Metabolism - Exam #3, Fat-Soluble Vitamins Flashcards
1
Q
What is Vitamin A?
A
- Several compounds that either start or lead to all-trans retinol = RETINOL;
- Also called preformed Vitamin A or Retinoids
2
Q
What are the Retinoids?
A
- Retinol;
- Retinal;
- Retinoic acid;
- Retinyl esters;
- Synthetic analogues
3
Q
Who discover Vit. A?
A
- McCollum and Davis followed by Osborne and Mendel (1915);
- Found essential for growth in animals and was called fat-soluble A
4
Q
What are PROvitamin A Carotenoids?
A
- Compounds that are PRECURSORS to vitamin A;
- More than 600 carotenoids (lipid-soluble red, orange, and yellow pigments produced by plants);
- But fewer than 10% can be converted to vitamin A (provitamin A);
- NO requirements have been set for any carotenoids other than those included with vitamin A as provitamin A
5
Q
What is the structure of Retinoids?
A
-Beta-ionone ring and a polyunsaturated side chain, trans- or cis double bonds possible;
-Carotenoids are mainly all-trans, but can be cis;
-3 main active carotenoids =
oBeta-carotene
oAlpha-carotene
oBeta-cryptoxanthin
6
Q
How is Vit. A found in foods?
A
- Retinyl esters and retinyl esters and carotenoids often complexed with PROTEIN;
- Then freed by PEPSIN in the stomach or PROTEOLYTIC ENZYME in the duodenum
7
Q
How is Retinol digested?
A
- Retinol is freed by pancreatic and intestinal brush border HYDROLASES and ESTERASES;
- Bile is important for typical fat digestion
8
Q
How is Vit. A absorbed into the Intestine?
A
- Micellar “solutions” containing carotenoids and vitamin A are absorbed across brush border into enterocytes in duodenum and jejunum;
- Normal doses = specific protein carriers;
- High doses = passive diffusion, which is nonsaturable;
- Carotenoids may be absorbed by a carotenoid transporter called “scavanger receptor class B type 1” (SR-B1)
9
Q
What is the rate of Vit. A absorption?
A
- 70% to 90% of retinol is absorbed if meal contains ~10 g or more of fat;
- Carotenoid absorption is quite variable depending on the food processing = <5% absorption from uncooked vegetables to about 60% if present as a pure oil or in aqueous dispersion supplement
- *Typical range of absorption is 20 to 50%
10
Q
What can inhibit Vit. A absorption?
A
- Fiber (pectin) appears to INHIBIT MICELLE formation and inhibit absorption of carotenoids;
- Carotenoids also enhance/inhibit other carotenoids (so variety and moderation are key words);
- High dietary levels of vitamin E can also lower carotenoid absorption
11
Q
What happens to Retinol once the micelle passes it through to the intestinal CELL?
A
- Secondary RE-ESTERIFICATION pathway for retinol is by ARAT (acyl-CoA retinol acyl transferase);
- Vit. A is put back together with other lipids once absorbed and “inside” the body;
- Creates Chylomicrons created WITHIN the intestinal cells
12
Q
What happens to the Chylomicrons that are made in the enterocytes?
A
- Intestinal chylomicrons will leave the cell and enter the lymph and ultimately blood circulation;
- As pieces break off these chylomicrons in the blood and tissues (catalyzed by Lipoprotein Lipase), the remnants will be sent back to the LIVER and packed for VLDLs and other lipoproteins to once again enter circulation;
13
Q
How is Retinoic acid treated differently once absorbed?
A
Retinoic acid can directly enter the blood where it attaches to ALBUMIN for transport to the liver
14
Q
What is the mechanism for Vit. A incorporation into chylomicrons?
A
- Cellular-Retinol-bindind pro II (CRBPII) bind both retinol and retinal;
- Retinal attached to CRBPII becomes retinol also making CRBPII-retinol
- Lecithin retinal acyl transferase (LRAT) esterifies a fatty acid (palmitic) to CRBPII-retinol complex = CRBPII-retinylpalmitate
- Retinyl esters are added with Phopholipids, TAGs, cholesterol esters, carotenoids and apoproteins = Chylomicrons
- Chylomicrons leave for lymph and then blood
- Retinoic acid can directly bind albumin for transport to liver
15
Q
What are the PROvitamin A carotenoids?
A
- Beta-carotene
- Alpha-carotene
- Cryptoxanthin
- Metabolized to RETINOIDS in the enterocyte (intestinal cells) and to some extent in liver, adipose, lungs and some in other tissues;
16
Q
What controls the conversion of the provitamin A forms?
A
- Conversion is influence by Vit. A status and amounts/forms of carotenoids consumed;
- High vitamin A intake REDUCES ABSORPTION of carotenoids and conversion to vitamin A;
- Also as beta-carotene increases in diet its conversion decreases
17
Q
How does synthesis of All-Trans Retinal from beta-carotene occur?
A
- Beta-Carotene is hydrolyzed within the enterocyte (as well as liver, lungs, kidney, and retina) by either noncentral cleavage to alcohols, aldehydes, etc. or by beta-carotene 15,15’-carotenoid dioxygenase;
- Oxygenase (iron-dependent) converts beta-carotene into 2 molecules of RETINAL;
- ~ 60% to 75% of beta-carotene is hydrolyzed and up to 15% of beta-carotene ends up in chylomicrons
18
Q
What are the basics of Retinoid metabolism?
A
- Retinol and Retinal are interchangeable;
- Retinal undergoes IRREVERSIBLE conversion to Retinoic Acid, which can enter the portal blood;
- Or Retinoic acid becomes 4-Oxoretinoic acid or Retinoyl Beta-glucuronide;
- Retinol is only converted to Retinyl Beta-glucoronide
19
Q
What do Chylomicrons carry?
A
Transport retinyl esters, some free retinol, and carotenoids to EXTRAHEPATIC tissues and then chylomicron remnants taken up by liver;
- Remnants are leftover as Lipoprotein lipase cleave fatty acids and other components off to be used by the tissues;
- Liver wil then created VLDLs
20
Q
How is Vit. A stored within the body?
A
- 80% to 95% of Retinol stored in the liver as retinyl esters in STELLATE cells;
- 15 to 20% of body’s vitamin A stored in adipose;
- Retinoic acid does NOT accumulate in tissues
21
Q
What are the binding proteins for Vit. A and carotenoids?
A
- CRBPI is high in liver and kidneys
- CRBPII in intestine
- CRBPIII in liver, skeletal muscle, kidneys, and heart; CRBPIV in heart, kidneys, and colon
→ By binding to retinol protects retinoids from oxidation and directs retinoid traffic in cells
22
Q
What are considered adequate body concentration of Vit. A?
A
- LIVER stores a minimum of 20mcg/g of liver;
- PLASMA conc of holoRBP (retinol)-TTR (T4) remain fairly consistent = 1.05 to 3 micromol/L (30 to 86 micrograms /dl) and remain fairly constant even when liver stores drop (as long as not too low)
23
Q
What is the mechanism for uptake by the TISSUES?
A
- Believed to be through cellular RBP receptors;
- TTR appears to dissociate and holo-RBP binds to the RBP receptor and the new complex is endocytosed;
- Retinol released inside the cell;
- Apo-RBP is released back into the blood for reuse or degradation by the kidney;
- Also a receptor-independent uptake as well (dependent on the tissue)
24
Q
How are Carotenoids transported and stored within the body?
A
- STORED in the liver and adipose tissue, but some other tissues concentrate specific carotenoids as the retina of the eye is rich in lutein and zeaxanthin;
- TRANSPORTED in lipoproteins and taken up by lipoprotein specific apoprotein receptors, EX: LDL
25
What is the Retinoic Acid produced within tissue cells?
