Test 2

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Test 2
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  1. Niacin Deficiency
    • Lesions of the skin, mouth, GI tract, nervous symptoms
    • Mal del la Rosa – a form of leprosy
    • Associated with poverty and consumption of spoiled corn
  2. Niacin History
    • Food shortages during/after Civil War
    • Reported case by ATL MD
    • Associated with an insect vector
    • Water soluble B
  3. Niacin: Water-Soluble B
    • The antipolyneuritis factor
    • Found in yeast 
    • •Prevented both beriberi and pellagra
    • •Antipolyneuritis factor was unstable to heat
    • •Could still prevent dermatitis in rodents
    • Considered 2 substances  
    • •A-N – Antineuritic factor (thiamin)
    • •P-P – pellagra preventative factor
  4. Niacin: Pellagra Preventative Factor
    • ID slowed by two factors
    • Influence of the germ theory of disease
    • Lack of an animal model
  5. Joseph Goldberger
    • Observed that the diets were different
    • Professional staff diet included milk and meat
    • Secured funding to supply milk and meat to orphans
    • Believed pellagra was caused by diet
    • Needed to prove pellagra was not infectious
  6. Joseph Goldberger: Pellagra
    • Ingest/inject the biological fluids of pellagrins
    • Oral supplementation with cysteine and tryptophan were effective treatments
    • Still no animal model
    • Unsophisticated research
    • Nutrient deficiency can cause disease
  7. Pellagra: Animal Model
    • Dogs were fed a diet associated with humans afflicted with pellagra
    • Black tongue disease – the necrotic degeneration of the tongue
    • The identification of an animal model for pellagra led to further experimentation
  8. Pellagra
    • Yeast, wheat germ, liver prevented canine black tongue AND promoted recoveries in pellagra patients
    • The human pellagra and canine black tongue curative factor is heat stable
    • Can be separated from other B2 complex components
  9. Elvehjem
    • Isolated nicotinamide from liver extracts with high anti-black tongue activity
    • Nicotinamide and nicotinic acid cure canine black tongue
  10. Warburg & Christian
    • Isolated nicotinamide from hydrogen-transporting coenzymes I and II
    • Nicotinamide adenine dinucleotide
    • Nicotinamide adenine dinucleotide phosphate
  11. Sources of Niacin
    • Meats, poultry, fish
    • Legumes, peanuts, enriched flours and grain products
  12. Major Forms of Niacin in Uncooked Foods: Plants
    • Bran, cereals - niacin esterfied to complex carbohydrates (niacytin)
    • Niacin esterfied to peptides (niacinogens)
    • Esterfied niacin is not readily bioavailable
  13. Yucatan Peninsula
    • Tradition in food preparation - treated their corn with lime water - released bound niacin
    • Consumption of coffee - roasting green coffee converts trigonelline to niacin
  14. NAD
    • Synthesized in the liver from tryptophan
    • 2.75% of tryptophan is metabolized to nicotinic acid mononucleotide
    • Converted to serotonin, melatonin, CO2 and H2O
    • The rest is converted to quinolinate NAD(P)
  15. Niacin RDA
    • NE (niacin equivalent)
    • 60 mg tryptophan = 1 mg niacin
    • 1 NE = 1 mg niacin = 60 mg tryptophan
    • Proteins average ~1% tryptophan
    • A diet consisting of 100g protein/d could provide 16 mg NE
    • Adult females - 14 mg NE
    • Adult males - 16 mg NE
  16. NAD Synthesis
    Impaired by diets deficient in vitamin B6, riboflavin 
  17. Niacin Digestion Intestine: Extracellular
    • Removing phosphates 
    • NAD or NADP -nonspecific pyrophosphatases> NMN -alkaline phosphatase> nicotinamide riboside -slow release> nicotinamide
  18. Niacin Digestion Intestine: Intracellular
