NTDT401 Exam 2

UL of Vitamin C =

2g

body cannot convert homocysteine to methionine due to a __________________ deficiency

5-methyl-THF

B12 Can be stored and retained in the body for long periods o 50% in the _______

50% in the liver

non enzyme roles of Vitamin B6

Affects gene expression - Modulates steroid hormone binding and transcription factor to regulatory regions of DNA

____________ phosphatase (or other intestinal phosphatases) hydrolyze the phosphate from the phosphorylates vitamers to yield free pyridoxine (PN), pyridoxal (PL), or pyridoxamine (PM).

Alikaline phosphatase

function of Vitamin C o Collagen is most abundant protein in body, major component most connective tissue o 3 hydroxylation reactions require vit c, functions as reductant

Collagen synthesis

Folate assessment of nutriture

Folate assessed in plasma, serum and RBCs - Dietary intake (serum/plasma) - Tissue status (RBCs) • Plasma homocysteine concentrations - ⇧when body cannot convert homocysteine to methionine due to a 5-methyl-THF deficiency - Not a highly specific indicator of folate status

Folate Sources

Found in vegetables (folate) o Leafy, green o Higher concentration in raw foods vs. cooked o Destroyed by heat, oxidation, and UV light Enriched foods (folic acid) o Mandatory Fortification began in 1998 § Downside of mandatory fortification is the concern that people could be getting too much of that nutrient (ex: vitamin A in golden rice; some countries need it to prevent deficiency but the US have more occurring sources and could get too much if they pass the UL) o Now more Americans are meeting recommendations Dietary supplements (folic acid) o Multivitamins and prenatal vitamin o Most important to meet folate needs in prenatal/preconception period because women could miss the critical point for their baby if they did not know they were pregnant in first couple of works; also need to have an adequate amount of time to have a good folate status while prior to/while getting pregnant Bacterial production in colon

Recommended Dietary Allowance of Vitamin C -people who are smokers require ______mg more of vitamin C than non-smokers

People who are smokers require 35mg more of vitamin C than non-smokers image

Absorption of Vitamin B6

Primarily by passive diffusion in jejunum - Free forms (PN, PL, and PM) are released into portal blood - Overall absorption high - About 75% (range 61-92%)

main carrier responsible for absorption of Vitamin C

SVCT1

· Assessment of nutriture for B12

Serum concentrations § Can be maintained at expense of tissues · Methylmalonic acid · Doxyuridine suppression test · Schilling test

Structure of folate

Structure · THF = Tetra-hydro-folate

UL of folate = ? folate toxicity

UL = 1 mg syntehtic (nonnatural) Side effects - Insomnia - Malaise - Irritability - GI distress • Large amounts mask vitamin B12 • Amounts > 2 1/2 RDA ⇧ cancer risk

· Largest and most complex chemical structure · Contains the mineral cobalt o B12 chemical name is cobalamin

Vitamin B12

function of Vitamin C o reducing agent (antioxidant) (AH-) (electron donor) § donate electrons and hydrogen ions § react with free radicals and reactive oxygen species (ROS) § reduces several oxygen centered radicals and reactive oxygen species · hydroxyl radical (• OH) · hydroperoxyl radical (HO2 • ) · superoxide radical (O2.) · alkyl radical (RO• ) · peroxyl radical (R02• ) · singlet oxygen (02)

antioxidant

functions of Vitamin C

antioxidant pro-oxidant activity collagen synthesis carnitine synthesis tyrosine neurotransmitter synthesis

at usual intakes absorption high (% absorption ____________ with increased intake)

at usual intakes absorption high (% absorption decrease with increased intake) -at low intake, body absorbs more; vice versa; high intake body absorbs less -body can change how much you absorb and how much you excrete/lose

transport of Vitamin C across the:

basolateral membrane

· Most losses of B12 in the:

bile

function of Vitamin C o compound made from AA, transports LCFAs into the mitochondria so they can be oxidized to produce energy o vitamin C involved in two hydroxylation reactions required for it's synthesis

carnitine synthesis

Role of vitamin B12 in oxidation of L-methymalonyl-CoA

diagram

Vitamin C does not require:

digestion

Vitamin C is transported in plasma in which form?

