Fat Soluble Vitamins Midterm #1 Flashcards
vitamin A background
shortages of its consumption affect 200 million children worldwide and 20 million women of childbearing age especially in South Asia Chronic deficiencies contribute to child mortality secondary to infection and the xerophthalmia and night blindness, which are eye diseases. Vitamin A is also required to prevent measles
Vitamin A Chemistry and metabolism
Retinol is the biologically active form. Essential structure necessary for activity is called substituted beta-ionon nucleus. esterification occurs at C-15. retinyl palmitate is the principal storage form and what is normally ingested from animal sources.
Pro-vitamin A
polyisoprenoid plant pigments that may yield vitamin A after metabolism BCMO: beta-carotene monooxygenase is the enzyme the cleaves the 15-15’ bond. The enzyme is inefficient and self-regulated through negative feedback. Higher body stores of vitamin A decreases BCMO activity. All carotenoids when cleaved either produce retinol or antioxidants. Not all will produce retinol but all carotenoids will produce some antioxidant.
Carotenes
carotenoids with no oxygen atoms Beta-carotene: only carotenoid where we get two molecules of vitamin upon cleavage. Richest source of vitamin A from plants, and is the main form present in carrots. alpha-carotene: when cleaved it forms one molecule of vitamin A and one antioxidant
Lycopene (Carotene)
when cleaved forms two molecules of antioxidant. Has been associated with preventing prostate cancer
Xanthophylls
carotenoids that contain an oxygen atom cryptoxanthin: when cleaved forms one molecule of retinol and one molecule of antioxidant lutein: when cleaved forms two molecules of antioxidant, and may be helpful in treating or preventing macular degeneration
Vitamin A metabolic mechanism
retinyl esters which are stored in the liver are esterified by REH (retinyl ester hydrolase) to form retinol. NAD-dependent alcohol dehydrogenase (RDH) convert retinol to all-trans-retinaldehyde which is a reversible reaction. Transfer of hydrogen through an “electron sink” created by the lone pair on the nitrogen of NAD+/NADH. ALDH converts this to all-trans retinoic acid which is non-reversible. Cys is present on the enzyme and required to make the quaternary intermediate. NAD+ in and NADH out CYP enzymes makes the final polar metabolite which is a non-bioactive form. Hydroxylation occurs on the beta-ionone ring.
vitamin A sources
Plants: provide carotenoids. Examples include carrots, sweet potatoes, red peppers Animal: provide retinol esters (palmitate/stearate) and primarily are from animal liver Fish: primarily liver, oils, eggs, and fortified dairy products
Vitamin A transport and storage
Specific transport proteins including CRBP, CRABP, RBP and they transport retinoic acid and retinol Stored in liver as retinol esters, mostly retinyl palmitate
Vitamin A functions
vision, growth/development and immunity
Vitamin A vision
part of the rhodopsin cycle. rhodopsin cycle is present in cons. Involves critical isomerizations to produce rhodopsin from opsin, important in monochromatic dark vision 1. First isomerization, catalyzed by light, converts 11-cis retinal bound to opsin to all-trans retinal. 2. Second isomerization, catalyzed by retinoid isomerohydrolase, converts all trans retinyl palmitate to 11-cis retinol 3. Oxidation of 11-cis retinol by ALDH converts to 11-cis retinal which binds reversibly to opsin via a Schiff base to generate rhodopsin the light sensitive pigment
Vitamin A growth and development
vitamin A regulates cell synthesis of macromolecules through RAR and RXR receptors Xerophthalmia: keratinization of the cornea, resulting in risk of blindness especially in children. Irreversible Anemia: involved in synthesis of transferrin, deficiency causes low erythrocyte iron that results in anemia Bone: low intake, and especially high intake increases risk for weak bones Skin: deficiency results in low mucin synthesis and high keratin synthesis. Fissures allow microbe penetration and infection. vitamin A is known as the “anti-infective” vitamin
Vitamin A and immunity
deficiency causes pathological alterations in mucosal surfaces, impaired antibody responses to challenge with protein antigens, changes in lymphocyte subpopulations and altered T-cell and B-cell function. Measles is a killer in children with deficiency.
vitamin A deficiency
plasma retinol level
Vitamin A Daily requirements
DV = 5000 IU; UL = 10,000 IU (about 3000 ug) RAE: retinol activity equivalent. 1 RAE = 12 ug food based all trans retinol = 2 ug all trans beta-carotene in oil (highly absorbable) = 24 ug other mixed dietary cartenoids.
