Vitamins - med.cmu.ac.th · • Absorption of vitamin B12 ... acid production in the stomach) and...
Transcript of Vitamins - med.cmu.ac.th · • Absorption of vitamin B12 ... acid production in the stomach) and...
Vitamins:
Structure, function, deficiency & clinical application
Ratana Banjerdpongchai, M.D., Ph.D.
Associate Professor
Department of Biochemistry, Faculty of Medicine,
Chiang Mai University
Email: [email protected]
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วตัถุประสงค์: เพ่ือให้นักศึกษาสามารถ
• บอกชนิดของวิตามินท่ีละลายในน ้า และไขมนัได้• อธิบายหน้าท่ีของวิตามิน การท างาน การเร่งในปฏิกิริยาใดในวิถีเมแทบอ
ลิซึม (หากมี) และการส่ือสญัญาณในการออกฤทธ์ิได้ • บอกช่ืออาการหรือโรค หากขาดวิตามิน• บอกลกัษณะท่ีส าคญัของวิตามินท่ีละลายในไขมนั กลไกการท างานได้• อธิบายความส าคญัของวิตามินในโรคบางชนิดได้ และการใช้วิตามินใน
การรกัษาและป้องกนัโรคบางชนิดได้ เช่น cystic fibrosis, renal osteodystrophy, parathyroidism, premature infancy, alcoholism, drug interaction และ aging
• อธิบายความเป็นพิษหากได้รบัวิตามินมากเกินไป
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Classification of vitamins
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Classification of nutritional anemias by cell size
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Production and use of tetrahydrofolate
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folate
• Diminished synthesis of purines
and thymidine, which leads to an
inability of cells to make DNA, so
they cannot divide.
• One carbon group transfer
Alcohol, smoking, aspirin, oral contra-ceptive: inh absorption
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Neural tube defects in the fetus
anencephaly 7
Spina bifida: folate def.
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B12 : intrinsic factor
• Absorption of vitamin B12
• Deficiency of B12: Pernicious anemia
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Vitmain C: antioxidants
• Scurvy: hemorrhage
and swollen gums
• Decrease incidence of
CHD, certain cancer,
common cold, some chronic diseases
• Coenzyme of proline
hydroxylalse
• Promote Fe2+ absorption
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Pyridoxine
• Isoniazid (isonicotinic
acid hydrazide): treat
TB, can induce B6 def.
• Alcohol, cigarette
smoking, oral
contraceptive, penicillin:
inh absorption
• B6 supplement in TB treatment with isoniazid
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B6: reaction types and examples
• Transamination
• Deamination
• decarboxylation
• Condensation
• Oxaloacetate + glutamate <-> aspartate + α-KG
• Serine <-> pyruvate + NH3
• Histidine <-> histamine + CO2
• Glycine + succinyl CoA -> δ-aminolevulinic acid
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Thiamine
• Active form: TPP :
thiamine
pyrophosphate
• Intermediate form in
PDH catalyzed rxn
• Intermediate form in α-
KG dehydrogenase
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TPP
• Transkelotase
• pyruvate dehydrogenase
• α-Ketoglutarate ehydrogenase
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Thiamine deficiency
• Beriberi: tachycardia, vomiting, convulsion,
death (if not treated)
• Wet beriberi: cardiovascular disorder
• Dry beriberi: peripheral nerve disorder
• Wernicke-korsakoff syndrome: apathy, loss of
memory, rhythmical to-and-fro motion of
eyeballs
• Alcohol, sulfur dioxide in dry fruits, tea, coffee: inhibit B1 absorption
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Niacin or nicotinic acid: NAD+, NADP+
Catalyze: Oxidation-reduction, fatty acid synthesis
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• Deficiency of niacin:
Pellagra 3 D
Dementia
Dermatitis
Diarrhea
[Death (if untreated)]
• 1 mg of nicotinic acid from 60
mg Tryptophan
• Use for treatment of type IIb hyperlipoproteinemia
Reduction of NAD+ to NADH
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Early pellagra affecting the arms in Niacin Def.
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Structure and biosynthesis of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)
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Cheilosis in or Angular stomatitis in Riboflavin Def.
• FAD, FMN:
• Oxidation-reduction rxn
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Biotin
• Carboxylation rxn
• Avidin: raw egg white
• Glycoprotein bind tightly and
prevent its absorption from
intestine
• 20 eggs per day to induce a
deficiency syndrome
• Covalently to Lys residue of a biotin-dependent enzyme
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Pantothenic acid (B5)
• A component of coenzyme
A, which functions in the
transfer of acyl gr.