free form

· One of the main functions as vitamin C is to work as an antioxidant and squash the _______ __________ in the body

free radicals

Neural Tube Defects Prevalence

graph

· Humans are not able to synthesize vitamin C because of lack of ______________ _____________ (last enzyme to be able to convert vitamin C to active form)

gulonolactone oxidase

· Undergoes little to no degradation prior to excretion Most B12 reabsorbed in the _________ (75%)

ileum

Folate Deficiency- Macrocytic Anemia

image

Megaloblastic Macrocytic Anemia

image

Role of Pyridoxal Phosphatase in Heme Synthesis

image

vitamin C is oxidized primarily in the:

liver (also in kidneys)

function of Vitamin C o Norepinephrine o Other neurotransmitters and hormones

neurotransmitter synthesis

losses occur 3 ways for B12:

o 0.1% excreted in bile (where the largest amount is lost) o Urinary excretion o Trace dermal losses

Vitamin B12 Digestion and Absorption in the ileum

o Absorbed via binding with receptors (cubilins) o Binds to transcobalamin II for transport o absorbed by carrier-mediated absorption

· 2 major enzymatic reactions require vitamin B12

o Conversion of homocysteine to methionine (methylcobalamin) (image) § Folate deficiency could mask Vitamin B12 deficiency § Both folate and Vitamin B12 are required for the conversion of homocysteine to methionine § May have increases of homocysteine if enzymatic reaction does not occur o Conversion of L-methylmalonyl CoA to succinyl CoA (adenosylcobalamin) (image)

Vitamin B6 interact with certain medications, and several types of medications might adversely affect vitamin B6 levels

o Cycloserine (Seromycin®) § Increases in urinary excretions o Antiepileptic Medications § Will increase breakdown of Vitamin B6 in the body o Theophylline (Aquaphyllin®, Elixophyllin®, Theolair®, Truxophyllin®) § Pulmonary disease and asthma medications Cause low PLP concentrations

at risk groups of folate deficiency:

o Excessive alcohol users o Malabsorptive disorders o Use of certain medications

folate vs folic acid

o Folic acid - Oxidized form found in fortified foods/dietary supplements - Dietary sources from fortified foods o Folate - Reduced form found naturally in foods and tissues - Naturally occurring folate foods include leafy green vegetables

Vitamin C Assessment of Nutritive

o Plasma concentrations (assess recent intake) o White blood cell (leukocytes) content (reflects body stores) § Difficult to assess § Results are not always reliable

· 6 vitamers for Vitamin B6

o Pyridoxine (PN) = alcohol (OH) form o Pyridoxal (PL) = aldehyde form o Pyridoxamine (PM) = amine (NH2) form · Each has a 5'-phosphate derivative o Pyridoxine phosphate (PNP) o Pyridoxal phosphate (PLP) - has most activity in the body o Pyridoxine phosphate (PMP) (image)

Vitamin B12 Digestion and Absorption in the duodenum

o R protein hydrolyzed - free cobalamin o Binds to intrinsic factor (IF)

· B12 in food is bound to proteins

o Requires gastric acid and intrinsic factor in stomach for absorption o As people age they will have problems with absorption of Vitamin B12 o Deficiencies could be from dietary reasons or physiological reasons that impair absorption

For Vitamin B12 Transport, and Storage- In blood, bound to one of three cobalamins:

o TCII - main protein that carries newly absorbed cobalamin in 1:1 ratio o TCI and TCIII - exact functions unknown

At risk groups for Vitamin B12 Deficiency

o Vegans (consume no animal foods) § Exclusively breastfed infants of women who consume no animal products o Gastric bypass patients o GI disorders (celiac, Crohn's disease) o Individuals with pernicious anemia (lack intrinsic factor) o Elderly § Diminished intake § Impaired absorption § Reduced gastric acid and intrinsic factor § Must get it from dietary supplement for this reason or fortified products