    NAD or NADP -glycohydrolase> nicotinamide
  19. Nicotinamide Absorption
    • Occurs primarily in the small intestine
    • Sodium-dependent, saturable process
    • Passive diffusion at higher non-physiological concentrations
  20. Nicotonic Acid Absorption
    • Occurs primarily in the small intestine
    • Temperature & energy dependent
    • Na+ - independent
    • Dependent on extracellular pH
  21. Niacin Uptake
    • By facilitated and simple diffusion
    • In RBCs, an anion transport protein is involved in facilitated diffusion
  22. Niacin in Cells: 2 Pathways
    • Preiss-Handler pathway
    • Dietrich pathway
  23. Preiss-Handler Pathway
    • NAD de novo pathway
    • Tryptophan -> NAD
    • Nicotinic acid -> NAD
    • Occurs primarily in the RBCs of liver
  24. Dietrich Pathway
    • NAD salvage pathway
    • Nicotinamide -> NAD
    • Phosphoribosyl transferase= rate limiting enzyme
    • Much simpler
    • NAD inhibits nicotinamide phosphoribosyl transferase 
  25. Hydrolysis of Nicotinamide
    Nicotinamide -nicotinamidase H2O> nicotonic acid -> preiss-handler pathway
  26. Catabolism & Excretion
    • Nicotinic acid and nicotinamide are reabsorbed by the kidney
    • Metabolites are excreted in the urine
  27. Niacin Functions
    • Participates in oxidation/reduction reactions
    • Coenzymes will be dehydrogenase/reductase
    • NAD and NADP are parts of the intracellular respiratory mechanism
    • Posttranslational modification of proteins
    • -ADP-ribosylation of proteins
  28. NAD-Dependent Enzymes: Catabolic Reactions
    • Beta-oxidation of fatty acyl CoAs
    • Oxidation of ketone bodies
    • Degradation of carbohydrates
    • Amino acid catabolism
  29. NAD-Dependent Enzymes: Biosynthetic Reactions
    • Reducing agent for steroid synthesis
    • Reducing agent for fat synthesis
  30. Niacin Deficiency
    • Produces pellagra - dermatitis, dementia, diarrhea, death
    • An antituberculosis drug (isoniazid) binds to pyridoxal phosphate (B6), reducing the activity of kynureninase
    • Zinc deficiency affects pyridoxal phosphate synthesis
  31. Hartnup Disease
    • Impaired tryptophan absorption (affecting niacin synthesis)
    • Hyperaminoaciduria
    • Pellagra
    • Neurological changes
    • Unabsorbed tryptophan is degraded in the intestine by microbial tryptophanase to pyruvate and indole
    • Indole is a neurotoxin
  32. Schizophrenia
    • Failure to provide sufficient NAD to critical areas of the brain
    • Nicotinamide oxidation is increased
    • Greater excretion of metabolic products
    • Responsive to 1g/d niacin
  33. Niacin: Hereditary Disorders
    • Hartnup disease
    • Schizophrenia
  34. Niacin: Pharmacy Uses
    • 1g nicotinic acid 3x per day has been used to treat hypercholesterolemia and hyperlipidemia.
    • Inhibits lipolysis in adipose tissue
    • Inhibits LDL synthesis in the liver
    • Lowers total serum cholesterol, lowers LDL, increases HDL
  35. Nicotinamide: Clinical Depression
    • Used with tryptophan - enhances the effect of tryptophan supporting brain serotonin levels
    • Reduces urinary excretion of tryptophan metabolites
  36. Nicotinamide: Diabetes
    • Reduced the risk of developing insulin-dependent diabetes in high-risk subjects
    • Reduced loss of pancreatic beta cell function
  37. Niacin Toxicity
    • Release of histamine and flushing
    • Working via prostaglandin synthesis
    • Liver injury
    • Increased uric acid levels (niacin competes with uric acid for excretion)
    • Itching
    • Elevation of plasma glucose levels
  38. Nicotinamide Toxicity
    No toxic effects, but does not reduce blood lipids
  39. Assessment of Nutriture: Niacin
