Vitamin

• Sekelompok nutrien organik yang

dibutuhkan dalam jumlah sedikit
untuk berbagai macam fungsi
biokimiawi
* Biasanya tidak dapat disintesis oleh
tubuh, sehingga harus ada dalam
diet
Vitamin yg larut dalam air
 
1. Vitamin B-complex
 
a) vitamin B untuk metabolisme energi (Co enzim)
Thiamine (B1)
Riboflavin (B2)
Niacin (B3)
Biotin
Pantothenic acid
b) vitamin B untuk metabolisme konversi gugus metil
Folic acid (asam folat)
Cobalamin (B12)
c) Vitamin B untuk konversi metabolik
Pyridoxine (B6)
Pyridoxal
Pyridoxamine
 
2. Vitamin C
 Overview of Water-Soluble
Vitamins
• Dissolve in water
• Generally readily excreted
• Subject to cooking losses
• 50-90% of B vitamins are absorbed
• Marginal deficiency more common
 B Complex Digestion
• Broken down from coenzyme form into free
vitamins in the stomach and small intestine
• Absorbed, primarily in the small intestine
(50%-90%)
• Once inside cells, coenzyme forms are
resynthesized
– No need to ingest coenzyme forms; we can
make them
 pyruvate dehydrogenase complex

O
O
-
O
H3 C CoA + CO2
H3C S
O

pyruvate acetyl CoA

Champe and Harvey, p. 106
 NH2 H
NH2 H
+ N N+ S
N N S
H3 C N
H3C N

thiamine pyrophosphate TPP O

HO O
P O O
thiamine (B1) -
O P O-
-
O

H3C OH
NH2 CH
O
N N+ S
- + CO2
O
H3C H3C N
O

first step in pyruvate dehydrogenase complex O O

P O O
-
O P O-
-
O
 Thiamine
Food sources and distribution:
Whole grain, meats, legumes (peas, beans and lentils)
 
Signs and symptoms of deficiency
Beri-beri: severe deficiency
Primarily in areas where polished rice is primary food source
Symptoms include dry skin, irritability, disorderly thinking and
progressive paralysis
Wet beriberi-cardiovascular symptoms, cardiac failure
Infants: onset can be rapid, resulting in tachycardia and death
(look to nutritional status of mother)
 
Wernicke-Korsakoff syndrome:
Primarily associated with severe alcoholism.
Symptoms include apathy, loss of memory
Wandering eye movement
 
Toxicities, contraindications, and other notes
Only known use in treating deficiency
Commonly given to alcoholics in ER(emergency room)
Excess of any one B-vitamin can cause deficiency of others.
Rubin and Farber, Pathology - 2nd edition, p. 329
Wet and Dry BeriBeri
 RDA For Thiamin
• 1.1 mg/day for women
• 1.2 mg/day for men
• Daily Value on food label is 1.5 mg
• Most exceed RDA in diet
• Low income people and older people may
barely meet needs (highly processed and
unenriched foods, sugar, fat, alcohol)
• Surplus is rapidly lost in urine; non toxic;
no Upper Level
 Alcohol and Thiamin
• Alcoholics are at greatest risk for thiamin
deficiency because absorption and use of
thiamin are profoundly diminished and
excretion is increased by alcohol
consumption
• Poor quality diet makes it worse
• Little stored in body, so alcoholic binge of
1-2 weeks may result in deficiency
Riboflavin
 
Food sources and distribution:
Milk, cheese, meat, leafy vegetables, breads,
cereals
 
Signs and symptoms of deficiency
Sore throat, glossitis, cheilosis (red lips)
Anemia, neuropathy
 
Toxicities, contraindications and other notes
Only known use in treating deficiency
Excess intake can cause yellow urine
Excess can interfere with B1 & B6
Rubin and Farber, Pathology - 2nd edition, p. 331
 O
H3C N H H
N O
H3C N H
N
H3C N N O
O
CH2 N H H3C N N O
H3C
N
OH H
H3C N N O
OH FADH2
CH2
OH
OH
OH
OH
riboflavin (B2) OH
O NH2
O
O P N
-
O O P N
- O
O
N N
O