• Succinyl CoA, fatty acylCoA, acetyl CoA
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Retinoids
• Visual cycle: rhodopsinconsists of opsin and 11-cis retinal
• Growth & differentiation: bone, nervous system : retinoic acid
• Reproduction: retinal and retinol : supporting spermatogenesis and preventing fetal resorption
• Maintenance of epithelial cells
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Absorption, transport, and storage of vit. A signaling
RBP = retinol binding protein25
• RDA for adults is 1000 retinol equivalents (RE)
• One RE = 1 mg of retinol, 6 mg of β-carotene, or 12 mg of other carotenoids
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Summary of actions of retinoids
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Bitot’s spot material involving cornea
and conjunctiva
Keratomalacia
Vitamin A ( Retinol) def.
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Clinical indications:
• Night blindness: earliest
sign of vit A def.
• Xerophthalmia: pathologic
dryness of conjunctiva and
cornea, if untreated, results
in corneal ulceration and
formation of opaque scar tissue -> blindness
Prevention of chronic disease
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Psoriasis
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Acne
• Mild acne: Darier disease:
tretinoin (all trans retinoic
acid) : topical use
• Severe recalcitrant cystic
acne: drug of choice
isotretinoin (13-cis retinoic acid), oral administration
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• Diet: ergocalciferol (D2) found in
plants
• Diet : cholecalciferol (D3) found in
animal tissues
• Endogenous vitamin precursor:
7-dehydro-cholesterol: dermis + epidermis
Vitamin D
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Actions of vitamin D Response to low plasma Ca2+
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Effect of vit D on intestine & bone
• 1,25-diOH D3 stimulates intestinal absorption of calcium and phosphate
• In intestinal cells: hormone receptor cpx moves to nucleus, enhance synthesis of spf calcium-binding protein: nuclear receptor
• 1,25-diOH D3 stimulates the mobilization of calcium and phosphate from bone by a process that requires protein synthesis and the presence of PTH.
Clinical indications
• Nutritional rickets: vit D def.
causes a net demineralization
of bone, resulting in rickets in
children and osteomalacia in
adults
• Renal rickets: renal
osteodystrophy; chronic renal
failure causes the decrease
ability to form active form of vitamin D
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Calcium and Vitamin D def.
Signs of ricket
- Knock knees - Osteomalacia - Bow leg (in
child)
- Rachitic rosary - Pigeon breast 35
vitamin K
• Carboxylation of Glu to form Gla
Role of vitamin K in blood coagulation
• Def. of vitamin K: unusual because adequate amounts are produced by
intestinal bacteria: oral antibiotics
• Hypoprothrombinemia: bleeding tendency
• Def of vitamin K in the newborn: sterile intestine: prophylaxis : i.m. vitamin K: prevent hemorrhagic dz
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Vitamin E
• α-tocopherol: most active from 4 tocopherols
• 4 Tocotrienol: alpha, beta, delta, gamma
• Antioxidant in prevention of oxidation of PUFAs
• Def is restricted to premature infants: sensitivity of red cells to peroxide and abn cell membrane
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Clinical applications:
*Cystic fibrosis
*Renal Osteodystrophy
*Parathyroidsm
*Newborn infants: premature birth
*Alcoholism
*Drug interaction
*Elderly
*Toxicity
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Cystic fibrosis
• Dysfunction of exocrine glands
• Obstruction of bronchi and bronchiols-> pulmonary infections
• Exocrine cells of pancreas->def. of pancr. enzymes-> partial obstruction of common bile duct
• Deficiency of pancr. Lipase and bile salts
• -> malabsorption of fat + fat-soluble vitamins
• Starch and proteins: trapped in fatty bolus
• Def. of pancr. Amylase and protease -> severe protein-calorie malnutrition -> treatment : microsphere prep. of pancreatic enzymes, MTV supplement
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Renal Osteodystrophy
• CRF, inability to produce 1,25-(OH)2D
• Hypocalcemia, hyperphosphatemia, increased parathyroid hormone
• Bone calcium becomes the only important source of serum calcium
• Increased renal retention of phosphate -> hyperphosphatemia
• Metastatic calcification ->calcification of soft tissues ->lower
serum Ca2+
• Calcium acetate and cationic polymer - Sevelamer hydrochloride –
phosphate binders are to make dietary phosphate unavailable for
absorption 40
Treatment of parathyroidsm
• In treatment of severe
parathyroidism:
intravenous 1,25-(OH)2D
since oral is not sufficient
and not effective
• Calcium mimetic agents :
bind to calcium sensor
located on the
extracellular mb of
parathyroid gland and
decrease PTH synthesis and release
Newborn infants & vitamin K
• Sterile GI tract: lack of vitamin K
• Hemorrhagic disease
• Vitamin E and K: do not cross placental mb well
• Supplement with iron, vitamin K and D: since they are low in breast milk
• In assisted ventilation case: vit E may reduce the risk of bronchopulmonarydysplasia and retrolental fibroplasia: potential complication of oxygen therapy
• Anemia of prematurity : folate and B12 supplement
*Calcium mimetic agents :41
Anticonvulsant drugs & vitamins
• Phenobarbital and diphenylhydantoin: seldom develop rickets or severe osteomalacia
• 65% of those on long term treatment : low serum calcium and phosphorus, high ALP, some bone loss
• Vit D supplement : help to correct hypoCa2+ and osteopenia
• Anticonvulsants: increase the need for vit K (mothers on anticonvulsants: newborn increase incidence of hemorrhagic disease)
**Increase the need for folic
acid and B6: megaloblastic
anemia, mother on anticon-
vulsant drugs: increase the
risk of neural tube defects(folate) in infants
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Alcoholisms
• Chronic alcoholics : risk of neurologic symptoms associated with B1 or B6 def.