    • Measurement of urinary N’ methyl nicotinamide (mg/g creatinine) following a 50 mg test dose of nicotinamide
    • Measured during a period 4 to 5 hr after the test dose
    • Deficient= <0.5 mg/g creatinine
    • Marginal= 0.5 to 1.59 mg/g creatinine
    • Adequate= >1.6 mg/g creatinine
  40. Pellagra
    • Dermatitis, dementia, diarrhea, death
    • Begins with sunburn-type symptoms on face, neck, extremities
    • Neurological symptoms include peripheral neuritis, paralysis of extremities, dementia or delirium
    • GI symptoms include glossitis, cheilosis, nausea, vomiting, diarrhea
  41. Niacin EAR
    • Based on N-methyl-nicotinamide excretion in urine
    • 12-16 mg NE/d - minimal level for metabolite excretion
    • 11 mg NE/d - prevents pellagra
    • 1 mg/day - urinary excretion level that represents barely adequate niacin intake but above the intake that results in clinical deficiency
  42. Niacin EAR: Pregnancy
    • Increased energy utilization and growth of maternal and fetal compartments
    • Increase of 3 mg NE/d
    • 3 mg NE + 11 mg NE (EAR)
    • For the RDA, a CV of 15% is used
    • 18 mg NE/d
  43. Niacin EAR & RDA: Lactation
    • 2.4 mg NE + 11 mg NE (EAR)
    • 1.4mg preformed niacin secreted + 1 mg to cover energy expenditure
    • 15% CV is used to determine the RDA
    • 17mg NE/d
  44. Niacin: Upper Limits
    • No adverse effects - niacin in foods
    • Adverse effects from supplementation, fortified foods, pharmacological doses
    • Flushing - burning, tingling, itching sensation on face, arms, chest
    • 30 to 1,000 mg/day within 30 min to 6 days after initial dose
    • Nicotinamide does not produce flushing
    • Caused by rapid rise in plasma concentrations
    • Reduced when taken with food
  45. Adverse Effects of Niacin
    • Hepatotoxicity - associated with 3-9 g/day doses
    • -Levels used to treat hypercholesterolemia
    • -Chronic doses - months to years
    • Impaired glucose tolerance -levels used to treat hypercholesterolemia
    • Ocular effects - 1.5 to 5 g/day
    • -Few cases in the literature
    • -Blurred vision, toxic amblyopia, macular edema, cystic maculopathy
    • -Reversible and dose-dependent
  46. Niacin: LOAEL
    • Flushing reactions - the patient changed the amount or form of niacin used, or withdrew from treatment
    • 50 mg/day in several studies
    • Uncertainty factor - 1.5
    • 50 mg/1.5 = 35 mg/day
  47. Scientific Theory
    • Plausible explanation for a set of observed phenomena
    • Acceptance relies on a preponderance of supporting evidence
    • Not necessarily proven, but there’s a huge amount of evidence used to develop
    • Won’t be tested
  48. Scientific Hypothesis
    • Tentative supposition that is assumed for the purposes of argument or testing
    • Used to generate evidence by which theories can be evaluated
  49. Empirical Approach
    • Involves the generation of theories strictly by observation
    • Observation of the natural world
    • Generation of ideas about how the natural world operates
  50. Experimental Approach
    • Involves the undertaking of experiments to test the truthfulness of hypotheses
    • Generation of hypotheses using these generalizations
    • Experimental testing of the hypotheses
    • 2 key tools were the animal model and purified diet
  51. Germ Theory
    • Discoveries in microbiology
    • Disease is caused by germs (anthrax, etc.)
    • Widely held for nutritional disease 
  52. 4 Diseases Associated with Diet
    • Scurvy-Vitamin C
    • Beriberi-Thiamin
    • Rickets-Vitamin D
    • Pellagra-Niacin
  53. Scurvy
    • Sore gums, painful joints, hemorrhages
    • Prevented by consuming green vegetables or fruits
    • Found in skeletal remains of primitive humans.