HO OH

Flavin adenine dinucleotide FAD

 H H O
O
- NH2
O

+ N
N
H
H O NADH
niacin (B3)
NH2

N+ H- = H+ + 2e-

O O
O
O P O- NH2
OH
NH2 N
O OH N

N+ O
N N
P O O
H
-
O
nicotinamide
HO OH
nicotinamide adenine dinucleotide NAD+
 Food Sources of Riboflavin
• Milk/products
• Enriched grains
• Ready to eat cereals
• Liver
• Oyster
• Brewer’s yeast
• Vegetables (asparagus, broccoli, greens)
• Sensitive to uv radiation (sunlight)
• Stored in paper, opaque plastic containers
 RDA for Riboflavin
• 1.1 mg/day for women
• 1.3 mg/day for men
• Average intake is above RDA
• Toxicity not documented
• No upper level
niacin
Nicotinic acid and nicotinamide
 
Food sources and distribution:
Fish, meat, poultry, cereal, nuts
Tryptophan in diet can serve as alternative source

Signs and symptoms of deficiency

Pellagra (pella agra: rough skin)
3D’s: dermatitis, diarrhea, dementia
red, swollen tongue
observed in chronic alcoholics
symptoms reverse within 24H of administration
 
Toxicities, contraindications and other notes
Harnup’s disease: defective renal and intestinal transport of tryptophan
Fast growing tumors can exhaust tryptophan supply
Excess can cause high BP and uric acid, cardiac arrhythmias
Can lower cholesterol
Rubin and Farber, Pathology - 2nd edition, p. 330
Pellagra
 Pellagra
• Prevented with an adequate protein diet
• Enrichment Act of 1941
• Became epidemic in southern Europe in early
1700s when corn became a staple food (poor
source)
• Reached epidemic proportions in the
southeastern U.S from late 1800s to 1930s
– Only dietary deficiency disease to reach epidemic
proportions in the US
 RDA for Niacin
• 14 (mg) NE/day for women
• 16 (mg) NE/day for men
• Daily Value on labels is 20 mg
• Upper Level is 35 mg
• Toxicity S/S: headache, itching, flushing,
liver and GI damage
• Megadose can lower LDL and TG and
increase HDL
Biotin
 
Food sources and distribution:
Can be synthesized by intestinal bacteria
Found in most foods
 
Signs and symptoms of deficiency
Very rare, include dermatitis, muscle pain

Toxicities, contraindications, and notes

Chronic consumption of raw eggs can induce
deficiency.
Chronic inflammatory bowel disease can cause
deficiency.
 Biotin
• Free and bound form
• Metabolism of CHO and fat
• Assists the addition of CO2 to other
compounds
• Synthesis of glucose, fatty acids, DNA
• Help break down certain amino acids
 O O
CO2 O
H N N H C N N H
-
O
Enzyme Enzyme
S S

biotin
 H OH
O CH3
N
OH
-
O O CH3
pantothenic acid

H OH
O
N CH3

O NH2
N O CH3
H O P O- N N
O
O P O- N N
O O
SH
acceptor site for acetyl group OH

OH
coenzyme A: CoA
 Biotin Needs
• Adequate Intake is 30 ug/day for adults
• This may overestimate the amount needed
for adults
• Deficiency rare
• No Upper Level for biotin
• Relatively nontoxic
Pantothenic (B5)
 
Food sources and distribution:
Ubiquitous
Easily destroyed by heating
 
Signs and symptoms of deficiency
Very rare
Neuromuscular degeneration
 
Toxicities, contraindications and other notes
Megadose can cause diarrhea and water
retention
Review
 
B-complex vitamins and energy metabolism:
 
Thiamine B1 TPP, pyruvate dehydrogenase
 
Riboflavin B2 FAD, FADH2
 
Niacin B3 NAD+, NADH
 
Pantothenic acid coenzyme A
 
Biotin decarboxylation reactions
(decarboxylase)
Pyridoxine (B6)
 
Food sources and distribution:
Meat, whole-grain breads and cereals, vegetables
 
Signs and symptoms of deficiency
Skin lesions
Convulsive disorders resulting from low levels of GABA
Needed for NAD+ synthesis
 
Toxicities, contraindications and other notes
Excess can lead to sensory nerve destruction, loss of
feeling in fingers, legs
Extra pyridoxine needed when using ISONAZIDE for
treatment of TB
ISONAZIDE binds covalently to pyridoxal phosphate
 vitamin B6