Vitamin A uses
antioxidant, cancer, skin disorders
Vitamin A use: antioxidant/free radical scavenger
Lycopene: Found in tomatoes, watermelon, red grapefruit. No vitamin A activity. May have benefit in preventing prostate cancer in doses of 6-30 mg. Huge dose Luteine: Found in broccoli, spinach, and kale. No vitamin A activity. May help prevent macular degeneration in doses of 7-20 mg. Huge dose.
Vitamin A uses: cancer
Retinoic acid important for cell differentiation and inhibiting cell proliferation. Smokers: low carotene intake associated with increased risk of lung cancer, however supplementation of beta-carotene in current and previous smokers resulted in an increased risk of lung cancer. studies have shown no protective effect of vitamin A against breast or ovarian cancer Tretinoin (all trans retinoic acid) used in patients with acute promyelocytic leukemia. Acts through induction of terminal differentiation. In PML myeloid cells don’t differentiate. Remission rates are 90% and is one of the most highly treatable cancers. Development involves gene for RXR.
Vitamin A uses: skin
preserves epithelial morphology acne: topically as retinoic acid. Systemically as 13-cis retinoic acid (isotretinoin) Accutane. IPLEDGE program: instituted in mid-2000’s as an on-line registry system to mitigate the risks of taking isotretinoid. Common birth defects include exencephaly, caniofacial abnormalities and eye and cardiac effects. psoriasis: etretinate (Tegison) and acitretin (Soriatane) Strong teratogens when taken orally
Vitamin A: first generation drugs
1st generation: includes all-trans retinoic acid (Tretinoin), 13-cis retinoic acid (isotretinoin) and 9-cis retinoic acid (alitretinoin). Alitretinoin is used to treat Kaposi’s sarcoma a T-cell lymphoma which is associated with AIDS and causes severe skin lesions.
Vitamin A: second generation drugs
Acitretin and etretinate. Etretinate was removed from the market in 1998 because of complications with dosing leading to birth defects. It’s half life is about 4 months, and it was well accepted to be tetragenic. It was removed and replaced with acitretin which is the hydrolysis product of etretinate. It’s half life is 2 days except that if you take it with alcohol it converts back to etretinate.
Vitamin A: third generation drugs
bexarotene and tazarotene. Typically are RXR ligands/agonists that are used for skin conditions usually photodamage. Often used for certain cancers as well such as T-cell lymphomas. Tazarotene is a category X medication.
Vitamin A toxicity
Unknown whether teratogenic when taken as retinyl palmitate/acetate in supplements. Hypervitaminosis A: characterized by hydrocephalus, vomiting, hypercalcemia and brittle bones, fatigue, malaise, joint pain, headaches, rough skin, swellings on the extremities, papiledema caused by increased production of spinal fluid, hepatotoxicity. Hypercarotenosis: eating too many carrots. Causes skin to turn yellow but no harm done. Risk for bone fractures with over 10,000 IUs daily.
Vitamin D and rickets
- Anti-rachitic factor present in cod liver oil and after exposure to sunlight. 2. Rickets is a bone-deforming disease typified by bowed legs and enlargement of the epiphyses of the long bones and rib cage (rachitic rosary). 3. In the late 19th century up to 90% of children in industrialized Western Europe had rickets, and it became clear it was associated with crowded polluted cities. 4. C-sections grew out of the rachitic epidemic because women with deformed pelvic bones were unable to give normal birth. 5. Cod liver oil was recognized to be an effective treatment, and even heated/denatured cod liver oil still cured rickets so it was suspected to not be the vitamin A component. 6. Later showed that fat soluble vitamin A is actually A + D and D is not destroyed at high temperatures 7. In the 1920’s it was found that rickets could be treated with UV radiation.
vitamin D function
Principal physiological function of activated vitamin D in humans is to maintain serum calcium and phosphate concentrations in a range that maintains critical cellular processes.
Vitamin D structure
D3: cholecalciferol which is made naturally in the body when the skin is exposed to UVB radiation in sunlight. Generally thought to be more effective at increasing circulating concentrations of 25-OH D and its metabolites bind more strongly to the vitamin D receptor, and is considered to be the more potent form of vitamin D.