    • Fatal if untreated
    • Common in Northern Europe in Middle Ages
    • Sailors
    • Consume salt (preserved foods)
  54. Beriberi
    • Peripheral neuropathy, cardiac enlargement, edema
    • Described in ancient Chinese herbals 
    • Thought was caused by insufficient dietary protein, or by a relative excess of fat and carbs to protein
    • White (dehulled) rice
  55. Rickets
    • Deformation of long bones, swollen joints, enlarged heads
    • Associated with urbanization/industrialization
    • Growth plate is disrupted
    • There’s not the appropriate deposition of calcium in the growth plate
    • Northern latitudes (low sunlight)
    • Cod liver oil (Baltic and North sea coasts)
    • Consume few 'good fats'
  56. Night Blindness
    • Disease associated with diet
    • Recognized by ancient Greek, Roman, Arab physicians
    • Treated with animal liver
  57. Scientific Research: Repeatability
    • Natural truths are considered to be constant
    • Purified diet
  58. Repeatability: Purified Diet
    • Highly refined ingredients
    • –Isolated proteins
    • –Refined sugars/starches
    • –Refined fats
    • Known chemical composition
    • Prepared repeatedly by different investigators to yield comparable results
  59. Scientific Research: Relevance
    • Testing a hypothesis in the context of the ‘real world’
    • Use of a representation of that context
    • –A model
    • If you create the deficiency, you should have the similar effect as if treating it
    • –Must be analogous to situations that cannot be studied directly
  60. Animal Models
    • Appropriate to the diseases of interest
    • Initially discovered by chance
    • Lead ultimately to the discovery of all the vitamins and their roles in metabolism
    • Allows for investigations that are otherwise impossible or unthinkable in humans
  61. Nutrition as Science
    • Recognition that certain diseases are related to diet
    • Development of appropriate animal models
    • Use of defined diets
  62. Christian Eijkman
    • Dutch East Indies (Jakarta, Indonesia)
    • Determine the cause of beriberi
    • Expected to find a bacterium
    • Observation – one day the chickens were too weak to stand
    • -Continued for 5 months
    • -Similar to symptoms of human patients with beriberi
    • -Suddenly disappeared
    • Polyneuritis within days of feeding polished rice
    • Signs disappear following feeding of unpolished rice
    • Beriberi was extractable with water or alcohol, dialyzable, easily destroyed with moist heat
  63. Lunnin
    • Feed animals purified diets alone – no survival
    • Add milk to synthetic diet – mice survive
  64. Fredwick Hopkins
    • Discovered - accessory growth factors; glutathione, tryptophan
    • Independent of appetite
    • Biologically active in very small amounts
  65. Independently Developed Lines of Inquiry
    • The study of substances that prevent deficiency diseases
    • The study of accessory factors required by animals fed purified diets
  66. Antipolyneuritis Factor
    • Found in rice husks, was nitrogenous
    • An amine and vital (or pertained to life), he chose the term vitamine
  67. Funk's Vitamines
    • Antiberiberi
    • Antirickets
    • Antiscurvy
    • Antipellagra
  68. Vitamine Theory
    • Provided a new concept for interpreting diet-related phenomena
    • Provides a new intellectual construct
    • –Determining the causes of disease in no longer constrained by the germ theory
  69. Vitamine Accessory Factors
    • Fat-soluble factor A - extracted from certain foods with organic solvents
    • -Milk fat and egg yolk, not lard and olive oil
    • Water-soluble factor B - extractable with water
    • -Wheat, milk, egg yolk, not polished rice
  70. Antixerophthalmic Factor
    • Animals fed fat-free diet – ocular disorders
    • Ocular disorders prevented by feeding cod liver oil, butter, or fat-soluble A
  71. Water-Soluble Factor B
    • Normal growth in rats
    • Prevention of polyneuritis in chicks
    • Thought to be identical or contain Funk’s antiberiberi vitamine
    • Prevents beriberi and pellagra
    • Antipolyneuritis factor lost with heating
  72. Isolation of Heat-Labile Factor
    • Aneurin = thiamin +
    • -Thought to be a single vitamin but was several B vitamins
    • Animal model – the rice bird
  73. Rice Bird Bioassay
    • 2 g polished rice/d
    • Polyneuritis evident within 9-13 days
    • Delay onset of symptoms
  74. Thiamin Diphosphate
    Coenzyme of thiamin
  75. Thiamin Food Sources
    • Unrefined cereal germs & whole grains
    • Enriched flours & grains
    • Meats, especially pork
    • Nuts, legumes
    • In nutritional supplements
    • –Thiamin hydrochloride
    • –Thiamin mononitrate salt
  76. Thiamin Stability in Foods
    • Stable at pH <7
    • Labile at neutral to alkaline conditions
    • –Cleaves methylene bridge
    • Heat labile
    • Easily oxidized
    • -Forms disulfides & thiochrome
  77. Thiocrome
    • Oxidized thiamin
    • UV-induced blue fluoresence used to measure thiamin levels in biochemical assays
  78. Thiamin Exposure to Sulfite
    • Rupture of methylene bridge
    • Foods preserved with sulfur dioxide
    • Found in preservative foods that have antimicrobial properties
  79. Thiamin Antagonists
    • Sulfites
    • -Intestinal bacteria convert (reduce) sulfates to sulfite
    • Thiaminases
    • Chastak paralysis
    • Hydroxypolyphenols
  80. Thiamin Antagonist: Thiaminases
    • Bacterial
    • -Exoenzymes
    • –Cell surface
    • -Also in ruminants
    • -Fish/shellfish breaks
    • -Heat-labile
  81. Thiamin Antagonist: Chastak Paralysis
    • Neurological disorder in commercially raised foxes fed raw carp
    • Remedy – cook the fish before feeding
  82. Thiamin Antagonist: Hydroxypolyphenols
    • Coffee, tea, blueberries, Brussels sprouts, etc.
