Thiamin, Riboflavin, and Niacin By

Thiamin, Riboflavin,
and Niacin
By: Kaitlin Deason and Confidential
Group Members
 Brief history and fun facts of thiamin, riboflavin, niacin
 Overview of absorption, digestion, and transportation
 Overview of RDAs, sources, deficiencies, toxicities, and
assessment tests
 Overview of metabolism
Vitamin B1
 1880s Dr Takaki: relationship
between “the nitrogenous
substances …in the food” and
the disease beriberi (I can’t –I
can’t) in Japanese Navy
 1890 Diet to prevent beriberi
was written into law
 1886 Dr. Christian named
beriberi as polyneuritis
 “anti-polyneuritis factor”
could be extracted from rice
hulls with water and ethanol
History con’t.
 1911 Dr. Funk crystallized an
amine substance from rice bran
 1926 Dr. Jansen and Dr. Donath
crystallized vitamin B1 from rice
bran named antineuritic vitamin;
however, they missed the sulfur
atom and their formula was
 1936 Williams published the
correct formula
 Thiamine as reflection of amine
nature of vitamin
Thiamin: Absorption Transport Storage
 Water soluble vitamin
 In the blood bound to
 Absorption in the jejunum
 Storage: 30 mg
 ~90 % within blood cells
 Small amount in the liver,
skeletal muscles, brain,
heart, kidney
 Passive diffusion if thiamin
intake is high
 Active diffusion Sodium
Dependent if thiamin intake
is low
 Ethanol ingestion interferes
with active transport of
Thiamin: Main Active Forms
Thiamin Di- or Pyrophosphate (TDP/TPP)
Thiamin: Main Active Forms
Thiamine triphosphate (TTP)
Thiamine di-phosphate + ATP  Thiamine
triphosphate (TTP)+ ADP
Metabolism Thiamin: Energy Transformation
TDP in Enzyme Systems
Oxidative Decarboxylation of
- Pyruvate
- -ketoglutarate
- Three branched chain amino acids: isoleucine, leucine and
Physiological & Biochemical
 Noncoenzyme: Membrane and nerve conduction
 Coenzyme:
 Energy transformation
 Synthesis of pentoses and NADPH
Recommended Daily Amounts
Men: 1.2 mg/day
Women: 1.1 mg/day
Pregnant: 1.4 mg/day
Lactating : 1.5 mg/day
Sources of thiamin
 Excellent sources:
 Pork and Sunflower seeds
 Good sources:
 Enriched and fortified or whole
grains: (bread, ready-to-eat
Funny fact
 If you can’t get enough of sushi you might want to think
twice. Raw fish contains thiaminase – an enzyme that
deactivates thiamin. Cooking fish makes the enzyme
Thiamin Deficiency: Groups at Risk
 Biological half-life of thiamin in the body is about 15 days, deficiency
symptoms can be seen in people on a thiamin deficiency diet as little
as 18 days.
 Groups with a greater risk:
 individuals with kidney diseases on dialysis
 Malabsortion syndrome or genetic metabolic disorders
 Pregnant women with more then one fetus
 Seniors
 Chronic dieters
 Elite athletes
 Alcoholics
Thiamin Deficiency
 Beriberi –true deficiency is not
 Failure to oxidize -keto acids
common in USA
 Dry beriberi from low thiamin
intake in older adults
 Wet beriberi with
cardiovascular system
 Acute beriberi in infants
from leucine, isoleucine and
valine causes accumulation in
blood the branched –chain
 Findings are characteristic of
Maple Syrup Urine Disease
Thiamin Deficiency Symptoms
Associated with alcoholism
Wernicke-Korsakoff Syndrome:
muscle wasting and encephlopathy
Mental confusion
Speech difficulties
Weight loss
Burning pain in the extremities
Heart failure
Toxicity Symptoms
 Oral intake of 500 mg/day for 1 month
 Headache
 Convulsion
 Cardiac arrhythmia
 Anaphylactic shock
 No tolerable upper intake level
Assessment Thiamin
 Measurement of erythrocyte transketolase activity ( an
increase in transcetolase activity >25% indicates thiamin
 Measurement of urinary thiamin excretion
 Clinical response to administered thiamin (symptoms
improve after the person is given thiamin supplements)
Thiamin: Disease implications
Benfotiamin- lipid-soluble thiamin derivative can activate pentose
phosphate transketolase to prevent experimental retinopathy
Hammer, H-P, Du, X., Edelstein, D (2003) Benfotiamine Blocks Three Major Pathways of Hyperglycemic Damage and
prevents Experimental Diabetic Retinopathy. Nature Medicine, 9,3,294-299
 Case study: 5-week girl was hospitalized due heart failure. The infant
was diagnosed with dilated cardiomyopathy. Parents refused the
heart transplantation and treatment with thiamine hydrochloride was
started. 48 hours later the patient condition was improved,
suggestion that her condition was due to defect of thiamin intake.