D2: Ergocalciferol which is found naturally in plants. Has a shorter shelf-life than does vitamin D3 and is thought to be less potent than D3.
D1: made from early efforts to make pure D2 from ergosterol. Is a mixture of D2 and lumisterol which is a photochemical degradation product of ergosterol.
Secosteroids: both D2 and D3 are secosteroids derived from ergosterol and 7-dehydrocholesterol. Lack the B ring of the typical steroid nucleus.
Vitamin D synthesis
- Start with 7-dehydrocholesterol which is also called pro-vitamin D3 and is equivalent to ergosterol. It is located in the lower epidermis of the skin and is activated by UV light (295 nm optimal) to form pre-vitamin D3. Activation from the sun requires an angle of greater than 45 degrees above the horizon, which almost never happens north of Los Angeles (35th parallel).
- Pre-vitamin D3 is converted to Vitamin D3 in the skin through thermal isomerization.
- Vitamin D3 is transferred to the liver where 25-hydroxylase, CYP2R1 and CYP271 covert it to 25-OH D3 (Calcidiol). CYP2R1 is associated with hereditary rickets and is not responsible for any drug metabolism.
- Calcidiol is transferred to the kidney where 1 alpha-hydroxylase and CYP27B1 catalyze the conversion to 1,25 (OH)2 D3 (Calcitriol) which is the active hormone. This step is the most important control point for bioactivation.
Inactivation of calcitriol
CYP24A1: catalyzes 6 very specific oxidations and is specific for calcitriol. Forms calcitroic acid
CYP3A4 and CYP24A1: can produce hydroxylations that mark calcitriol for elimination. CYP3A4 elimination is responsible for drug-induced osteomalasia affecting patients who are on chronic therapy with older anti-epileptics (phenytoin) which induces up-regulation of CYP3A4.
UGT1A4: glucuronidation of calcitriol.
Vitamin D: mechanism
1,25 DHCC binds to the vitamin D receptor (VDR) which is a steroid hormone receptor.
The complex is translocated to the nucleus VDR heterodimerizes with RXR which allows it to bind to specific response elements in the promoter region of vitamin D responsive genes, such as calbindin (Ca binding protein) and osteocalcin/osteopontin (bone-forming proteins)
Vitamin D: modulation of calcium
PTH is secreted from cell and causes three physiological responses: Calcium resorption in the bone increases (release of calcium from bone) Calcium reabsorption in the kidney increases In the kidney there is an increase in formation of 1,25 (OH)2 vitamin D.
This increase causes an increase in gut absorption of calcium.
All of these mechanisms act to increase serum calcium concentrations
This increase is detected at Ca GPCR sensors which activates PLC which decreases secretion of PTH through a negative feedback loop.
Vitamin D: cancer
VDR signaling is involved in modulating cell proliferation and differentiation High intake of vitamin D may reduce the risk for certain cancers, specifically colorectal cancer and possibly breast, prostate, and pancreatic cancers. Calcitriol promotes cellular differentiation, decreases cancer cell growth and stimulates apoptosis Another possible mechanism is genetic variation within the vitamin D receptor. Polymorphisms in the receptor have been linked with cancer development. Data are inconsistent regarding a protective effect of vitamin D agonist any specific type of cancer. Though there is an association with vitamin D supplement use and decreased death due to all causes.
Vitamin D: sources
Fish liver, fish products, sunshine, eggs (in D supplemented hens), liver, milk (fortified) Cod liver oil has about 400 IU/5mL
Vitamin D requirements
DV =400 IU UL = 4000 IU
Vitamin D toxicity
typically happen over a period of time rather than from a single large dose. hypercalcification: calcification in soft tissues such as the lung and kidney can be very dangerous Have to have sustained intake of 1000 mg (40,000 IU) a day, for 1-4 months to produce severe toxicity (calcification of soft tissues such as the lung and kidney) in children under 12 months. For adults intake of 2,500 mg/day can result in toxicity in a few months.
Vitamin D: deficiency state
Assessed on basis of plasma levels of 25-OH D3. Natural levels in adults who live or work in the sun are 50-70 ng/day Minimum level to prevent rickets and osteomalacia is 15 ng/mL Deficiency commonly assessed at levels
Vitamin D: uses
Deficiencies due to low sun exposure causing osteomalacia and osteoporosis
Strong evidence that vitamin D supplements and calcium help prevent fractures in postmenopausal women at 700-900 IU/day
Kidney failure: renal synthesis of activated vitamin D and renal reabsorption of calcium decrease, resulting in low serum calcium levels and increased PTH secretion.