• Alcohol: poor diet & poor absorption
• 40% of hospitalized alcoholics: megaloblastic erythropoiesis : folate def.
•• Alcohol interferes with Alcohol interferes with folatefolate absorption absorption and alcoholic cirrhosis impairs and alcoholic cirrhosis impairs folatefolatestorage.storage.
• 30% have sideroblastic anemia: B6 def.
• Peripheral neuropathy: impaired activation or increased degradation of B6
• Acetaldehyde displaces pyridoxal-P from carrier proteins and causes B6 rapidly degraded and excreted
• Wernicke-Korsakoffsyndrome:
• B1 def: impaired absorption and storage
are reported.
• Decreased bone density: osteoporosis: defect in
or increased rate of metabolism of vitamin D to inactive products by cytochrome P450 system
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Nutritional Needs of Aging People
• The absorption and
utilization of vit B6
decreases with age.
• Vit B12 def. is also more
prevalent in the elderly.
• Many older adults develop
atrophic gastritis (decreased
acid production in the stomach)
and decrease production of
intrinsic factor -> poor
absorption of B12
• The blood level of
homocysteine, a possible risk
factor for atherosclerosis,
dementia, and Alzheimer
disease, is often elevated in
elderly.
• Homocysteine is a by-product of DNA methylation and is normally metabolized to methionine or cysteine in rxn requiring folate, B12 and B6.
• Elderly -> not spend much time in sunlight -> decrease vit D, decrease kidney function -> decrease conversion of 25-(OH)D to 1,25-(OH)2D -> neg. Ca2+ balance -> osteoporosis
• Vit A absorption increases with age and its clearance by liver decreases, so vit A remains in the circulation for a longer time.
• Multivitamin supplements is ok but avoid separate vit A supplement.
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Toxicity of Vitamins??
• Lipid soluble vitamins: A, D, E, K
• Accumulation in adipose tissue
• Isolate consumption: vitamin A, D, E, K
• MTV supplement : OK
• Vit E: 400 iu/day
• Vit B6 toxicity: microcytic anemia
• Sources of vitamins: Fruits & vegetables: safe
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Toxicity of vitamin A
• Skin: dry and pruritic
• Nervous system: increase intracranial pressure may mimic symptoms of brain tumor
• Congenital malformation of developing fetus
• Isotretinoin : teratogen: prolonged use -> hyperlipidemia, increase in LDL/HDL ratio, increase risk of CHD
Toxicity of vitamin D
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Toxicity of vitamin K: rare
• Prolonged administration:
Hemolytic anemia and
jaundice in the infant, due
to toxic effects on the red cell membrane
Clinical indications of vit E
• Clinical trials: lack
cardiovascular benefits
• High dose of vit. E increases
incidence of stroke
• Toxicity: least toxic of fat-
soluble vitamins
• No toxicity observed at doses of 300 mg/day
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Toxicity of vitamin B6
Symptoms:
High dose:
*sensory neuropathy
Toxic dose:
*loss of co-ordinating/righting reflexes
*severe convulsion
*complete paralysis
*microcytic anemia
J Pharmacol Exp Ther 1940 (70): 400-7Unna K & Greslin J
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ReferencesReferences
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8. Download file power point ได้ใน website ของ E-learning ใน CMU online ของภาควชิาชีวเคมี49