- Cells in tissues produce small amounts of retinoic acid from retinal for FUNCTIONAL purposes;
- Plasma retinoic acid concentrations are usually low;
- in Cytoplasm, Retinoic acid is bound to cellular retinoic acid binding proteins (CRABPs), similar to CRBPs - - both can be found in the same tissues, but their relative distributions can vary;
- CYP26, a cytochrome P-450 enzyme system helps create functional metabolites
26
What are the bodily processes that require Vit. A?
Essential for Vision;
- cell differentiation;
- Growth;
- Reproduction;
- Bone development;
- immune function
27
What is Cell Differentiation?
Immature cells are transformed into a specific type of mature cells by inhibiting the cell cycle in rapidly dividing cells;
-Epithelial cells are especially affected by RETINOIC ACID;
28
How does Retinoic Acid influence cell differentiation?
- Retinoic acid helps maintain the structure and function of epithelial cells;
- Immature skin cells called keratinocytes become mature epidermal cells;
- With Retinoic Acid deficiency keratin- producing cells replace mucus-secreting cells;
- Affects gene expression
29
How does Retinoic Acid affect immune function?
- Vit. A very important to immune function!;
- EX: Without retinoic acid, myeloid progenitor cells do not differentiate into mature myeloid dendritic cells that present antigens to other immune cells such as T cells
30
How does Retinoic Acid affect gene expression?
- Retinoic acid promotes normal cell growth and inhibits growth of some tumors; controls cell growth by regulating gap junctions between cells;
- There are hetero- and homodimers of proteins that are transcription factors that act as receptors = RXR and RAR
31
What are RXR and RAR?
Nuclear receptors that mediate the biological effects of retinoids by their involvement in retinoic acid gene activation;
•RXR – retinoid x receptors
•RAR – retinoic acid receptors
32
What is the mechanism for vision when light hits the eye?
1. LIght hits the retina in the back of the eye
2. Rhodopsin in the rod cells is transformed and signals are sent to the brain
3. Rhodopsin is cleaved into opsin and cis-retinal and then cis-retinal to trans-retinal;
4. Trans then goes back to cis;
5. Cis-retinal reattaches to opsin to remake rhodopsin
* *Cone cells in center of retina = bright light;
* *Rod cells = dim light
33
What is the mechanism for Retinoic acid to affect gene transcription?
1. All-trans or 9-cis Retinoic acid moves into the nucleus of the cell;
2. All-trans retinoic acid binds to RAR and 9-cis trans retinoic acid binds to RXR. Vitamin-bound receptors attach to DNA at retinoid acid response elements (RARE), on the promoter regions of genes;
3. Receptors binding to RARE enhances specific gene transcription
34
What other form of Vit. A affects growth?
-Aso retinyl beta-glucuronide also does and it is also a waste product in bile
35
What are the other functions of Vitamin A?
- Stabilizes connexin 43 that in gap junctions so cells can communicate boundaries and not overgrow;
- Retinol and retinoic acid may affect glycoprotein on cell surfaces;
- Retinol and reproduction;
- Immune functions through gene expression (deficiency impairs fighting);
- Morphogenesis/embryogenesis – retinoic acid is called a morphogen in embryonic tissue
36
How is bone development affected by Vit. A?
- Bone development and maintenance at physiological dietary levels– mechanism unclear;
- Deficiency causes too much bone deposition (osteoblasts) and not enough resorption (osteoclasts); excess vitamin A has the opposite effect, decreasing bone density and increasing fracture risk
37
How is Vitamin A excreted?
1. Retinol and Retinal are interchangeable;
2. Retinol becomes Retinyl Beta-glucoronide and then Bile and lost in feces;
3. Retinal becomes Retinoic Acid and 2 step conversion to 4-oxoretinoic acid and either lost in urine or lost in feces as bile
38
How are do Carotenoids act as Antioxidants?
Carotenoids have an extended system of conjugated double bonds that make them soluble in lipids and capable of quenching singlet molecular oxygen, a more excited state than the ground state of molecular oxygen, and free radicals;
**LYCOPENE is the best for singlet oxygen and lipid peroxidation
39
What is order of antioxidants strength for carotenoids?
1. lycopene
2. α-tocopherol
3. α-carotene
4. β-cryptoxanthin
5. zeaxanthin
6. β-carotene
7. lutein
40
How do the carotenoids work together?
- Lycopene and lutein seem to act well together;
- β-carotene and vitamin E appear to work synergistically;
- β-carotene is believed to act in the interior of the membrane when protecting PUFAs and vitamin E functions on the surface of the membranes
41
How do carotenoids affect eye health?
- Lutein and zeaxanthin are found in the macula, which is the center of the retina;
- Reduced macular degeneration correlated with highest intakes of lutein and zeaxanthin and higher levels of plasma values of these carotenoids;
- FDA does NOT allow health claims
42
How do carotenoids affect heart disease?
- Large doses of beta-carotene not effective and just consume fruit and veggies;
- Supplementation is NOT recommended for heart disease
43
How do carotenoids affect cell proliferation, growth, and differentiation?
-May function similar to retinoic acid by UP-regulating gene expression of connexin 43 for normal gap junction communications
44
How do carotenoids affect cancer?
- Megadoses of beta-carotene NOT beneficial;
- Increased risk of lung cancer in long-time smokers – maybe a megadose of beta-carotene impairs absorption of the variety of other carotenoids and they all work together for better health
45
What are the health claims related to Carotenoids?
- Institute of Medicine states that “beta-carotene SUPPS are NOT advisable for the general population”;
- Health Claims EXIST for fruits and vegetables and heart disease and cancer with low fat diet, but NOT carotenoids
46
How does Vit. A interact with other bits in Hemoglobin synthesis?
- Several nutrients affect hemoglobin synthesis;
- Vit A is involved - deficiency reduces iron incorporation in red blood cells and diminished mobilization of iron from stores;
- Causes microcytic, hypochromic, iron-deficiency anemia;
- Would be secondary deficiency if IRON intakes ADEQUATE
47
What are other interactions of Vit A?
- Excess blocks Vit. K absorption;
- High beta-caro reduces plasma Vit. E;
- Iron is a cofactor for the 15,15’ mono-oxygenase – conversion of β-carotene into retinal
48
How does protein deficiency affect Vit. A status?
- Protein and zinc influence vitamin A status and transport;
- Low dietary protein affects protein status and zinc is needed for protein synthesis and RBP and alcohol dehydrogenase activity, which converts retinol to retinal
49
How is Vit. A EXCRETED?
- Catabolites of vitamin A are excreted in the urine (60%) and feces (40%);
- Except with high intakes it is REVERSED;
- Urinary excretion there is oxidation of the β-ionene ring conjugated with components to make them WATER soluble;
- Compounds with intact side chains excreted in BILE and some is reabsorbed to help conserve body’s vitamin A;
- Lots of carotenoid excretion products excreted in BILE
50
What is the RDA for Vit. A?
- Men = 900 micrograms RAEs
- Women = 700 micrograms RAES
* *Retinol activity equivalents (RAE) – RAE is 1 microgram retinol, 12 microgram beta-carotene, and 24 micrograms of alpha-carotene or beta-cryptoxanthin
51
What is Vit. A DEFICIENCY?
Common for children in developing countries leading to:
- Xeropthalmia (dryness of eye leading to bacterial infections and blindness);
- Night blindness can be an early indicator;
- Retarded growth;
- Increased susceptibility to infections;
- Keratinization of the skin
52
How is Vit. A status assessed?
- Blood levels of retinol are NOT reliable for status unless liver stores are deficient;;
- Relative dose response (RDR) test with retinol;
- Modified relative dose response (MRDR) with an analogue of retinol = similar to tests with thiamin and transketolase activity
53
What is the reverse conversion fro RAEs?