Excessive bone resorption can cause metabolic bone disease.
Rocaltrol: used to provide active form of vitamin D3 directly.
Paricalcitol (Zemplar): modification of active form used orally for hyperparathyroidism.
Vitamin D: consumer counseling and advice
most multivitamins contain the DV Evidence that more than the DV may be beneficial if sun exposure is minimal. Study results generally show 800 IU/day sufficient postmenopausal women should take a vitamin D supplement as well as calcium supplement.
vitamin K: background
discovered when researches tried to understand why chickens and other experimental animals fed diets with low lipid contents developed hemorrhages and why their blood clotted slowly. It was later found that you could cure this with supplementation with lipid extracts of green plants and fish-meal that had been subjected to bacterial action. they later isolated the plant material from alfalfa, which was vitamin K1 and identified vitamin K2 as the factor from putrefied fish-meal
Vitamin K: structures
K1: phylloquinone, is the most prevalent form of vitamin K and is found at high concentrations in green leafy vegetables.
2’ - 3’ - dihydro-K1: form of vitamin K produced during the hydrogenation of vitamin K1-rich vegetable oils. Not enough evidence to say if it can substitute for vitamin K1 yet.
K2: Menaquinones, at least 13 known. MK-4: present in certain foods, eggs, and formed in the body from K3 by reaction with geranylgeranylphosphate. MK-7: high concentrations in some fermented foods, like natto (fermented soy bean). Used in Japan as a prescription to treat osteoporosis. MK-8-13: synthesized by bacteria in the gut
K3: Menadione. provitamin that lacks the side chain required for vitamin K activity. Can be converted in the body to MK-4 upon reaction with geranylgeranyl diphosphate.
Vitamin K: function and cycle
- vitamin K quinone is reduced to form the essential cofactor for the vitamin K cycle, hydroquinone.
- Hydroquinone, glutamic acid on protein, CO2 and O2 form vitamin K epoxide and Gla proteins through the enzyme GGCX, Gamma-glutamyl carboxylase enzyme. GGCX puts a carboxylic acid onto glutamate of a protein, thus activating it (after chalation with calcium).
- These proteins include the clotting factors II, VII, IX and X.
- The epoxide is converted back to hydroquinone through VKORC1, Vitamin K epoxide reductase enzyme. Warfarin is an antagonist for VKORC1 and inhibits conversion back the the active for of vitamin K. This prevents formation of Gla proteins, and activation of the clotting factors.
- Hypothesis that vitamin E interferes with clotting because it inhibits GGCX.
vitamin K metabolisms
First step is omega-hydroxylation by CYP4F2 and CYP4F11 Subsequent beta-oxidations cause chain shortening sulfate and glucoronide conjugates are produced and is excreted in urine and bile
Vitamin K deficiency
Deficiency increases spontaneous hemorrhaging. Can be due to chronic failure to ingest plant-based K1 or after long-term antibiotic use removing gut source of K2. Both sources are considered equal, but may overestimate the impact of gut K2 due to poor bioavailability in lower intestine Only natural deficiency is newborns. The placebo does not transmit lipids or vitamin K well, and the neonatal gut is sterile during the first few days of life. Breast milk is low in vitamin K as well and would require 2 L/day for maximal amount
Vitamin K: uses
K1 shot routinely given at birth to prevent neonatal hemorrhage Anticoagulant overdose, use K1 oral (2.5mg-5mg) with increased INR but no bleeding and K1 IV (>10 mg) for serious bleeding. Bone health: Vascular calcification: possible emerging role related to gamma-carboxylation of MGP (matrix Gla protein) which is the body’s natural calcification inhibitor. People on dialysis are at a higher risk for calcification.
Vitamin K: source
green leafy vegetables including spinach, collard greens and kale.
Vitamin K: dose requirements
DV is 80 ug and there is no UL. Note, DV may be too low for optimal activities as Adequate Intake levels set by IoM are 90-120 ug/day.
Vitamin K: toxicity
Some allergic reactions reported with IV, otherwise nothing special
vitamin K: counseling
Adequate intake is important for the ability of blood to clot and for health bones A good diet with leafy vegetables is usually sufficient
Vitamin E: structure
all have antioxidant properties due to a chromanol ring, which contains a hydroxyl group which can donate a hydrogen atom to reduce free radicals.