· Group of compounds for Vitamin B12 (Cobalamin)

o macrocyclic ring o atom of cobalt o if attached to (1 of following): § CN= cyanocobalamin § OH= hydroxobalamin § H20= Aquocobalamin § N02= Nitrocobalamin § 5'-adenosyl=adenosylcobalamincoenzyme § CH3=methylcobalamin-coenzyme Know general structure of Vitamin B12 - know that there are different forms (structure)

Vitamin C was included on the ____ food label

old (new food label does not include Vitamin C)

PN, PM, PL are absorbed by ________ __________ in the jejunum

passive diffusion

· In very large doses it would be __________ diffusion, then circulation in the liver · Very long biological half life · Different proteins in the blood it will bind to and will transport it · Can be stored for longer periods of time

passive diffusion image

function of Vitamin C o reduces transition metals (eg. cupric ions to cuprous and ferric ions to ferrous ions) o Fe2+ and Cu2+ can cause cell damage by generating ROS and free radicals minimal at physiological concentrations

pro-oxidant activity

absorption of Vitamin C occurs throughout:

small intestine brush membrane o proximal jejunum

Vitmain C absorption requires which transporter?

sodium dependent vitamin C transporters (SVCT) 1 & 2

lack of __________ can impair absorption of B12

stomach acid

Formation of Neurotransmitters involving B6

structures

RDA of folate

table · When women are pregnant they must have adeuwate amount for both her and the fetus (hence 600mcg DFE) · 2 types of neural tube defects: o Spina bifida (problems with spine; not able to walk some cases; need multiple surgeries to correct it) · Anencephaly (brain problem that would not be compatible)

function of Vitamin C o Hydroxylation of phenylalanine to form tyrosine requires vitamin C

tyrosine

Vitamin B6 is ____-soluble

water-soluble

folate is a ______-soluble vitamin

water-soluble

Vitamin B12 Digestion and Absorption in the stomach

· (1st step) o Released from proteins/ polypeptides o Binds to an R protein (found in saliva and gastric juices)

History of Vitamin C

· 1700's: Sailors on long ocean voyages, with little or no vitamin C intake, contracted or died from scurvy · 1747: Sir James Lind, conducted experiments and determined that eating citrus fruits/juices could cure scurvy · 1928: Vitamin C isolated · 1933: Structure determined · 1937: Nobel prize awarded

Food Sources of Vitamin B6

· All vitamers found in food · Pyridoxine (PN) o most stable form, o found only in plants § bananas, potatoes, nuts, fortified cereals · Pyridoxal (PL) and Pyridoxamine (PM) o found in animal products o main source of Vitamin B6 are animal products § beef, pork, fish, chicken = best sources · Bioavailability affected by food processing (diagram)

Folate Functions and Mechanisms of Action

· Amino acid and choline metabolism · Serine and Glycine Degradation (serine to be broken down to Glyceine) · THF is important to serve as a donor for different reactions (either a single or double Carbon group) · Gene expression · Purine and pyrimidine synthesis/ nucleotide metabolism structure · Choline degradation

Structure and Interconversions of Vitamin C

· Ascorbate --> ascorbic acid · Free radicals · One of the main functions as vitamin C is to work as antioxidant and squash the free radicals in the body · Dehydroascorbic acid has the ability to be converted to ascorbate in the body's cells -->has vitamin activity image

food sources of vitamin C

· Bright colored fruits/veggies (oranges, bell peppers) Also a preservative in foods image

Vitamin B6 Functions of coenzyme roles

· Coenzymes (>100 enzymes) o Involved in nutrient (amino acid) metabolism o Production of neurotransmitters, nucleic acid, heme, cartinite and glucose · The PLP form functions as a coenzyme for 100 different enzymes in the body o Mostly involved in nutrient metabolism o Certain amino acids that require PLP

other functions of Vitamin C:

· Colds o Inconsistent results o Prophylactic use vs. use after onset o People exposed to extreme physical exercise or cold environments · Cancer o Epidemiological studies have found association with certain cancers, studies inconsistent · Cardiovascular disease o Epidemiological studies demonstrate association, but supplementation studies no benefit · Eye health o Age related macular degeneration, most benefit in combo with other vitamins / minerals o Cataracts- no benefit

