Vitamins:

Structure, function, deficiency & clinical application

Ratana Banjerdpongchai, M.D., Ph.D.

Associate Professor

Department of Biochemistry, Faculty of Medicine,

Chiang Mai University

Email: ratana.b@cmu.ac.th

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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

1. Harvery RA, Ferrier DR. Lippincott’s Illustrated Reviews: Biochemistry. 6th ed. Lippincott

Williams & Wilkins, Baltimore, 2014.

2. King MW. Integrative Medical Biochemistry: Examination and Board Review. McGraw Hill

Education. 2014. Singapore.

3. Rodwell VW, Bender DA, Bothan KM, Weil PA. Harpes’s Illustrated Biochemistry. 30th ed. Mc

Graw Hill Education. 2015. Singapore.

4. Bhagavan N, Ha C-E. Essential Medical Biochemical Biochemistry with Clinical Cases. 2nd ed.

Elsevier. Academic Press. 2015. Singapore.

5. Baynes KW, Dominiczak MH. Medical Biochemistry. 4th ed. Elsevier Limirws. Saunders. 2014.

China.

6. Medical Biochemistry: An Illustrated Review. Panini SR. Thieme Medical Publishers, Inc. 2005.

New York.

7. Devlin TM. Textbook of Biochemistry with Clinical Correlation. 7th ed. John Wiley & Sons. Inc.

2011. New York. United States of America.

8. Download file power point ได้ใน website ของ E-learning ใน CMU online ของภาควชิาชีวเคมี49