Tocopherols Naturally occurring has the R configuration at all three chiral centers alpha homolog is the most potent and contains two methyl substitutions. Beta and gamma has one substitution and delta has only hydrogen substitutions Potency of antioxidant activity increases with increasing methyl substitution.
Tocotrienols: Saturated version of tocophenols. Doesn’t satisfy the body’s requirement for vitamin E
Vitamin E: antioxidant properties
One electron oxidation of alpha-tocopherol leads to resonance stabilization Vitamin E considered as a “chain breaking, free radical scavenger” that prevents propagation of free radical damage
Vitamin E: pharmacological activity and transport
alpha-tocopherol is the most potent RRR-alpha-tocopherol is the most biologically potent stereoisomer Only stereoisomers with the 2R configuration can satisfy the vitamin E requirements in human. The alpha-tocopherol transport protein (aTTP) located in the liver is responsible for the selective transfer of (2R)-alpha-tocopherol into VLDL. The receptor does not recognize the beta, gamma or delta homologs of tocopherol. Non-alpha tocopherols are also better metabolized than alpha and are not conserved in the body.
Vitamin E daily requirements
DV = 30 IU (20 mg natural) UL = 1500 IU (1000 mg natural) RRR-alpha-tocopherol natural is 1 mg = 1.5 IU alpha-tocopherol synthetic is 1 mg = 1.1 IU alpha-tocopherol synthetic acetate is 1 mg = 1 IU
Vitamin E: dietary sources
Ubiquitous: rich sources are wheat germ and sunflower seed oils, green vegetables, whole grain cereals Fortified margarine supplies represent much of our intake in the US
Vitamin E: deficiency state
rare in developed countries but usually due to fat malabsorption Deficiency in rats causes sterility in male rates and fetal resorption in pregnant females in adults, generally characterized by neuromuscular abnormalities and myopathies. Peripheral neuropathies are considered to be due to free radical damage in nerves In premature infants it is often characterized by hemolytic anemia, fragile RBCs, and has been described because stores of vitamin E are low at birth due to poor placental transport
Vitamin E: deficiency diagnosis
based on measuring the ratio of plasma alpha-tocopherol to total plasma lipids (
Vitamin E: toxicity
Generally considered non-toxic Bleeding can be an adverse effect but this is rare at doses less than 1000 mg/day Exacerbated bleeding when given together with warfarin is the most significant interaction. Bleeding mechanism has been suggested to involve inhibition of the GGCX in the vitamin K cycle and direct effect on platelet function.
Vitamin E: uses
Cancer: 600 IU every other day provided no overall benefit in healthy women Heart Disease: No benefit in dozens of trials comparing risk of cardiovascular or atherosclerosis disease progression Alzheimers disease: high doses (2000 IU/day) showed some benefit in slowing progression, but not prevention Benefit in retrolental fibroplasia and bronchopulmonary dysplasia. Some protection for eye and lung damage in premature infants on oxygen Possible that negative trial outcomes reflect too low of vitamin E doses
Vitamin E: consumer counseling and advice
supplements higher than 200 IU are not beneficial and could be harmful amount in a multivitamin is probably adequate 30 IU
Quinonone cycle
.
O2 –> H2O cycle
enzymes: superoxide dismutase, peroxide catalase. reduction as you go upwards
Haber Weiss reaction.
.
Unsaturated Lipid peroxidation cycle
damages cell membranes and other lipoprotein structures. Can be stopped in the propagation cycle by vitamin E
Chain breaking by vitamin E mechanism
.
Regeneration of vitamin E by Ascorbate mechanism
.
Other protective mechanisms
superoxide dismutase mechanism: requires a Mn cofactor in mitochondria and Cu and Zn cofactor in cytosol Catalase mechanism: requires iron
Glutathione pathway
G6PD regulating enzyme, important in RBC
G6PD deficiency is the most common genetic defect in the world, primarily affecting African and Mediterranean descent. Defective enzymes cause oxidative stress often seen as hemolytic anemia.
Requirements: Glutathione peroxidase requires selenium, glutathione reductase requires vitamin B2 (riboflavin) and vitamin B3 (niacin) is necessary to maintain cellular concentrations of NADP(H)
