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

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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 gallinarum
“anti-polyneuritis factor” could be extracted from rice hulls with water and ethanol

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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 incorrect
1936 Williams published the correct formula
Thiamine as reflection of amine nature of vitamin

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Water soluble vitamin
Absorption in the jejunum
Passive diffusion if thiamin intake is high
Active diffusion Sodium
Dependent if thiamin intake is low
Ethanol ingestion interferes with active transport of thiamin
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In the blood bound to albumin
Storage: 30 mg
~90 % within blood cells
Small amount in the liver, skeletal muscles, brain, heart, kidney

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Oxidative Decarboxylation of
-
-
Pyruvate

-ketoglutarate
Three branched chain amino acids: isoleucine, leucine and valine

 Noncoenzyme: Membrane and nerve conduction
 Coenzyme:
 Energy transformation
 Synthesis of pentoses and NADPH

Men: 1.2 mg/day
Women: 1.1 mg/day
Pregnant: 1.4 mg/day
Lactating : 1.5 mg/day

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Excellent sources:
 Pork and Sunflower seeds
Good sources:
 Enriched and fortified or whole grains: (bread, ready-to-eat cereals)

 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 inactive.

 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

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Beriberi –true deficiency is not common in USA
Dry beriberi from low thiamin intake in older adults
Wet beriberi with cardiovascular system involvement
Acute beriberi in infants
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Failure to oxidize
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-keto acids from leucine, isoleucine and valine causes accumulation in blood the branched –chain acids
Findings are characteristic of
Maple Syrup Urine Disease
(MSUD)

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Associated with alcoholism
Wernicke-Korsakoff Syndrome: muscle wasting and encephlopathy
Mental confusion
Speech difficulties
Nystagmus
Diarrhea
Edema
Fatigue
Weight loss
Burning pain in the extremities
Ataxia
Coma
Heart failure

 Oral intake of 500 mg/day for 1 month
 Headache
 Convulsion
 Cardiac arrhythmia
 Anaphylactic shock
 No tolerable upper intake level

 Measurement of erythrocyte transketolase activity ( an increase in transcetolase activity >25% indicates thiamin deficiency
 Measurement of urinary thiamin excretion
 Clinical response to administered thiamin (symptoms improve after the person is given thiamin supplements)

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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
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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

 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 B
2 found in liver, kidneys, and heart
Flavin
Ribitol http://themedicalbiochemistrypage.org/images/riboflavin.jpg

 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 B
2 http://sandwalk.blogspot.com/2007/09/nobel-laureate-richard-kuhn.
html

 FMN - Flavin Mononucleotide
 FAD - Flavin Adenine Dinucleotide
 Most commonly found in foods
 In the intestinal lumen the coenzymes are converted into riboflavin
FAD
FAD pyrophosphatase
FMN
FMN phosphatase
Riboflavin

 Main Function - Electron Hydrogen Transfer Reactions
 Oxidative Decarboxylation of pyruvate
 Succinate Dehydrogenase
 Fatty Acid Oxidation
 Sphinganaine Oxidase
 Xathine Oxidase
 Aldehyde Oxidase
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Pyridoxine phosphate oxidase
Active form of folate
Synthesis of niacin from tryptophan
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Choline Catabolism
Thioredoxin reductase
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Monoamine oxidase
Oxidized form of glutathoine

 Riboflavin most commonly found bonded to protein in foods.
 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

 Mucosal cells:
Flavokinase
Riboflavin FMN
ATP ADP
 Serosal surface:
 FMN is dephophorylated to Riboflavin
 B
2 is transported to the liver
 Converted to FMN or other coenzyme by flavokinase
 FAD is most predominant flavoenzyme in tissues

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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 B
2 and FAD

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 Cheilosis – lesions on outside of lips
 Angular Stomatitis – Corners of mouth
 Glossitis – Inflammation of tongue
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Hyperemia – Redness or bleeding in oral cavity
Edema – swollen mouth/ oral cavity
Seborrheic Dermatitis – inflammatory skin condition
Anemia
Nueropathy- peripheral nerve dysfuction

 Congential heart disease
 Some Cancers
 Excess alcohol intake
 Thyroid disease
 Diabetes Mellitus, trauma, stress
 Women who take oral contraceptives

 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

 FMN and FAD
 Most common
 Free or protein bound
 milk, eggs, enriched breads and cereals
 Phosphorous bound

 Men – 1.3 mg/day
 Women – 1.1 mg/day
 Pregnant – 1.4 mg/day
 Lactating – 1.6 mg/day

 Level has yet to be determined
 Fun Fact 400 mg of Riboflavin – is an effective treatment dose for migraine headaches without any side effects

 Erythrocyte glutathione reductase
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Good measurement because requires FAD for a coenzyme
If reaction is limited than Riboflavin intake is low

 Riboflavin increase lowers homocysteine reducing the risk of coronary atherosclerosis
 Riboflavin and folate work together to reduce plasma tHcy (total homocysteine)
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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 Q twice per day.
10
, 10 mg riboflavin and 50 mg niacin (CoRN), one dosage per day along with 10 mg tamoxifen
Premkumar, V. G., Yuvaraj, S., Shanthi P., and Sachdanandam, P . (2008). Co-enzyme Q
10
, 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

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Niacin was discovered because of its deficiency pellagra
 Documentation of pellagra dates back to the 1760’s in Spain and
Italy
 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.

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:
1.
2.
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

 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

 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

 NAD+ and NADP act as electron acceptors (and donors)
Boyer, R. (2002). Concepts in biochemistry. Canada: John Wiley and Sons. Fig. 16.7

 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.
WHY?
 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
NAD

 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

• 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 http://www.nlm.nih.gov/medlineplus/mobileimages/ency/fullsize/18104_xlfs.png

 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

Fred, H. L., & Van Dijk, H .A. (2007). Images of memorable cases: 50 years at the bedside. Houston: Long Tail Press/Rice University Press.

 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

 Besides pellagra, deficiency or diminished niacin status can also occur
Populations at risk:
 Those taking certain medications (Ex. Antituberculosis drug isoniazid)
 Malabsorptive disorders- chronic diarrhea, inflammatory bowel disease, some cancers…
 Those with Hartnup disease- impairs tryptophan absorption decreasing synthesis to niacin
 Alcoholics

 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)

 Side effects include:
 Niacin flush- redness, burning, itching, and tingling of the skin.
 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

 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.

 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

 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

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Glycolysis (fig. 4.14)
β-oxidation of fatty acids (fig
6.24)
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.
7.23)
Choline Catabolism (see pg.
305)
Thioredoxin reductase (see ch.
12)
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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.
9.39)
Active form of folate(fig. 9.31)
Synthesis of niacin from tryptophan (fig. 9.18)
Monoamine oxidase

 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

 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

home.ccr.cancer.go
v

 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 6phosphogluconate dehydrogenase both require NADP as a cosubstrate.
 Transketolase requires thiamin in order to work.

 http://ull.chemistry.uakron.edu/Pathways/FA_synthesis/in dex.html

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 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,
314-345.
 Gropper, S.S., Smith, J.L., & Groff, J.L. (2005 ,2009). Advanced nutrition and human metabolism.
Belmont, Ca: Thomson Wadsworth.
 http://www.vitaminsworld.org/vitamins/vitamin-b2.html
 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.