- 1 IU = 0.3 micrograms retinol;
- 3.6 micrograms beta-carotene;
- 7.2 micrograms alpha- carotene and beta-cryptoxanthin
54
How is cody Vit. A calculated?
AxBxCxDxExF
A = % vit. A stores lost/day when not consuming vit. A;
B = minimal liver reserve;
C = liver wt:body wt ratio;
D = Reference wt;
E = Ration total body-liver vit. A reserves;
F = Efficiency of storage of dietary vit. A
55
What is the UL for Vit. A?
* UL = 3,000 micrograms/day (10,000 IU);
- Large SINGLE dose can give acute hypervitaminosis A = nausea, vomiting, double vision, headache, dizziness, and general desquamation of skin
56
What is caused by chronic doses of Vit. A 3 or 4 times the RDA?
- Hypervitaminosis A, but usually takes higher doses: anorexia =
- Dry, itchy, and desquamated skin;
- Alopecia (hair loss) and coarsening of the hair;
- Ataxia;
- Headache;
- Bone and muscle pain;
- Increased bone fractures;
- Conjunctivitis and ocular pain;
- Liver damage
57
What is the toxicity associated with the drug Accutane?
- NOT during pregnancy;
- Pregnancy test is required before beginning the drug use because excess vitamin A or analogues are TERATOGENIC (causes birth defects)
58
What are considered high serum levels of Vit. A?
- HIGH dose vitamin A increases serum levels and problems seem to be greatest when above 200 micrograms/dl;
- NORMAL is 30 to 86 micrograms/dl
59
How are HIGH doses of Vit. A transported that can cause problems?
- High doses of Vit A transported by LIPOPROTEINS is dangerous compared to transport by RBP (retinol binding protein);
- Detergent-like effect on membranes (disrupts);
- Lots of problems in liver where excess is then stored
60
What is the UL for carotenoids?
No UL for carotenoids, but supplements are NOT recommended
61
Who discovered Rickets?
Whistler (1645) and Gilson (1650);
| -Vitamin D deficiency disease of children associated with improper bone development
62
How did Vit. D "accidentally" become a vitamin?
-Sir Edward Mellanby raised dogs in 1919-1920 indoors with no sunlight or any source of UV light;
-Dogs developed rickets and attributed to a dietary deficiency;
-1921 he wrote about a fat-soluble component as a vitamin or accessory food factor and that it was probably identical to Vit. A;
→Emphasis was placed on the DIET, so became a vitamin
*Cod liver oil was an anti-rachitic factor given to children
63
How were Vit A and Vit. D first distinguished from each other?
E.V. McCollum and associates observed bubbling O2 through the "fat-soluble vitamin" they distinguishes b/w vit. A (which was inactivated) and vit. D (which retained activity).
64
What was discovered about the precursor of Vit. D?
1923 - Goldblatt and Soames;
-Porved precursor of vitamin D in the skin (7-dehydrocholesterol) was irradiated with sunlight or UV, a substance equivalent to the fat-soluble vitamin was produced
65
What is Vit. D known as?
Calciferol
66
How was "light equals Vit. D" proven?
Hess and Weinstock;
- Irradiated a small portion of skill with UV and then fed it to RACHITIC rats;
- Irradiated skin provided an ABSOLUTE PROTECTION;
- UNIRRADIATED skin provided NO protection → Animals could make enough in skin suggesting that it was not an essential dietary trace constituent.;
- Steenbock and Black also found irradiated rats food became antirachitic
67
Why was the "antirachitic factor" ultimately made a vitamin even with other evidence?
- Rapid rise nutrition;
- Discovery of the families of water-soluble and fat-soluble vitamins;
- Firmly established that the antirachitic factor was to be classified as a vitamin.
68
Who discovered the structures of Vit. D?
1930s by A. Windaus;
- Vitamin D2, produced by UV irradiation of ergosterol in plants;
- Vitamin D3, produced from UV irradiation of 7-dehydrocholesterol;
- Aaround this time the elusive antirachitic component of cod liver oil was shown to be newly characterized vitamin D3
69
When were the Vit. D metabolites discovered?
- 60s and 70s;
| - Learned that the active form of vitamin D is a STEROID HORMONE
70
What are the variations of Vit. D "derived" from?
- Vitamin Ds, 2 or 3, are derived from STEROIDS and are considered seco-steroids;
- The B ring is broken with energy from UVB light at wavelengths ~285 to 320 nm;
- Break is between carbons 9 and 10 of the B ring and then there is rotation of the A ring
71
What happens to Ergosterol previtamin D2 (plant foods) when irradiated?
Becomes Egocalciferol Vitamin D2 = sold commerically
72
How is Vitamin D synthesized in the skin?
1. Body cholesterol is converted to 7-dehydrocholesterol (skin's sebaceous glands);
2. 7-dehydro when exposed to UV becomes Lumisterol and slough off skin; UVB converts to Previtamin D3;
3. Previtamin D3 either is exposed to more UV and becomes Tachysterol and sloughed off; or Theramal-isomerization converts to Vitamin D3 (Cholecalciferol);
4. Lumisterol can then be made from Vitamin D3 also
73
Why is the production of Lumisterol and Tachysterol important?
- Products that protect from OVERPRODUCTION of vitamin D3;
- Both compounds and previtamin D3 have LOW affinity for the vitamin D binding protein (DBP);
- Basically ONLY vitamin D can diffuse from the skin into the blood;
- Other compounds are lost from the body with sloughing off of the skin cells with normal turnover
74
What is Lumisterol?
- Crystalline compound stereoisomeric with ergosterol;
- Formed by UV as an intermediate product in the production of tachysterol and vitamin D2;
* Regulator products to prevent too much D3 from being made;
- Lost as skill cells
75
Why is Vitamin D2 less common than D3?
- Vitamin D2 is LESS frequently consumed now than years ago (used to be SUPPS);
- Appears to be less efficiently converted to CALCITRIOL than vitamin D3
76
What are the food sources of Vit. D?
- Not found in many foods;
- Animal origin;
- Fortified milk and margarine;
- Fatty fish and oils, liver
77
How is Vit. D absorbed into the intestine?
- ~ 50% of Dietary vitamin D is absorbed by passive diffusion from MICELLES along with lipids;
- Absorption is most RAPID in the duodenum and jejunum, but MOST is absorbed in the distal (end) small intestine;
78
What happens once Vit. D enters the intestine?
- Vitamin D is then incorporated into CHYLOMICRONS;
- Follows lipoprotein metabolism except that there is some transfer to DBP (Vitamin D binding protein) in PLASMA → taken up by muscle, adipose and liver;
- - Vitamin D from SKIN slowly diffuses into BLOOD and binds to DBP taken up mainly by liver;
* *different source affects distribution
79
How is Vit. D metabolized?
Primarily in the LIVER, the 25-hydroxylase (NADPH-dependent) functions in the mitochondria to form 25-hydroxyvitamin D = CALCIDIOL (two) or 25-hydroxycholecalciferol;
-Enzyme = (CYP2R1) is most efficient when vitamin D is LOW, but levels of 25-hydroxyvitamin D increase with increased vitamin D
80
What happens to the formed 25-hydroxyvitamin D (25OHD)?
- 25OHD released into the blood bound to DBP;
- Blood is the major storage site of 25OHD (muscle to some extent) ;
- Half-life of 25OHD in BLOOD is 15 days to 3 weeks (contrast with much shorter for calcitriol of 4 to 6 hours);
- Major storage site of the parent vitamin D is ADIPOSE tissue
81
What happens to the blood levels of 25OHD during the winter?
In winter, blood levels of 25OHD decrease in most people because of less skin synthesis
82
How is formed 25OHD then taken up by the kidney?