OH O
OH OH
OH OH
+ +
N CH3 N CH3
H H

pyridoxine pyridoxal
O
-
O O
NH2 - O
OH O
OH
OH
+
+
N CH3
N CH3
H
H
pyridoxal phosphate
pyridoxamine
 vitamin B6 - catalyzed reactions
R
O R O
O H N O
-
O O H O- -
O N O-
-
O O - O H
O
OH O
+ +
N CH3 N CH3
H H
pyridoxal phosphate Schiff base

Transamination: oxaloacetate + glutamate --> aspartate + alpha ketoglutarate

Deamination: serine --> pyruvate

Decarboxylation: histidine --> histamine

Condensation: glycine + succinyl CoA --> gamma-aminolevulinic acid

Folic acid
 
Food sources and distribution:
Fresh green vegetables
Cooking can destroy folic acid
 
Signs and symptoms of deficiency
Hemolytic anemias

Toxicities, contraindications and other notes.

Critical for pregnant women
Megadose can interfere with Zinc absorption.
May interfere with antiepileptic meds
(phenobarbitol)
 O
S NH2
O

H2N
sulfanilamide

6-methylpteridine
O
H N CH3
N
para-aminobenzoic acid, PABA
H2N N N
+
O

-
O

H2N
+ NH2
glutamate

O
O

- -
O O

O
NH

HN 10
O O O-
H N CH2
N 5 O-

H2N N N
folate, folic acid
 O

O
NH
HN 10
O O O-
H N CH2
N 5 O-

H2N N N folate, folic acid

O
NH
HN 10
O O O-
H N CH2
N 5 O-

H2N N N H
dihydrofolate, DHF
H

O
NH

H HN 10
O O O-
H H CH
N 2
N 5 O-

H2 N N N tetrahydrofolate, THF
H
H
 NH2
O
H
O OH
O
H NH
O-
serine HN 10
O O O-
H
H N CH2
-
N 5 O
tetrahydrofolate, THF
H2N N N
H

NH2
O
O OH
H O
NH
O
- H2C
glycine N 10
O O O-
H
H N CH2
N 5 O-

10-hydroxymethyl-THF
H2N N N
H

O
- H2O
O
NH
H2C N 10
O O O-
H N CH2
-
N 5 O

5,10 methylene-THF
H2N N N
H
Stryer, Fig 29-16
Rubin E, Pathology, p1379
Goodman Gilman, A. The Pharmacological Basis of Therapeutics, p.1245
 Folate and Homocysteine
• High homocysteine levels in blood
associated with increased risk of CVD
• Folate deficiency → homocysteinemia
 RDA for Folate
• 400 ug/day for adults
• (600 ug/day for pregnant women)
• Average intake below RDA
• FDA limits nonprescription supplements to
400 ug per tablet for non-pregnant adults
• OTC Prenatal supplement contains 800 ug
• Excess can mask vitamin B-12 deficiency
• Upper Level set at 1 mg
Cobalamin (B12)
 
Food sources and distribution:
Synthesized only by microorganisms
Deficiency usually results from absorption problem, not
availability
 
Signs and symptoms of deficiency:
Pernicious anemia
Megaloblastic anemia
Neurologic dysfunction
Can result in abnormal fatty acid accumulation in membranes
 
Toxicities, contraindications and other notes
Substantial stores of B12 are found in the body.
Could take years to develop deficiency.
Caution with patients who have had GI(gastro-intestinal)
surgery.
Champe and Harvey, p. 327
 Methyl loading of methionine
O

O
NH
H2C N10 -
O O O
H N CH2
N 5 O-

H2N N N 5,10 methylene-THF

H

O
NH methylcobalamin from
H 3C HN10
O O O
-
vitamin B12
H N CH2
N 5 O-

H 2N N N 5-methyl-THF
H
NH2 NH2
H CH3
O S O S
O- O-
homocysteine methionine
 RDA for Vitamin B-12
• 2.4 ug/ day for adults and elderly
adults
• Average intake exceeds RDA
• B-12 stored in the liver
• Non-toxic (no Upper Level)
Rubin and Farber, p. 1020
Vitamin C
 
Food sources and distribution:
Citrus fruits, potatoes
 
Signs and symptoms of deficiency:
Scurvy results from deficiency in collagen hydroxylation
Results in spongy gums, loose teeth and bleeding under the skin
 