Dietary Folate Equivalents (DFE)

· Differences in the bioavailability of the two different sources of folic acid · Half of food folate is absorbed · Read ALL of chart

Vitamin B6 primarily excreted in the:

· Excreted primarily in urine o 4-pyridoxic acid is major metabolite o Ingesting large doses (about 100 mg) as pyridoxine and 5-pyridoxic acid Little excreted in feces

Assessment of Nutriture of folate

· Folate assessed in plasma, serum and RBCs o Dietary intake (serum/plasma) o Tissue status/stores (RBCs) · Plasma homocysteine concentrations o ⇧when body cannot convert homocysteine to methionine due to a 5-methyl-THF deficiency - Not a highly specific indicator of folate status

folate is absorbed ___% folic acid is absorbed close to ______% depending where it comes from

· Folate is absorbed 50% o Food folate is least bioavailable o Highest bioavailability from dietary supplements · Folic acid is absorbed close to 100% depending where it comes from

Recommended Dietary Allowance (RDA)

· Found in animal products · Plant products not naturally occurring source · Increased needs as you get older 2.4mcg for adults image table

Synthesis of Ascorbic Acid

· Humans are not able to synthesize vitamin C because of lack of gulonolactone oxidase (last enzyme to be able to convert vitamin C to active form) · Vitamin C would be considered essential (need from dietary sources) image

Vitamin C's interactions with other nutrients

· Increases intestinal absorption of nonheme iron o reduces Fe3+ to Fe2+ or forms soluble complex with the iron · High intakes (>600 mg/day) may interfere with copper (Cu) absorption o Because of iron overload syndromes

Selected Pharmacological Uses/Other Roles ofVitamin B6

· Individuals with primary hyperoxaluria (type 1) · Some infants with inherited intractable seizures (use could help reduce these seizures) · Individuals with homocyteinura

Folate and B12

· Interactions with other nutrients o Synergistic with Vitamin B12 Methyl Folate Trap image

Vitamin B6 Metabolism and Transport

· Main organ that takes up B6 (passive diffusion) and metabolizes it · Various enzymes involved · Interconversions of B6 vitamers · Mostly PLP and PL released into blood for transport o 2 main forms of Vitamin B6 that are found in the blood o Most PLP is bound to albumin (which is bound to several different micronutrients in the blood)

Folate Deficiency

· Megaloblastic macrocytic anemia o weakness, fatigue, irritability, headaches, heart palpitations, shortness of breath · Neural tube defects (NTDs) o Spina bifida, Anencephaly · Development of some cancers (Epidemiological evidence- correlation does not equal causation) o colorectal, lung, pancreatic, esophageal, stomach, cervical, breast

folate Interactions with Medications

· Methotrexate (Rheumatrex®, Trexall®) · Antiepileptic (antiseizure) medications, such as phenytoin (Dilantin®), carbamazepine (Carbatrol®, Tegretol®, Equetro®, Epitol®), and valproate (Depacon®) · Sulfasalazine (Azulfidine®)

Signs of B6 Deficiency

· Microcytic Anemia (impaired heme synthesis) · Impaired immune function · Weakness · Seborrheic Dermatitis · Chelosis · Neurological disorders · Infants o Irritability, convulsive seizures

· Mostly _____ and ____ released into blood for transport

· Mostly PLP and PL released into blood for transport

UL

· One of the water-soluble vitamins that DOES have a UL table · UL for adult = 100 mg/day

Digestion of Vitamin B6

· Phosphorylated vitamins must undergo dephosphorylation to PN, PL, or PM (alkaline phosphates and intestinal phosphatases) image

Assessment of Nutritive for vitamin B6

· Plasma PLP concentrations (best indicator) · Urinary vitamin B6 and 4-pyridoxic acid (short term indicator) o measured over several days

Folate: Digestion, Absorption, Transport, and Storage

· Polyglutamate forms hydrolyzed to monoglutamate form (folate in fortified foods already in monoglutamate form) · Reduced to tetrahydrofolate (THF) in enterocytes · Transported in portal circulation as 5-methyl THF by proton-coupled folate transporter (PCFT) · Found as a monoglutamate in blood Stored primarily in liver (50%) and also in blood and body tissues