-Uptake of 25OHD by the kidney is by the 25OHD-DBP binding to a cubulin-megalin membrane receptor system on kidneys’ proximal tubule cell plasma membrane and is endocytosed;
-RENAL cells convert to 1,25 dihydroxyvitamin D (1,25OH2D) = CALCITRIOL;
-
83
What enzyme converts 25OHD to 1,25OH2D in the kidney?
The 1-hydroxylase is CYP27B1
84
How is the 1-hydroxylase (CYP27B1) highly regulated?
- Plasma calcium DROPS, parathyroid hormone (PTH) INCREASES 1-hydroxylase activity;
- Low phosphorus in blood either because of diet or increased PTH results in INCREASED CALCITRIOL;
- Fibroblast-like growth factor 23 (FGF23) slows down hydroxyls to stop making Calcitriol;
- High levels of 1,25OH2D inhibits the 1-hydroxylase
85
How does Fibroblast-like growth factor 23 (FGF23) slow down the 1-hydroxylase?
- It is secreted by osteocytes and osteoblasts;
| - When this factor is increased production of the 1-hydroxylase is reduced, which means also less calcitriol
86
How do high levels of 1,25OH2D inhibit the 1-hydroxylase?
- High levels of 1,25OH2D inhibits the 1-hydroxylase;
- Another hydroxylase is STIMULATED, this is 24-hydroxylase found in the kidney and some other tissues producing 1,24,25-trihydroxyvitamin D or 24,25-dihydroxyvitamin D;
* *1,25OH2D is the product of the hydroxylase acting on CALCIDIOL = Feedback regulation
87
What is the ACTIVE form of Vitamin D?
1,25OH2D is the physiologically active form of the vitamin;
| -Although 24,25OH2D has been debated over the years about its function
88
How are the active forms of Vit. D released from the kidney for use in the body?
- 1,25OH2D and 24,25OH2D are released form the kidney and are bound to DBP in blood;
- 1,25OH2D is bound with LESS affinityto DBP than 25OHD;
- Allows 1,25OH2D to be more readily taken up by target tissues than 25OHD → LESS binding to the DBP carrier protein means that it can easily be given to the tissue that need it!;
- In target TISSUES 1,25OH2D binds to vitamin D receptor (VDR)
89
What is the half-life of Calcitriol?
- Half-life of CALCITRIOL is 2 to 6 hours (4 to 6 stated earlier);
- Concentration in blood is 20 to 40 pg/ml
90
What are the target tissues and main function of Vit. D?
- Target tissues for 1,25OH2D = intestine, bone, and kidney;
| - Function of vitamin D to promote absorption of calcium and phosphorus for healthy mineralization of bone
91
What is the DRI for Vit. D based on?
BONE HEALTH was considered the measure for determining the DRI emerging hypotheses
92
What are the two mechanisms for action of 1,25OH2D?
- Genomic = gene regulation
| - Nongenomic = signal transduction for calcium regulation
93
What are the NON-Genomic actions of 1,25OH2D?
- Involve binding to receptors in the membrane and promoting signal transduction for...
1. Increased intestinal cell uptake of CALCIUM from the lumen of intestine;
2. Uptake into other tissues;
3. Release of calcium from stores in cells;
- One receptors = membrane-associated rapid response steroid-binding protein (MARRS)
94
What is the GENOMIC action for 1,25OH2D?
-Controlling genes/DNA;
-Calcitriol’s function in retinoic acid → receptor as VDR protein functions as a transcription factor
95
What is the Mechanism of the genomic action?
1. Binding to nuclear VDR in tissues is how 1,25OH2D functions as a STEROID HORMONE ;
2. Nuclear VDR functions as a transcription factor interacting with a variety of other factors to either INCREASE OR DECREASE transcription of genes
96
How do Vit-D related hormones function when blood calcium levels are HIGH?
1. Elevated blood calcium;
2. Thyroid glad releases CALCITONIN;
3. Reduces calcium relase from bones;
4. Reduces calcium retention in the kidneys
97
How do Vit-D related hormones function when blood calcium levels are LOW?
1. Low blood calcium;
2. Parathyroid gland releases PTH;
3. Stimulates calcium release from bones;
4. Increases calcium uptake in intestines (increases 1,25OH2 synthesis by kidneys);
5. Increases calcium retention in the kidneys
98
What is the mechanism for Bone MOBILIZATION (breakdown)?
1. LOW IONIZED calcium increases PTH;
2. PTH and calcitriol induce the receptor activator of NFкB ligand RANKL;
3. RANKL interacts w/ RANK (receptor pro) of immature monocytic osteoclast precursors (pre-osteoclasts);
4. Stimulates the PROLIFERATION and MATURATION of osteoclasts;
5. Osteoclasts release HCl alkaline phosphatase, collagenase, and other hydrolytic enzymes and substances to break down bone
99
What is the mechanism for Bone MINERALIZATION (new bone)?
1. HIGH IONIZED calcium in plasma (has been mobilized and released from the bone);
2. CALCITONIN is produced by endocrine cells of the thyroid gland;
3. High plasma calcium and phosphorus are believed to PROMOTE deposition of these minerals;
- Calcitriol ELEVATES the plasma levels of calcium and phosphorus;
- Calcitonin STOPS bone resorption (breakdown)
100
What transporters facilitate Calcium Absorbed into the Intestine?
- Calcium channel Transporter TRPV6 → Calcium through membrane;
- Calbindin D9k transports over 90% of calcium that enters cells through the cell (inside);
- Calcitriol enhances gene expression of claudins 2 and 12 that are essential for paracellular calcium absorption in the intestine;
- KO mice for calbindin D9k and TRPV6seem to be fine as far as calcium absorption with paracellular being stepped up
101
What type of process is Calcium Absorption?
- TRANCELLULAR w/ 3 components stimulated by 1,25OH2D (active form of Vitamin D):
1. Uptake of calcium from the intestinal lumen to the microvillus border;
2. Translocation of calcium across the cell to the basolateral membrane.
3. Active extrusion of calcium into circulation
102
What is involved in the uptake of calcium into the microvilli from the lumen?
- Calcium channel which is an integral membrane transporter (CaT1);
- Then controlled movement of calcium down a steep electrochemical gradient;
- Calmodulin (calcium binding protein) binds several target protein such as myosin –I, a membrane ATPase that can link F-actin filaments to the microvillar membrane that may affect the permeability of the membrane
103
What is involved in the translocation of calcium across the cel to the basolateral membrane?
Calbindin functions as a calcium transporter and a buffer for cytosolic calcium
104
What is involved in the active extrusion of calcium into circulation?
- Calcium ATPases residing in the basolateral membrane;
| - Done against a substantial thermodynamic gradient
105
What affects Phosphorous absorption?
- Calcitriol affects phosphorus homeostasis by acting on the SAME target organs as it does for calcium;
- Calcitriol INCREASES the activity of brush border alkaline phosphatase, which hydrolyzes phosphate ester bonds and enhancing phosphorus absorption;
- Calcitriol increases the number of sodium-dependent carriers for increasing phosphorus absorption at the jejunum and ileum brush border;
- In BONE, calcitriol promotes bone RESORPTION (breakdown) and INCREAES calcium and phosphorus to the blood;
- In the KIDNEY PTH promotes increased loss of phosphorus in URINE, but calcitriol promotes increased retention in BLOOD
106
What plasma level of 25OHD indicated MAX calcium absorption?
- Book: Plasma levels should be 75 to 80 nmol/L (30 to 32 ng/ml);
- Conversion is 1 ng/mL = 2.496 nmol/L;
- DRI: 50 nmol/L = 20 ng/ml (97.5% of population,);
- Range = 30 nmol/L (12 ng/ml) and 50 nmol/L;
- Some have used a level (20 to 30 ng/ml) that is correlated with no increase in PTH. → Elevated PTH is considered BAD for bone health by some
107
What are the Vit. D. deficiencies?