Toxicities and contraindications:
Can cause oxidation, particularly in presence of free metals
Can be toxic with hemodialysis patients, iron storage diseases
Ascorbate is metabolized to oxalate which can form insoluble
precipitates with Ca++
Result in low Ca++, kidney stones, heart deposits.
 Vitamin C and collagen synthesis

O OH
O
OH
HO OH

vitamin C: ascorbic acid

sugar attachment site
OH

H H H H
N N N N N
N

O O O O

proline hydroxyproline
Rubin and Farber, Pathology - 2nd edition, p. 333
 Vitamin C and hydroxyl radical formation

superoxide dismutase
2 O2- + 2H +
H2O2 + O2
superoxide hydrogen peroxide

catalase
2 H2O2 2 H2O + O2

H2O2 + Fe2+
Fenton reaction

Fe3+ + HO  + HO
-


ascorbic acid

HO DNA damage
lipid peroxidation
Review:
 
Diseases associated/resulting from deficiencies in water
soluble vitamins:
 
BeriBeri: Vit B1
 
Wernicke-Korsakoff syndrome: Vit B1
 
Pellagra: Vit B3
 
Pernicious anemia: B12
 
Megaloblastic anemia: B12
 
Scurvy: Vit C
Fat-soluble vitamins
 
Vitamin A
 
Vitamin D
 
Vitamin E
 
Vitamin K
Vitamin A
 
Food sources and distribution:
Low fat dairy products, deep yellow, orange vegetables

Function: Vitamin A(retinol) is the precursor of retinel, the light-

sensitive group in rhodopsin and other visual pigments.

Signs and symptoms of deficiency:

Night blindness, dry eyes and skin
Slow growth in children
Lowered resistance to infection
 
Toxicities and contraindications:
Overdose can result in dry skin, headache
Can result in birth defects in pregnant women
Can cause liver damage
 
Vitamin A derivatives (isotretinoin, accutane) can cause
birth defects and has been associated with suicide.
 H3C
CH3 CH3 CH3 H3C

CH3 CH3 CH3

CH3
CH3
-carotene

CH3 CH3 CH3

CH2OH

CH3
CH3 all-trans-retinol
Rubin and Farber, Pathology - 2nd edition, p. 328
Goodman and Gilman, The Pharmacological Basis of Therapeutics, p. 1599
Vitamin D
 
Food sources and distribution:
Egg yolks, fortified milk, fish oil, sun exposure

Function: A metabolite of vitamin D is a hormone that

regulates the metabolism of calcium
and phosphorus.

Signs and symptoms of deficiency:

Rickets in children
Osteomalacia (osteoporosis) in adults
 
Toxicities and contraindications:
The most toxic of vitamins in excess
Calcium deposits in heart, hypertension, high cholesterol
Fragile bones
 Vitamin D

HO 7-dehydrocholesterol

UV light

25
kidney hydroxylation
activated by parathyroid OH
hormone when Ca++ is low HO
1
liver hydroxylation
HO
1,25 dihydroxy cholecalciferol (vitamin D3)

(acts as a hormone-transcription factor activating expression

of Ca++-binding proteins in intestine and bone)
Robbins, Pathologic Basis of Disease – 5th Edition, p. 1221
Vitamin E
 
Food sources and distribution:
Poultry, seafood, seeds, nuts, whole wheat
Function:  Reacts with and neutralizes reactive oxygen
species such as hydroxyl , radicals before they can
oxidize unsaturated membrane lipids, damaging cell
structure(antioxidant)

Signs and symptoms of deficiency:

very rare , Unknown in humans, in animal may cause
infertility
 
Toxicities and contraindications:
Excessive bleeding, reduced sexual function
 vitamin E

CH3
CH3 H3C
H3C O

HO
CH3 -tocopherol
Vitamin K
 
Food sources and distribution:
Made by intestinal bacteria
Spinach, leafy vegetables, oats, bran, potatoes

 Function: required for normal blood clotting(blood

coagulation)

Signs and symptoms of deficiency:

Excess bleeding, bleeding gums
 
Toxicities and contraindications:
Jaundice in infants
 vitamin K

O
- Ca++
O
O O-
menaquinone (vitamin K2)
O

N
H O

required for the carboxylation of glutamate to -carboxyglutamate

allows proteins to bind calcium
important in blood clotting
newborn infants usually get a vitamin K shot