Conclusion: All patient with early dilated cardiomyopathy should have
their thiamin plasma measured.
Rocco, M.D., Patrini, C., Rimini, A. (1997) A 6-month-old Girl with Cardiomiopathy Who Nearly Died. Lancet, 349, 616
Vitamin B2
Description of Riboflavin
 Water Souble Vitamin
 Riboflavin = Flavin + Ribitol
 Flavin means yellow in Latin
 Ribitol is a alcohol sugar
 Yellow fluorescent
characteristic of Riboflavin
comes from Flavin
 Greatest concentrations of B2
found in liver, kidneys, and
History of Riboflavin
 1933 Riboflavin was discovered by Kuhn, Szent, Wagner
 In the US, originally known as vitamin G
 Riboflavin’s unique fluorescent orange-yellow color help
researchers identify B2
Main Coenzymes
 FMN - Flavin Mononucleotide
 FAD - Flavin Adenine Dinucleotide
 Most commonly found in foods
 In the intestinal lumen the coenzymes are converted into
FAD pyrophosphatase
FMN phosphatase
Physiological and Biochemical
Functions of Riboflavin
 Main Function - Electron Hydrogen Transfer Reactions
Oxidative Decarboxylation of pyruvate
Succinate Dehydrogenase
Fatty Acid Oxidation
Sphinganaine Oxidase
Xathine Oxidase
Aldehyde Oxidase
Pyridoxine phosphate oxidase
Active form of folate
Synthesis of niacin from tryptophan
Choline Catabolism
Thioredoxin reductase
Monoamine oxidase
Oxidized form of glutathoine
Metabolism of Riboflavin
 Riboflavin most commonly found bonded to protein in
 Prior to absorption, riboflavin must be freed of the protein
 Divalent metals such as Copper, Zinc, Iron inhibit the
absorption of riboflavin
 Alcohol – impairs Riboflavin digestion and absorption
 ~ 95% Riboflavin is absorbed from foods up to 25 mg
 ~7% of FAD is covalently bound to AAs; Histidine or
Cysteine, can’t function in the body and remains bound
 Excreted in the urine
Absorption of Riboflavin
 Mucosal cells:
 Serosal surface:
 FMN is dephophorylated to Riboflavin
 B2 is transported to the liver
 Converted to FMN or other coenzyme by flavokinase
 FAD is most predominant flavoenzyme in tissues
Transportation of Riboflavin
 Systemic plasma
 Most flavins are found as riboflavin
 Riboflavin, FMN, and FAD are transported in the plasma
by a variety of proteins
 Albumin, fibrinogen, and globulins
 Albumin is the primary transport protein
 Free riboflavin uses carrier mediated process to traverse
most cell membranes
 In the brain riboflavin uses a high affinity transport system
for B2 and FAD
Deficiency of Riboflavin
 Ariboflavinosis
 Cheilosis – lesions on outside of lips
 Angular Stomatitis – Corners of mouth
 Glossitis – Inflammation of tongue
 Hyperemia – Redness or bleeding in oral cavity
 Edema – swollen mouth/ oral cavity
 Seborrheic Dermatitis – inflammatory skin condition
 Anemia
 Nueropathy- peripheral nerve dysfuction
Populations with greatest risk of
 Congential heart disease
 Some Cancers
 Excess alcohol intake
 Thyroid disease
 Diabetes Mellitus, trauma, stress
 Women who take oral contraceptives
Sources of riboflavin
 Excellent Sources – animal origin products
 Beef Liver, Sausage, Steak, Mushrooms, Ricota Cheese,
Nonfat Milk, Oysters
 Significant Sources – Eggs, meat, legumes
 Fairly Good Sources – Green Vegetables
 Minor Sources – Fruit and Cereal grains
Forms of Riboflavin in Foods
 FMN and FAD
 Most common
 Free or protein bound
 milk, eggs, enriched breads and cereals
 Phosphorous bound
RDA of Riboflavin
 Men – 1.3 mg/day
 Women – 1.1 mg/day
 Pregnant – 1.4 mg/day
 Lactating – 1.6 mg/day
Toxicity Levels of Riboflavin
 Level has yet to be determined
 Fun Fact - 400 mg of Riboflavin – is an effective treatment
dose for migraine headaches without any side effects
Assessment of Riboflavin
 Erythrocyte glutathione reductase
