)

–Methionine synthase (w/ folate)

•Return folate coenzymes back to THFA for use in other folate rxns

•allows normal DNA synthesis, maturation of RBC

• •RDA:
• hematological status, normal serum
• vitamin B12

•Interfering factors

–Genetic lack, inadequate synthesis of factors (R protein, intrinsic factor)

–Low stomach acid production

–Anti-ulcer medications (acid production by parietal cells)

–Bacterial overgrowth

–Tapeworm

• –Surgical
• removal of stomarch or
• ileum

•Deficiencies due to malabsorption, not low dietary intake

•At risk:

• –genetically inherited defect in one of many steps in B12
• absorption

–elderly

–vegans, especially infants born of vegans

–meat, poultry, seafood, eggs, milk, milk products

Vitamin C 

•Hydroxylation, cross linking of collagen and elastin

•Oxidation/reduction of Fe and Cu:

–As metals

–As metals in enzymes

• •Water
• soluble free radical scavenger

•Immune functions

–Fully saturated WBC

•Iron absorption (Fe+3 à Fe+2)

•Synthesis of carnitine, tryptophan to serotonin, thyroxine, cortiscosteroids, aldosterone, cholesterol to bile acids

•Critical for strong connective tissue

–Bone

–Blood vessels

–Wound healing

• Hydroxylation of lysine and proline uses iron, recycling it from Fe+3 back to Fe+2 oxidation state, using vitamin C to
• provide electrons

•3 week history of general malaise, dysphagia, chronic cough, nausea

•Hemorrhagic rash on legs, perifollicular and conjunctival hemorrhages.

•Rationale: near-maximal neutrophil concentration, minimal urinary excretion

•75 or 90 mg/day to fulfill rationale

•10 mg/day prevents scurvy; remainder for other functions to achieve “rationale.”

•UL: 2000 mg

•Nausea, abdominal cramps, stomach inflammation, diarrhea

•Enhances Fe absorption-(hemochromatosis beware)

•Oxalate stones, kidney failure (beware)

•Minor decrease in common cold severity, not incidence

•“Chelation Therapy” dangers