- Children = Rickets (first known in 1600s when reduced exposure to sunlight prevented production of Vit. D);
- Adults = osteomalacia from bone demineralization
108
Why are bones not developed or broken down during Vit. D deficiency?
- Low calcium absorption (due to lack of Vit. D) leads to loss of bone to preserve PLASMA calcium levels as long as possible;
- Body regulates blood calcium levels as the PRIORITY!!;
- Will remove bone to supply the blood!!;
- PTH is elevated and increases bone resorption;
- More PTH = Bone Breakdown!! When blood levels are LOW
109
What are the indicators of bone RESORPTION?
- Increased urinary excretion of bone collagen by-products such as hydroxyproline, N-telopeptide, pyridinoline, and deoxypyrodinoline, ;
- But sometimes the bone matrix is preserved and only demineralization occurs → resorption of the bone MATRIX protein would occur usually in osteoporosis
110
Who is at higher risk for Vit D. deficiency?
- Elderly = reduced skin synthesis w/ aging;
- People avoiding the sun for fear of skin cancer or use sunscreens that block the UV wavelengths that produce vitamin D in skin;
- Only need about 15 mins/day on face and arms
111
What supps are available for Vit. D?
- Supplements of Calcitriol;
- For people with kidney disease that are unable to produce this physiologically active metabolit;
- 1,25OH2D → formed in the kidneys by 1-hydroxylase in the renal cells
112
Why were the recommendation for Vit. D hard to determine?
- Very difficult to assign quantity of vitamin to synthesis in skin with sunlight exposure;
- Used studies in Northern latitudes in winter to minimize effects of skin synthesis and deal with requirements with minimal sunlight exposure effects
113
How do Vit. D and Calcium status affect one another?
- Vitamin D and calcium are coupled;
- Calcium turns out to be the “driver” nutrient relative to bone health;
- High dietary calcium can compensate for low vitamin D better than high vitamin D can compensate for low calcium
114
What was used for a marker of vitamin D status?
-PLASMA 25OHD levels linked to bone health indicators, → Level of dietary vitamin D to give a certain value or range of values for plasma 25OHD;
-Divided by Ages =
1. 19-50 bone maintenance;
2. >70 reduction in fracture risk;
(51-70 in between or combo of both but no higher requirement determined compared to 19 to 50)
115
Where is the body pool of Vit. D found?
The BLOOD is the LARGEST single pool of 25OHD and is the major storage site of this metabolite
116
What is the RDA for Vit. D?
- 19-70 yrs = 15 mcg (600 IU)/day;
- > 70 yrs = 20mcg (800 IU)/day;
- UL = 100 mcg/day (4000 IU/day)
117
What does the AAp recommend for breast fed infants?
Exclusively breast fed infants be given 10 μg (400 IU) of vitamin D per day
118
What can occur from OVER-SUPP of Vit. D?
- High blood and urine calcium concentrations, depositing of calcium in blood vessels and kidneys, cardiovascular damage and possibly death;
- Toxicity will NOT occur from NON-fortified foods or from exposure to sunlight → Natural sources will NOT cause a toxicity!
119
What can cause "acute hypervitaminosis D toxicity"?
Doses between 10,000 IU and 40,000 IU
120
What is the UL based upon for Vit. D?
- Based on PREVENTION of HYPERCALCEMIA and keeping plasma levels of 25OHD below 150 nmol/L (60 ng/ml);
- Doctors are/were routinely prescribing 50,000 IU (1,250 μg) → BAD
121
What is Calcinosis?
-Hypercalcinemia and calcifation of soft tissues due to too much Vit. D supp
122
What is the mechanism for Vit. D. toxicity?
- Large doses increase plasma 25OHD b/c liver 25-hydroxylase is NOT tightly regulated (unlike in the kidney) and there may be several non-specific hydroxylases that can hydroxylate Vit. D when present at high doses ;
- High levels of plasma 25OHD can act like 1,25OH2D at low doses and increase calcium absorption
123
How is Vit. D excreted?
- Most are secreted in the BILE and excreted in the feces, some are excreted in urine in small amounts;
- About 30% of excretion is in the form of vitamin D
124
What are the other roles of Vit. D besides bone health?
- Immune function → deficiency leads to some immune-related diseases;
- Blood pressure regulation → lowers bad cholesterol and raises good cholesterol;
- Pancreatic beta cell protection and increases insulin secretion
* BUT bone health determines DRI!
125
What are the Vit. D interactions?
- Calcium and Phosphorus;
| - Vitamin K
126
How was Vit. K named?
-From the Danish word “koagulation” = coagulation (also called hemostasis)
127
Who discovered Vit. K?
- 1929 -- H. Dam observed chicks fed a low fat and cholesterol free diet bled excessively and had very long clotting time → Determined that the substance was fat-soluble and was found in extracts of plant tissues and liver;
- 1939 -- K1 and K2 had been isolated from alfalfa and putrefied fish meal;
* *Dam and Doisy won the Nobel prize in 1941
128
What was the first Anticoagulant?
- 1941 -- the first ANTICOAGULANT was discovered when Campbell and Link;
- Identified in spoiled sweet clover reported to cause hemorrhagic disease in cattle in the US and Western Canada in the 1920s;
- Compound discovered was DICOUMAROL, a derivative of courmarin;
* *Access to vitamin K antagonists helped eventually to specify the role of vitamin K in blood coagulation
129
What are the derivatives of the first anticoagulant?
- Many derivatives of coumarin have been synthesized and used for anticoagulant therapy;
- One of these WARFARIN (3-(α-acetonyl-benzyl)-4hydroxycoumarin has been used successfully since 1941
130
Vit. K was thought to only be required for...
* Blood coagulation:
- Normal function of prothrombin (Factor II) as this DECREASED with LOW vitamin K;
- Later determined that factors VII, IX, and X were also decreased in vit. K deficiency;
- Also proteins C, S, Z, and M involved in blood clotting require vit. K
131
What is Prothrombin?
- Clotting factor produced in the LIVER in the presence of Vit. K;
- Converted to thrombin for clotting
132
What other role was discovered for vit. K?
- Early 1970s it was discovered that there was an amino acid in vitamin K dependent-proteins = Gama-carboxyglutamic acid (Gla);
- Involved in posttranslational modification;
- Led to the discovery of other vit. K-dependent proteins not involved in blood coagulation and an understanding of the vit. K at the molecular level;
* *To this day synthesis of Gla is the only known mechanism of action of vitamin K
133
What are the structures of Vit. K?
1. Manadione (syhtetic) – used in poultry feed
2. Phylloquinone (plat) → Key is 2-methyl 1,4-napthaquinone
3. Menaquinon-7 (MK-7) (bacterial); Abbreviated MK
134
What are the food sources of Vit. K?
- Leafy green vegetables and legumes are MAJOR sources;
| * *Light and heat can destroy the vitamin
135
What is Phylloquinone?
- Phylloquinone is the plant source → Vitamin K1;
- Synthesized by plants;
- Found in highest amounts in green leafy vegetables because it is directly involved in photosynthesis;
- "plant form" of vit. K;
- Active in animals and may perform the classic functions including production of blood-clotting proteins;
- Animals may also convert it to vitamin K2.
136
What is Vitamin K2?
- Animal storage form of Vitamin K with several subtypes;
- Vitamin K2 homologues are called MENAQUINONES, and are characterized by the number of isoprenoid residues in their side chains
137
How do humans absorb Vit. K?
- From the DISTAL small intestine and the large intestine → LI is not enough to meet the requirements of the vitamin;
- Supps are rarely needed, but phylloquinone supps are available and there are water-soluble forms (assume emulsified so really miscible and not soluble)
138
How are the different forms of Vit. K absorbed?