 Good measurement because requires FAD for a coenzyme
 If reaction is limited than Riboflavin intake is low
Riboflavin disease Implications
 Riboflavin increase lowers homocysteine reducing the risk
of coronary atherosclerosis
 Riboflavin and folate work together to reduce plasma tHcy (total
Moat, S., Pauline A. L., Ashfield-Watt, Powers, H. J., Newcombe R.G, and McDowell, I. (2003). Effect of Riboflavin Status on the Homocysteinelowering Effect of Folate in Relation to the MTHFR (C677T) Genotype. Clinical Chemistry. 2003;49:295-302
 Riboflavin can increase the amount of antioxidants in a
breast cancer patient, increasing DNA repair
 Supplemented with 100 mg co-enzyme Q10, 10 mg riboflavin and 50
mg niacin (CoRN), one dosage per day along with 10 mg tamoxifen
twice per day.
Premkumar, V. G., Yuvaraj, S., Shanthi P., and Sachdanandam, P . (2008). Co-enzyme Q10, riboflavin and niacin supplementation on
alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy. British Journal of Nutrition
100: 1179-1182
Vitamin B3
History of Niacin
 Niacin was discovered because of its deficiency pellagra
 Documentation of pellagra dates back to the 1760’s in Spain and
 Joseph Goldberger was the first to come up with a scientific
reason to explain pellagra
 He discovered that pellagra could be cured by milk and
concluded that it was not an infectious disease
 Continuing the work of Joseph Goldberger, Conrad Elvehjem
was able to isolate and identify niacin.
 Fun fact: Originally, referred to as only nicotinamide, it was
renamed to niacin because it was thought that nicotinamide too
closely resembled nicotine and the didn’t want people getting
confused and thinking they were harming themselves or that
cigarettes contained vitamins.
Niacin is the general term to classify
both nicotinic acid and nicotinamide
Suave, A. A. (2007). NAD+ and Vitamin B3: From metabolism to therapies. The Journal of Pharmacology and
Experimental Therapeutics, 324(3), 883-893.
 Most absorption of niacin occurs in the small intestine.
 Absorption/transportation occurs in one of two ways:
Passive diffusion- this happens when it is at high
concentrations (ex. Pharmacological doses)
Facilitated diffusion- This is a sodium dependent reaction
that occurs when niacin is in lower concentrations
 Niacin is transported through the blood stream and then is
able to move across cell membranes by simple diffusion
 The exception is when nicotinic acid is being transported into
the kidney tubules or the RBC’s. This requires a carrier.
 However, this is not very often because in the blood plasma,
niacin is most commonly in the form of nicotinamide
 Niacin is used by all tissues so it is transported throughout
the body
Importance of Niacin
 Nicotinamide is the primary precursor for NAD and NADP
 Approximately 200 enzymes require NAD or NADP
 NADNADH: main role is to transport electrons through
the ETC, but also acts as a co-enzyme for:
 Glycolysis
 β-oxidation of fatty acids
 Oxidative decarboxylation of pyruvate
 Oxidation of acetyl CoA via Krebs cycle
 Oxidation of ethanol
Importance of Niacin cont.
 NADPNADPH: main role is as a reducing agent in the
hexosemonophosphate shunt but also also acts as a coenzyme for:
 Fatty acid synthesis
 Cholesterol and steroid synthesis
 Oxidation of glutamate
 Synthesis of deoxyribonucleotides
 Regeneration of glutathionine, vit. C, and thioredoxin
 Folate metabolism
Mechanism of action
 NAD+ and NADP act as electron acceptors (and donors)
Boyer, R. (2002). Concepts in biochemistry. Canada: John Wiley and Sons. Fig. 16.7
Synthesis of Niacin
 Our body can synthesize NAD from the amino acid
tryptophan in the liver.