B6 Deficiency

· Rare in US · Occurred in infants in 1950's · At risk groups o Older adults o Chronic alcohol users o Systemic inflammation o End stage renal disease o Malabsorptive syndromes o Use of certain medications (eg. Isoniazid used for TB, antiepileptic drugs, corticosteroids)

RDA of Vitamin B6:

· Recommendations based on maintenance of adequate plasma concentrations chart

Vitamin C deficiency

· Scurvy o Rare in US o May develop quickly o Fatal if untreated - can cause internal bleeding o 4 Hs of scurvy § Hemorrhagic signs § Hyperkeratosis of hair follicles § Hypochondriasis (psychological manifestation) § Hematologic abnormalities o Treated with 100-500 mg daily until cured · Scorbutic gums (images) - unlike other lesions of the mouth, scurvy presents a symmetrical appearance without infection · Pinpoint hemorrhages (images) - small red spots appear in the skin, indicating spontaneous bleeding internally · Petechiae (images)

Groups at risk of Vitamin C adequacy

· Smokers and "passive smokers" · Infants fed evaporated or boiled milk · People with limited food variety · Chronic diseases o Some cancers o End-stage renal disease on chronic hemodialysis

Sources of Vitamin B12 (Cobalamin)

· Sourced primarily from animal products (bound to protein; only naturally occur in animal products) o Meat and meat products o Shellfish (clams rich source) o Dairy contains less but absorption may be better o Plant-derived foods sometimes fortified · Supplements (free form) o Usually present as cyanocobalamin o No differences among forms with respect to absorption or bioavailability o Either brewery yeast or nutritional yeast would be supplements of B12 o Not going to have B12 that is bound to a protein (people that lack intrinsic factor, particularly older individuals, it is recommended they get B12 supplements so they can absorb that) o If someone is older, they should try to get B12 through supplements instead of food

Toxicity - Vitamin B12

· Toxicity o None observed o No Tolerable Upper Intake Level · No benefit from excessive intake despite claims o No beneficial effect on performance in the absence of a nutritional deficit If not deficienct, they do not need to take large doses

transport and storage of Vitamin C

· Transport across basolateral membrane · Transported in plasma in free form o Ascorbate moves freely into cells o Tissue concentrations > plasma concentrations o Concentration much higher in some tissues § adrenal, pituitary gland, eye, brain, WBCs

Vitamin C Dietary Supplements

· Typically contain vitamin C in the form of ascorbic acid, ascorbate and/or sodium ascorbate · Equivalent bioavailability · Commonly used supplements (eg. common cold) o Emergen-C (1,000mg of Vitamin C) · Some people it is dangerous to take vitamin C in large amounts as a supplement o Hereditary hemochromatosis (iron overload syndrome) § Vitamin C helps absorb iron more vitamin C intake, more iron you will absorb, so it is seen to have large amounts of iron with large amounts of Vitamin C

UL of folate

· UL = 1 mg synthetic (nonnatural) · Side effects o Insomnia o Malaise o Irritability o GI distress · Large amounts mask vitamin B12 · Amounts > 2 1/2 RDA ⇧ cancer risk · If have a large amount of folate, it can mask symptoms of a B12 deficiency (but the deficiency still is still present, it is just masked) can happen in several different nutrients table

Vitamin C Toxicity

· UL = 2 g · Diarrhea most common side effect · Risks in select populations o Renal dysfunction o Hereditary hemochromatosis

Vitamin B6 Toxicity

· UL for adult = 100 mg/day · Supplements above the UL have been used as treatment for carpal tunnel, PMS, morning sickness & other states · Pain and numbness Irreversible neurological effects (unsteady gait, paresthesias in extremedities)

Metabolism and Excretion of folate

· Urine o Excess excreted intact and catabolized · Feces o Unabsorbed folate of microbial origin

Vitamin C is metabolized or oxidized to:

· dehydroascorbate image