    • Oxidize the thiazole ring
    • -Formation of thiamin disulfide – not bioavailable
  83. Thiamin Absorption
    • In plants, thiamin exists in free form
    • In animals, >95% is phosphorylated
    • –Thiamin pyrophosphate (TPP)
    • –Coenzyme form
  84. Thiamin: Carrier Mediated Uptake
    • High affinity thiamin transporter
    • SLC19A2
    • In the intestine
  85. SLC19A2
    • Thiamin transporter expression
    • Liver, stomach, duodenum, jejunum > ileum, colon
  86. Thiamin Responsive Megaloblastic Anemia
    • Rare
    • Mutations in SLC19A2
    • Don’t get uptake of thiamin?
    • Rogers Syndrome
    • Autosomal recessive mutation
    • Thiamin deficiency
    • Sensorineural deafness
    • Diabetes mellitus
    • Cardiomyopathy 
    • Optic nerve atrophy
    • Retinal atrophy
    • High doses of thiamin reverse anemia and diabetes
  87. Thiamin Transport
    • In portal circulation - free thiamin
    • Most thiamin in blood is in cells (~90%)
    • –Uptake by facilitated diffusion
    • –Within red cells, thiamin is phosphorylated – TPP
    • --Metabolic tracking
  88. Thiamin Uptake
    • Cell types have different transport capacity for thiamin
    • High in hepatocytes, enterocytes
    • Lower in erythrocytes
    • Number or efficiency of transporter differs among the type of tissue
  89. Thiamin Storage
    • The body contains ~30 mg
    • Most in the body is in skeletal muscles (~50%)
    • –Other organs include heart, liver, kidney, brain
    • No real storage site
  90. Intracellular Thiamin
    • Thiamin + ATP -thiaminokinase> TPP + AMP
    • TPP + AMP -TDP/ATP phosphoryl transferase> TTP + ADP
    • TTP -thiamin triphosphatase> TPP
    • 80% of total thiamin in the body is TPP
  91. Thiamin Metabolism
    • Excess is metabolized for urinary excretion
    • Cleavage of methylene bridge
    • –Form the pyrimidine ring and thiazole
    • --Further metabolized- 20 or more metabolites are formed
  92. Thiamin Functions
    • Catalyze the oxidative decarboxylation
    • Transketolations
    • Nerve function
    • TPP-dependent decarboxylases
    • –Multienzyme complexes with FAD and NAD
  93. Thiamin: Catalyze the Oxidative Decarboxylation
    • Pyruvate to acetyl CoA
    • α-ketoglutarate to succinyl CoA
    • α-keto acids from branched-chained amino acids to their acyl CoAs
    • Branched chain amino acids -> valine, leucine, isoleucine 
  94. Thiamin: Transketolations
    • Hexose monophosphate shunt
    • Transketolase
  95. Thiamin: Nerve Function
    • Electrical stimulation -> TPP and TTP released from axonal membranes
    • Found in mammalian brain, synaptosomal membranes
    • Pyrithiamin (antagonist) changes electrical activity
    • GABA shunt
  96. Thiamin: Nerve Function: GABA Shunt
    • Increased in brains during thiamin deficiency
    • A source of energy during thiamin deficiency
    • Thiamin deficiency induces recovery pathway to maintain energy -> GABA shunt
    • Increased GABA in hypothalamus causes anorexia
    • –A characteristic of thiamin deficiency
  97. Thiamin Deficiency
    • Don’t have TPP
    • Independent decarboxylation to form GABA
    • a-ketoglutamate -transamination> glutamate -decarboxylation> GABA
    • Beriberi
    • Wernicke-Korsakoff syndrome
  98. Thiamin: Nerve Function: No Metabolic Roles
    • Catalytic activity in Na+ permeability
    • Maintains negative charge on the inner surface of the membrane
  99. Dry BeriBeri
    • Muscle wasting
    • Atrophy of the legs with peripheral neuritis
    • Usually no cardiac involvement
    • Inactivity
    • Caloric restriction
    • Paralytic or nervous
    • Histology – degeneration of myelin in the muscular sheaths -> but without inflammation
    • Generally occurs in physically inactive patients when caloric intake is poor
  100. Wet BeriBeri
    • Edema
    • Cardiac hypertrophy