 This requires other vitamins and minerals.
 Despite this, we still require niacin from dietary sources.
 This only happens when we have adequate amounts of
tryptophan, AND it only occurs at a rate of 60:1. This ends
up being about 3% of tryptophan being used to synthesize
RDA for Niacin
 The RDA is expressed in niacin equivalents (NE)
 For men: 16 mg (NE)/day
 For Women: 14 mg (NE)/day
 During pregnancy and lactation this increases to 18 mg (NE)
and 17mg (NE)/day
 To determine NE we assume the 60:1 mg tryptophan to
niacin ratio
 Approximately 1% of each gram of protein is tryptophan
Sources of Niacin
• Foods high in protein
such as, fish*, chicken*,
beef, and pork
• Enriched/fortified
breads and cereals
• Legumes
• Small amounts from
dairy products and
green vegetables
*Excellent sources are
chicken breast and
canned tuna
Calculating NE
 Determine RDA for protein.
 0.8g/kg body wt. So, for someone who weighs 61 kg they need
49g of protein
 Anything above this (leftover protein) will be used to convert to
niacin. So lets say this person eats 79g protein
 Divide leftover protein by 100 to determine grams of
tryptophan and then x1000 to get mg
 Finally divide by 60 to determine niacin mg synthesized
 79g-49g= 30g ; 30g÷100=0.3 g tryptophan ; 0.3x1000= 300mg
tryptophan ; 300mg tryptophan÷60= 5mg niacin
Pellagra: niacin deficiency
Characterized by the 4 D’s:
Fred, H. L., & Van Dijk, H .A. (2007). Images of memorable cases: 50 years
at the bedside. Houston: Long Tail Press/Rice University Press.
Pellagra cont.
 Niacin can be covalently bound to proteins (niacinogen) or
carbohydrates (niacytin)
 The covalent bond is not sensitive to HCl in the stomach
and therefore niacin is not released for absorption
 Niacin is not absorbed and deficiency occurs
 Niacinogen and niacytin are most common in corn which
was a major source of food during the depression
 Now we know how to solve the problem
Niacin deficiency
 Besides pellagra, deficiency or diminished niacin status
can also occur
Populations at risk:
 Those taking certain medications (Ex. Antituberculosis drug
 Malabsorptive disorders- chronic diarrhea, inflammatory
bowel disease, some cancers…
 Those with Hartnup disease- impairs tryptophan absorption
decreasing synthesis to niacin
 Alcoholics
Niacin toxicity
 Nicotinic acid is used as a treatment for high
hypercholesterolemia. High doses (4g/day) have been
shown to increase HDL and lower LDL. The mechanism of
action is unknown.
 Side effects occur when consuming >1g niacin (usually in
form of nicotinic acid for benefits)
Niacin toxicity con’t.
 Side effects include:
 Niacin flush- redness, burning, itching, and tingling of the
Gastrointestinal problems
Hepatic toxicity
Hyperuricemia- Niacin competes with uric acid for excretion
which causes a build-up and possibly gout
Elevated blood glucose (glucose intolerance)
 Tolerable Upper Intake Level: 35mg/day for adults
Assessment of niacin
 Measurement of urinary metabolites of the vitamin:
 <0.8 mg/day N’ methyl nicotinamide= deficiency
 <0.5 mg N’ methyl nicotinamide/1 g creatinine= poor niacin status
 0.5-1.59 mg N’ methyl nicotinamide/1 g creatinine= marginal status
 >1.69 mg N’ methyl nicotinamide/1 g creatinine= adequate status
 Sometimes other ratios of urinary excretion are used to
assess status
 Measurement of ratio of erythrocyte concentrations of NAD to
NADP and just NAD has been used to assess status.
Niacin disease Implications
 Cardiovascular disease
 Niacin has been shown to increase HDL while at the same
time decreasing LDL and total TG.
 One review even stated that niacin, “is considered the most
efficacious agent currently available for therapeutic elevation of
subnormal HDL-C concentrations, and typically produces a 15 to
35% increment as a function of dose” (Chapman, Redfern,
McGovern, & Giral, 2010)
 Athersclerosis
 Niacin helps slow the progression of atherosclerosis by
slowing the thickening of arteries
Niacin disease implications con’t.