- Phylloquinone (plant) is absorbed in the JEJUNUM as part of MICELLES;
- Menaquinones (animal) from BACTERIA are absorbed by passive diffusion in ILEUM and COLON;
- Ability to absorb and use varies from person to person and has been difficult to quantitate over the years
139
What happens to Vit. K in the INTESTINAL cells?
- Within intestinal cell vit. K incorporated into CHYLOMICRONS;
- Liver takes up chylomicron remnants and puts vit. K into VLDL;
- Absorbed MENADIONES are alkylated (addition of isoprenoid units) in the liver
140
Where is Vit. K stored?
- Storage is highest in the LIVER;
- Body pool size is 50 to 100 micrograms, smaller pool than vitamin B12;
- Turnover of pool is fairly rapid of 1.5 days
141
What are the function of Vit. K?
-Production of Gla is necessary for binding calcium and interacting with other compounds → ONLY KNOWN MECHANISM;
-Allows for various functions:
oBlood clotting
oBone mineralization,;
oAlso involved in apoptosis, arterial calcification, signal transduction and control of growth;
-All glutamic acid residues on the proteins must be γ-carboxylated for protein to function? No
142
What are the steps in blood clotting?
1. Initial: Factor XII absorbs onto a substance that has been exposed b/c of injury (such as collagen) and activates;
2. Factor XIa, activated by XIIa, activates IX (vit. K-dep)
3. Factor IXa activates factor X (vit. K-dep);
{Move from intrinsic to extrinsic}
4. Factor Xa converts factor II, PROTHROMBIN (vit. K-dep) to Thrombin;
5. Thrombin alters fibrinogen to produce a fibrin clot;
6. Factor XIIIa (fibrin stablizing factor) makes insoluble fibrin for clot;
7. Extrinsic pathway: factor VII (vit. K-dep) is activated due to Thromboplastin released by injury;
8. Factor VIIa works with factor IXa to activate factor X
143
What other proteins does VIt. K affect in blood clotting?
- Vitamin K also acts on proteins S (also found in bone), C, Z that INHIBIT the coagulation process and protein M (function unknown);
- Vitamin K turns ON and SHUTS DOWN blood clotting
144
What is the Contact Activation Pathway?
INTRINSIC phase of clotting;
-Contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and FXII (Hageman factor)
145
What are the steps of the Contact Activation Pathway?
1. Prekallikrein is converted to kallikrein and FXII becomes FXIIa.;
2. FXIIa converts FXI into FXIa;
3. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa
146
How important is Contact Activation to blood clotting?
The MINOR role that the contact activation pathway has in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder. Instead, contact activation system seems to be more involved in inflammation
147
What is the function of Vit. K in the formation of Gamma-caboxy glutamic acid (Gla) in peptides?
- Enzyme Gamma-Glutamyl Carboxylase is Vit. K-dependent;
- It catalyzes the addition CO2 (carboxylation) of a Glutamic Acid residue to Gamma-Carboxy glutamic acid (Gla) in a peptide
148
Why is the synthsis of Gla important?
- Gla-proteins can bind Ca2+;
- Ca2+which then interacts with other cell components like phospholipids to affect blood clotting and bone mineralization and other processes;
* *Several gamma-carboxylated proteins in several tissues and functions not clearly defined, but indicate many functions of vit K-dependent proteins
149
What is the Vit. K cycle?
1. Vit. K is usually in the blood as Vit. K. Quinone;
- 2. Ditihiol or NADPH reduce Vit. K to create dihydroxyquinone (KH2);
3. KH2 is needed for gamma-glutamyl carboxylase to create Gla -- Gla can now bind Ca2+
5. During the synthesis of Gla, KH2 is converted to Vit. K 2,3-epoxide, which needs to be converted back to KH2;
6. Dithiol with epoxide reductase reduces Vit K 2,3-epoxide back to Quinone;
7. Cycle continues
150
What are the 2 Vit. K-dependent proteins?
- Identified in bone, cartilage, and dentine;
1. Osteocalcin (also called bone Gla protein and abbreviated BGP)
2. matrix Gla protein (MGP)
* *Synthesis of both proteins appears to be stimulated by 1,25OH2D and retinoic acid
151
What is Osteoclacin?
- 15 to 20% of NONCOLLAGEN protein in bone;
- Secreted by osteoblasts during BONE MATRIX FORMATION around the onset of hydroxyapatite deposition;
- Function remains unknown, but appears to be involvement in bone REMODLEING → Blood levels are used to indicate bone formation
152
What is MGP (matrix Gla protein)?
- May promote CALFICATION of bone, but role is still uncertain;
- Lack of MGP in KO mice results in arterial calcification;
- Under-carboxylation of vascular MGP increases calcification of arterial lesions;
- MGP may function to prevent calcium precipitation;
- mRNA for MGP found in many tissues
153
What other nutrients does Vit. K interact with?
- Vitamins A and E can NEGATIVELY affect vit. K;
| - Possible relationship on calcium metabolism among vitamins A, K, and D:
154
How does Vit. A negatively affect Vit. K?
EXCESS vitamin A interferes with absorption of vitamin K
155
How dies Vit. E negatively affect Vit. K?
- Vitamin E excess also interferes with absorption of vit. K, but has effects on vit. K metabolism and function;
- Vitamin E or the quinone (α-tocopheryl quinone) is thought to block regeneration of the reduced form of vitamin K or to affect prothrombin formation by a different mechanism (opposing clotting)
156
What is the possible relationship b/w vitamins A, K, and D on calcium metabolism?
- Vit. D regulates calcium metabolism in kidney and bone (more retention and absorption);
- Vit. K-dependent proteins BIND CALCIUM;
- There are Vit. K-dependent proteins in bone and kidney;
- Retinoic acid and 1,25OH2D have been shown to REGULATE, at least in part, the production of BGP, MGP, and KGP
157
How is Phylloquinone (plant source) metabolized/excreted?
- Phylloquinone (plant source) is almost completely metabolized to a variety of metabolites;
- The phytyl side chain is OXIDIZED;
- Then conjugation with glucuronides and EXCRETION in the BILE;
- Some excretion in the urine
158
How are Menaquinones (animal source) metabolized/excreted?
- Menaquinones (animal source) are metabolized to MENADIOL with conjugation with phosphate, sulfate, and glucuronide;
- All three are excreted in BILE, with some in urine
159
What is the AI for Vit. K?
AI = OBSERVED!
- Males - 120 micrograms
- Females = 90 micrograms
160
What is the AI based on?
- Based on the median intakes of Americans from the NHANES III in apparently healthy populations
- No signs of deficiency occur at >80 micrograms/day
- No abnormal protein induced by vit. K absence or antagonism in reference to prothrombin (factor II), and this acronym is (PIVKA-II), concentrations
161
What is caused by insufficient Vit. K?
- Insufficiency leads to secretion of under gamma-carboxylated forms of prothrombin;
- DEFICIENT enough, prothrombin time is associated with adverse clinical effects
162
How do the functions of Vit. K relate in recommended intakes?
Recommendations that lead to normal BLOOD COAGULATION function may not be enough vitamin K to maximize gamma-carboxylation of proteins for bone health
163
Who is at most risk for Vit. K deficiency?
- NEWBORNS are most at risk because inadequate amounts cross the placenta and their intestinal tract is not yet populated by vitamin K-synthesizing bacteria;
- Deficiency is rare in healthy adults;
- Antibiotics could be a problem resulting in vitamin K deficiency
164
What are the Vit. K recommendations for Newborns?
All newborns receive an intramuscular injection of 0.5 to 1 mg phylloquinone shortly after birth to prevent hemorrhagic disease of the newborn (HDNB)
165
What can result form Vit. K deficiency?