    • Lung congestion
    • Cardiac involvement
  101. Wet Beriberi Stages
    • 1. Peripheral vasodilation
    • 2. Edema
    • 3. Myocardial injury
  102. Wet Beriberi: Peripheral Vasodilation
    • High cardiac output
    • Renal salt & water retention
    • Renin-angiotensin-aldosterone system in the kidneys
  103. Wet Beriberi: Edema
    • The kidneys detect a relative loss of volume and respond by conserving salt
    • With the salt retention, fluid is also absorbed into
    • the circulatory system
    • The resulting fluid overload leads to this` of the
    • dependent extremities
  104. Wet Beriberi: Myocardial Injury
    • Hypertrophy
    • Tachycardia
    • High arterial/venous BP
  105. Wernicke-Korsakoff Syndrome
    • Subclinical thiamin insufficiency
    • Associated with excessive alcohol consumption
    • 25% cured with thiamin supplementation
  106. Wernicke-Korsakoff Syndrome: Clinical Signs
    • Paralysis of motor nerves of the eye
    • Nystagmus - rhythmic oscillations of eyeballs
    • Ataxia – no muscular coordination
    • Psychosis
    • Confabulation - readiness to answer any question fluently with no regard to facts
    • Impaired retentive memory and cognitive function
  107. Disorder in Transketolase
    • Low binding  affinity for TPP
    • Can be overcome by high intramuscular doses of thiamin
  108. Alcohol & Thiamin
    • Intake antagonizes thaimin in 2 ways
    • -Diets low in thiamin
    • -Alcohol inhibits the intestinal ATPase involved in absorption
  109. Dietary Factors Affecting Thiamin
    • Large consumption of raw fish (thiaminases), polished rice
    • Antagonists- coffee, tea
    • Alcohol
  110. Thiamin: EAR/RDA
    • Selected indicators
    • -Urinary thiamin excretion
    • -Erythrocyte transketolase activity
    • -Erythrocyte thiamin
    • –None of these indicators, by themselves, were used to estimate the thiamin requirement
  111. DRI Indicators for Thiamin
    • Erythrocyte transketolase activity 16-20%
    • -Deficiency <20%
    • Erythrocyte thiamin 70-90
    • -Deficiency >70
    • Urinary thiamin (creatine) 27-66
    • -Deficiency <27
    • Urinary thiamin 40-100
    • -Deficiency <40
  112. Erythrocyte Transketolase Activity Assay: Red Blood Cells
    • Lack mitochondria
    • No alternative means of generating NADPH
    • –Pentose phosphate pathway
    • NADPH is required to reduce glutathione
    • –Maintains the normal structure of red blood cell
    • –Maintains hemoglobin in the ferrous state
    • Transketolase is a thiamine pyrophosphate-requiring enzyme, which catalyzes reactions in the pentose phosphate pathway
    • -The level of transketolase activity in the red blood cell is a reliable diagnostic indicator of thiamine status
  113. Erythrocyte Transketolase Activity Assay: Sample of Hemolyzed Blood
    • Incubate with excess ribose 5-phosphate (or xylulose 5-phosphate)
    • Excess added thiamine pyrophosphate
    • Control that has no added TPP
  114. Erythrocyte Transketolase Activity Assay
    • Measure the amount of substrate remaining and the amount of product formed
    • -Use high performance liquid chromatography (HPLC), and a UV absorbance detector
    • Enhanced enzyme activity resulting from the added thiamine pyrophosphate
    • -The sample was originally deficient in thiamine
    • -The extent of deficiency in thiamine is expressed in percent stimulation over the control value
  115. Thiamin DRI
    • EAR - 1.0 mg/d (men) and 0.9 mg/d (women)
    • RDA - 1.2 mg/d (men) and 1.1 mg/d (women)
    • –Based on a CV of 10% because of lack of data to use the standard deviation
  116. Vitamin B2-Riboflavin
    • Contained niacin, riboflavin and others
    • Heat stable vs heat labile
    • Water soluble
    • Rat growth factor
    • Isolated from liver, kidney, muscle, yeast
  117. Kaiser Wilhelm Institute