 Alzheimer’s Disease
 Niacin is though to have a protective effect against niacin
although more research is needed to determine mechanism
of action and significance.
 Cancers
 Niacin is plays a role in DNA repair and therefore
supplementation may improve cancer outcomes by helping
prevent tumor growth.
Thiamin, Riboflavin, Niacin
Important in reactions:
 Glycolysis (fig. 4.14)
 β-oxidation of fatty acids (fig
Oxidative decarboxylation of
pyruvate (fig 9.12)
Oxidation of acetyl CoA via
Krebs cycle (fig. 4.15)
Oxidation of ethanol (fig. 4.23)
Fatty acid synthesis (fig. 6.30)
Cholesterol and steroid
synthesis (see ch. 6)
Oxidation of glutamate (fig.
Choline Catabolism (see pg.
Thioredoxin reductase (see ch.
 Synthesis of deoxyribonucleotides
 Regeneration of glutathionine,
vit. C, and thioredoxin (pg. 285,
269, & 460)
Sphinganaine Oxidase
Xathine Oxidase (fig. 7.18)
Aldehyde Oxidase (fig. 10.4)
Pyridoxine phosphate oxidase (fig.
Active form of folate(fig. 9.31)
Synthesis of niacin from
tryptophan (fig. 9.18)
Monoamine oxidase
of Pyruvate:
Vitamins B1,
B2, & B3
Oxidative decarboxylation of pyruvate
 In order for the formation of Acetyl CoA, thiamin
diphosphate must first be present.
 Pyruvate dehydrogenase combines thiamin diphosphate
with pyruvate in order to form Acetyl CoA.
 NAD and FAD are also required as reducing agents are
oxidized to NADH and FADH2
Krebs Cycle
and vitamin
B1, B2, & B3
Krebs Cycle and vitamin B1, B2, &
 NAD and FAD act as electron acceptors in the Krebs Cycle.
They are oxidized to NADH and FADH2
 NADH and FADH2 then move to the ETC where they
donate the hydrogen necessary to ultimately start ATP
synthase and produce ATP
 Thiamin is also required for the oxidative decarboxylation
of α-ketoglutarate to succinyl CoA
Hexosemonophosphate Shunt
Hexosemonophosphate Shunt:
thiamin and niacin only
 Important in the formation of NADPH and is most active in
tissues with a high need of NADPH for fatty acid synthesis.
 Glucose 6-phosphate dehydrogenase and 6-
phosphogluconate dehydrogenase both require NADP as a
 Transketolase requires thiamin in order to work.
Fatty acid synthesis: niacin only
Boyer, R. (2002). Concepts in biochemistry. Canada: John Wiley and Sons.
Chapman, M.J., Redfern, J.S., McGovern, M.E., Giral, P. (2010) Niacin and fibrates in atherogenic
dyslipidemia: Pharmacotherapy to reduce cardiovascular risk. Pharmacology and Therapeutics, 126,
Gropper, S.S., Smith, J.L., & Groff, J.L. (2005 ,2009). Advanced nutrition and human metabolism.
Belmont, Ca: Thomson Wadsworth.
Morris, M.C., Evans, D.A., Bienias, J.L., Scherr, P.A., Tangney, C.C., Herbert, L.E., Bennett, D.A.,
Wilson, R.S., Aggarwal, N. (2004). Dietary niacin and the risk of incident Alzheimer’s disease and of
cognitive decline. Journal of Neurology, Neurosurgery, and Psychiatry, 75, 1093-1099.
Premkumar, V.G., Yuvaraj, s., Satish, S., Shanthi, P., Sachanandam, P. (2008). Anti-angiogenic
potential of CoenzymeQ10, riboflavin and niacin in breast cancer patients undergoing tamoxifen
therapy. Vascular Pharmacology, 48, 191-201.
Suave, A. A. (2007). NAD+ and Vitamin B3: From metabolism to therapies. The Journal of
Pharmacology and Experimental Therapeutics, 324(3), 883-893.
Wrenger, C., Knöckel, J, Walter, R. D. & Müller, J. B.(2008). Vitamin B1 and B6 in the malaria parasite:
requisite or dispensable? Braz J Med Biol Res, 42: 82-88.

similar documents