- Vitamin K deficiency may lead to diminished bone mineral density → arterial calcification;
- Arterial calcification = Loss of calcium from the bone and deposits develop in the arteries and soft tissues
166
What is the UL for Vit. K?
-No UL has been established as ingestion of large amounts of either phylloquinone and menaquinones has ever caused toxicity
167
What toxicity can occur form synthetic Vit. K or MENADIONE?
- High amounts of menadione, the SYNTHETIC product, can cause liver damage;
- Some toxic effects in infants supplemented with menadione =
1. Hemolytic anemia (damage to membranes [oxidation of fatty acids in phospholipids] because glutathione becomes oxidized with binding to menadione)
2. Hyperbilirubinemia,
3. Severe jaundice
168
How is Vit. K status assessed?
- Not any really sensitive assessment measures;
- Plasma phylloquinones reflect RECENT (24 hr) intakes;
- Concentrations of plasma phylloquinone for healthy adults less than 0.5 micrograms/L are considered deficient
169
What tests are ineffective for Vit. K assessment>
1. Prothrombin times = considered relatively INSENSITIVE because active prothrombin must decline 50% or more to have effects on prothrombin times;
2. Measure gamma-carboxylation of proteins, but variable among different proteins
170
What are the forms of Vit. E?
8 compounds or vitamers divided into tocopherols and tocotrienols
-4 tocopherols
-4 tocotrienols
•Designated α, β, γ, and δ
171
What do all Vit. E structures have?
- Both have a PHENOLIC group on a chromanol/chromane ring (head of the molecule) and a phytyl (isoprenoid) side chain or tail;
- Vit. E structures ALL have = Phenolic Group on a Chromane Ring Head + Phytyl (Isoprenoid) Side Chain
172
Where does the word "Tocopherol" come from?
Two Greek terms:
- “tokos” which means “childbirth”
- “phero” which means “to bear or bring forth”
173
Who discovered Vit. E?
- 1920s -- Evans and Bishop discovered that rats could NOT REPRODUCE when fed a diet of rancid lard (bad fat) → wheat germ oil (active fat) provided the factor that allowed the rats to reproduce;
- Emerson later purified from wheat germ oil calling it vitamin E following the discovery of vitamin D
174
How has the RDA for Vit. E changed?
- First RDA in 1940s;
- 1989 = RDA for adults was 10 α-tocopherol equivalents (TE)/day = 15 IU or 10 mg of the natural RRR-α-tocopherol;
- 2000 = RDA set as 15 mg of α-tocopherol with the R configuration in the 2 position of the ring;
* *NO MORE equivalents of the other chiral carbons at the 4 and 6 carbons of the phytyl side chain
175
Why was the RDA changed?
A key discovery in the 1990s changed RDA for ONLY α-tocopherol;
- Discovery was α-tocopherol transport protein (α-TTP):
- α-TTP recognizes α-tocopherol, and poorly recognizes the other 7 naturally occurring forms of vit. E;
- α-TTP recognizes the 2R position in the α-tocopherol and binding by α-TTP is necessary for re-secretion of vitamin E into VLDL
176
What is the active form of Vit. E?
ONLY α-tocopherol has biological activity!;
-Other tocopherols are short-lived in blood as chylomicrons from GI tract until remnants are taken up by liver → EXCRETED in bile
177
How many naturally occurring forms of Vit. E are there?
- 8 NATURALLY occurring forms (all RRR) of Vitamin E;
178
What are the active and inactive configurations of Vit. E (Alpha-Tocopherol)?
- Active: RRR, RSR, RSS, RRS;
- •**Alpha-tocopherol = BIOLOGICALLY ACTIVE FORM
- Inactive: SRR, SRS, SSR, SSS;
- Half of the synthetic isomers are considered “active”;
- However, all 8 of the synthetic forms are considered for the UL
179
How is Vit. E Transported?
1. Vit. E is Ingested and then acted on by bile and pancreatic secretions in the intestine;
2. Digested Vit. E is then incorporated into Chylomicrons in the Lymph circulation;
3. LPL – lipoprotein lipase acts on the chylomicrons to release fatty acids and Vit. E to tissues as needed;
4. As LPL breaks off pieces 2 routes can occur
1. Chylomicron remnants, including some Vit. E that was in chylomicrons that was not dropped off at tissues by LPL is taken up by the Liver
2. Or Vitamin E continues to circulate in HDL lipoproteins
180
What happens to the Vit. E in chylomicron remnants that is taken up by the liver?
* *RRR-alpha-tocopherol is preferentially RESECRETED by the liver and distributed to circulatin lipoproteins =
- -First made into VLDLS in the liver and sent out;
- Then Lipolysis takes places (breaking down of lipoproteins) ;
- RRR-alpha tocopherols either remains circulating in LDLs and HDLs (which are interchangeable) or more remnants return to the liver to repeat the process
181
What forms of SYNTHETIC alpha-tocopherols are re-secreted?
Of the 8 synthetic α- tocopherols of the all racemic mixture RRR-,RSR-, RRS-, and RSS-α-tocopherol are re-secreted into VLDL and are considered active
182
What is the half-life for alpha-tocopherol?
- Half-life for RRR α-tocopherol is 48 hrs;
| - Hald-life for SRR α-tocopherol it is 13 to 15 hrs
183
What are the food sources of Vit. E?
- PLANT OILS are usually GOOD sources -- Corn and soybean oils contain less ALPHA-tocopherol than GAMMA-tocopherol (Victor Herbert story on gamma tocopherol);
- ANIMAL fat sources are INFERIOR compared to plant oils, but the vitamin would be concentrated in the ADIPOSE of animals
184
What can damage Vit. E in foods?
-Tocopherols can be OXIDIZED by lengthy exposure to air, and to light and heat, → roasting of nuts reduces their content of vitamin E
185
What are the forms of Vit. E supps and fortified foods?
- All-rac α-tocopheryl acetate;
- All-rac α-tocopheryl succinate
* *So an equal weight of the SYNTHETIC all-racemic α-tocopherol is HALF as “active” as the natural RRR α-tocopherol
186
How are Tocopherols found in foods?
Tocopherols are found in FREE form in foods
187
What are the ESTERIFIED forms of Vit. E?
- Tocotrineols are esterified;
- Supps are also esterified;
- The two esters have to be HYDROLYZED (digested) by pancreatic esterase and duodenal mucosal esterase (carboxyl esterase) BEFORE absorption
188
How is Vit. E absorbed?
- Vit. E s absorbed mainly in the JEJUNUM by non-saturable passive (requiring no carrier) diffusion;
- Absorbed along with fat and emulsifiers in micelles;
- Studies indicate 20% to 80% absorption → Similar for all types of tocopherols
* *Higher intake reduces its absorption efficiency
189
What happens to tocopherols once in the mucosal cells?
- In the MUCOSAL cell, tocopherols are put into chylomicrons;
- Transfer of tocopherols to LDL and HDL
190
How is Vit. E taken up by the cells?
Vitamin E taken up by cells by usual mechanisms for lipoproteins; there may be a phospholipid transfer protein to transfer vitamin E from lipoproteins to membranes
191
What gene defect can cause Vit. E deficiency?
Gene defects for α-TTP result in deficiencies of vitamin E
192
How is Vit. E found within TISSUE cells?
Vitamin E is located in cells primarily in MEMBRANES
- -Chromanol ring toward either SURFACE;
- -Phytyl side chain in the MIDDLE of the membrane
193
How is Vit. E moved around within the tissue cells?
- A couple of proteins appear to move Vit. E around the cell in the cytoplasm and nucleus
1. Tocopherol binding proteins;
2. Adenosine triphosphate-binding cassette (ABC) A1
194
Where is Vit. E stored within the body?
- Largest stores of vitamin E (over 90%) is as the UN-ESTERIFIED form in lipid droplets in the ADIPOSE;
- As intake goes up storage in adipose tissue INCREASES, but amounts in other tissues stay fairly constant unless the person was deficient
195
How are the stores of Vit. E from adipose released?
- Release from stores is relatively SLOW even when vitamin intake is low;
- Liver, plasma and skeletal muscle seem to be the source when intake is low to replenish BLOOD
196
What is the main function of Vit. E?
ANTIOXIDANT;
- Maintain integrity of cell membranes by preventing oxidation or peroxidation of unsaturated fatty acids contained in PHOSPHOLIPIDS in membranes;
- Phospholipids in mitochondrial and endoplasmic reticulum membranes contain MORE unsaturated fatty acids than in the plasma membrane
197
How does Vit. E act as an Antioxidant?
- Performs free radical termination (stops reactions involving free radicals), and quenches singlet oxygen (recall is an excited state of molecular oxygen);
- The PHENOLIC RING of vit. E allows it to give up a hydrogen ion b/c the phenolic ring can stabilize an oxygen with an unpaired electron
198
What forms of Vit. E is the BEST antioxidant?
- α-tocopherol is MORE effective than the other tocopherols;
- Except that reactive NITROGEN species, Nox, are handled better by γ-tocopherol (Victor Herbert was upset when the committee made the RDA α-tocopherol only)
199
What are the 3 phases of Free Radical Reactions?
1. Initiation
2. Propagation or ongoing generation
3. Termination with an antioxidant
200
What happen in Free Radical INITIATION?
-Hydroxy radical attacks carbon of the Unsaturated fatty acid = makes H20 + Lipid C-centered Radical (L)
201
What happens in Free Radical ONGOING Generation?
- O2 reacts with the Lipid C-centered radical;
- Produces Lipid Peroxyl Radical (LOO);
- Continuing chain reaction produces Lipid Hydroperoxide (LOOH)
202
What happens in Free Radical TERMINATION?
-Vitamin E in membranes can react with these radicals for termination to protect the membranes from oxidation
203
What is the mechanism for termination?
-- LOO• + EH → LOOH + E•
OR
-- L• + EH → LH + E•
**E• represents OXIDIZED vit. E also called α-tocopherol radical or a tocopheroxyl radical;
-α-tocopherol is REGENERATED → prevents formation of tocophreylquinone and loss of antioxidant function
204
How does "Vit. C" regenerate active alpha-tocopherol?
* Vit. C acts to reduce the oxidized alpha-tocopherol radical to regenerate active alpha-tocopherols;
1. Ascorbic acid reacts with the alpha-tocopherol radical;
- Alpha-tocopherol is regenerated;
- Ascorbic acid is oxidized to Dehydroascorbic acid
2. 2GSH (with NADP) is used to reduced the dehydro back to ascorbic acid
205
What other factors are involved in antioxidant protection of the body besides Vit. E?
- Vitamin E, vitamin C, carotenoids, and enzymes that require a variety of mineral cofactors such as zinc, selenium, iron, copper, and molybdenum;
- Vitamin E also quenches singlet oxygen similar to carotenoids
206
What does Vit. E INHIBIT?
- Inhibits protein kinase C;
- Inhibits platelets;
- Inhibits monocytes;
- Inhibits membrane-derived diacyglycerol
207
How does Vit. E inhibit protein kinase activity?
* Involved in cell proliferation/differentiation in smooth muscles;
- Inhibition of membrane-derived diacyglycerol effects protein kinase C activity because diacylglycerol facilitates translocation of the protein
208
How does Vit. E affect Endothelial cells?
•-Vitamin E in ENDOTHELIAL cells DOWN-regulates the expression of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1);
-Leads to DECREASED adhesion of blood cell components to the endothelium (OPPOSES clotting)
209
How does Vit. E affect the Arachidonic Acid Cascade?
- UP- regulates the rate limiting enzymes of the cascade;
- UP-regulates expression of cytosolic phospholipase A2 and cyclooxygenase-1;
- Explains why vit. E ENHANCES the release of prostacyclin (opposes clotting) → a potent vasodilator and inhibitor of platelet aggregation
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Does vitamin E prevent heart disease or heart attacks?
Initial epidemiology studies looked good, later studies indicated no benefit and reason why supplements not chosen for meeting RDA of vitamin E
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Does Vit. E and other antioxidants help prevent cataracts?
Studies that showed reduced cataracts with antioxidants used a MULTIVITAMIN preparation
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What are other minor roles of Vit E?
- Possible improved glucose transporter function probably by maintaining membrane stability for T2DM;
- Possibly anti-inflammatory effects of vit. E sups.;
- Gene transcription including production of miRNA;
- Tocotrienols (esterified form) suppress cholesterol synthesis, neuroprotective, anti-cancer
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What are the POSITIVE nutrient interactions with Vit. E?
1. Selenium-dependent glutathione peroxidase (lipid peroxides to lipid alcohols);
2. Vitamin C;
3. Sulfur amino acids;
4. Cysteine and methionine for synthesis of glutathione;
5. Foods high in PUFA are usually high in vitamin E, but increased PUFA increases need for vitamin E
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What are the NEGATIVE nutrient interactions with Vit. E?
- Inhibits absorption of carotenoids and conversion to retinol;
- May impair vit. K absorption (opposes clotting);
- May block the vit. K cycle blocking regeneration of REDUCED form of vit. K (opposes clotting)
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What are the URINARY metabolites of Vit. E?
- Tocopheronic acid conjugated with glucuronic acid;
- α-tocopheronolactone;
- α-CEHC (carboxyethyl hydroxychromans);
- γ-CEHC
- {both CEHCs conjugated with glucuronic acid}
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What is the RDA for Vit. E?
Men AND women 19+ years: 15 mg (34.9 µmoles)/day α-tocopherol
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What is the RDA for Vit. E based on?
- Original meeting = based on “induced vitamin E deficiency in humans and the correlation between hydrogen peroxide-induced erythrocyte lysis and plasma α-tocopherol concentrations.” ;
- But did consider that “ a large and growing body of experimental evidence suggests high intakes of vitamin E may lower the risk of some chronic diseases, especially heart disease.”
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What are the Symptoms of Vit. E deficiency?
Deficiency is RARE;
- Skeletal muscle pain (myopathy) and weakness
- Ceroid pigment accumulation
- Hemolytic anemia (increased RBC fragility)
- Degenerative neurological problems that includes =
- --Peripheral neuropathy
- --Cerebellar ataxia
- --Loss of vibratory sense
- --Loss of coordination of limbs
- --Increased ethane and pentane production (markers of increased oxidation)
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How is Vit. E Status assessed?
- 12 micromoles/L (516 micrograms/dL) = NORMAL in vitro hydrogen peroxide-induced hemolysis ;
- <5 micrograms/ml considered DEFICIENT
* *Based on correlation between hydrogen peroxide-induced erythrocyte lysis and plasma α-tocopherol concentrations
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What is the UL for Vit. E?
- UL for adults = 1,000 mg (2,325 µmoles)/day of ANY form of SUPPLEMENTAL α-tocopherol;
- Based on the adverse effect of increased tendency to HEMORRHAGE
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Should we be taking supplements of Vitamin E?
Yes, but for other reasons!;
-NO high dose vit. E supps, but why sups for vit. E =
Recommended a supplement at RDA levels to meet RDA of α-tocopherol because is relatively LOW IN THE DIET;
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What form of Vit. E predominates in the diet?
- In diet, GAMMA-tocopherol is relatively abundant;
- But ALPHA-tocopherol is the ACTIVE form!!;
- May need to take double dose if amount is based on all-racemic mix;
- **Remember only HALF the isomers have vit. E activity.