    • Rats were fed a thiamin-supplemented diet
    • –Exhibited growth failure
    • When fed a thiamin-free extract – thrived
    • –From yeast, liver, rice bran
    • –Each extract exhibited a yellow-green fluorescence
    • –Effect on growth was proportional to the intensity of fluorescence
    • Isolated the fluorescence factor from egg white and from whey
    • –Called it ovoflavin (egg)
    • –Called lactoflavin (whey)
  118. Riboflavin Food Sources
    • ~70% is in the coenzyme form flavin adenine dinucleotide (FAD)
    • In milk & eggs large amounts
    • ~30% of the adult RDA is supplied by milk & dairy products
    • Meats, especially liver, and green vegetables
    • Enriched flour & breakfast cereals
  119. Riboflavin Digestion
    • Gastric acidification/proteolysis release flavocoenzymes
    • In upper small intestine, pyrophosphatases & alkaline phosphatase remove phosphate
  120. Riboflavin Absorption
    • High affinity riboflavin transporter
    • RTF1, RTF2, RTF3
    • RFT1 & RTF2 – intestinal, placenta (RTF1), testes (RTF2)
    • RTF3 – brain
    • Concentrations <12 nM
    • -Above= diffusion
    • Saturable 
    • Active
    • Sodium-dependent
  121. Riboflavin Absorption
    • Bile salts facilitate uptake
    • A small amount is absorbed from the large intestine
  122. Riboflavin Transport
    • Albumin is the primary transport protein
    • Other transport proteins include fibrinogen, immunoglobulins
    • Estrogen-induced riboflavin-binding proteins for fetal uptake
  123. Riboflavin Tissue Uptake
    • Metabolic Trapping
    • -Riboflavin -ATP Zn2+ flavokinase> FMN
    • FAD is formed fron FMN
    • FMN-ATP Mg2+ FAD synthetase> FAD
  124. Riboflavin Functions
    • Oxidation/reduction reactions
    • Energy production by the respiratory chain
    • Protect cells from oxidative stress
    • –Glutathione reductase
    • –Methemoglobin reductases
    • Ionic & hydrophobic interactions bind flavin coenzymes to proteins
    • –Non-covalent interactions
  125. Riboflavin Functions: Covalent Flavoproteins
    • 8-α-N(3)-histidyl(peptide)-FAD
    • 8-α-S-cysteinyl(peptide)-FAD
    • Cannot resynthesize FMN or FAD
    • Not nutritional sources for riboflavin
  126. 8-α-N(3)-histidyl(peptide)-FAD
    • Succinate dehydrogenase
    • Sarcosine dehydrogenase
    • N,N-dimethylglycine dehydrogenase
  127. 8-α-S-cysteinyl(peptide)-FAD
    Monoamine oxidase
  128. Riboflavin Genetic Disorders
    • Multiple acyl-CoA dehydrogenase disorder (MADD)
    • Methylene THF reductase –  C677T
  129. MADD
    • FAD-dependent
    • Catalyze the 1st step in β-oxidation of fatty acids
    • Transfers electrons from oxidized fatty acids to the electron transfer protein complex
    • ETFα, ETFβ, ETF dehydrogenase
    • … to ubiquinone oxidoreductases
    • Major source of energy for heart, skeletal muscle, liver
    • Mutations in ETF
    • –Less stable; reduced half-life
  130. Riboflavin: MADD
    • Phenotype- neonatal cardiac defects and hepatic failure to adolescent myopathies
    • Null mutation- most severe
    • Missense mutations- responsive to riboflavin supplementation (sometimes)
    • –100 mg/d + carnitine
  131. MTHFR
    • CVD, neural tube defects, Downs syndrome, congenital cardiac malformations, dementia
    • Located in the FAD binding domain
    • Decreased FAD binding; decreased enzyme activity
    • Riboflavin supplementation increases enzyme stability
  132. Riboflavin Metabolism & Excretion
    • The primary urinary metabolite- 60-70%
    • Secretion in milk
    • –Reason for milk being a major food source
    • –Riboflavin is the highest (~50%); FAD (33%)
    • –10-(2’-hydroxyethyl) flavin 
    • –7-hydroxymethyl riboflavin
  133. Riboflavin
    • Light sensitive
    • Lumichrome & lumiflavin
    • Light-excited flavin oxidizes nucleic acid bases of bacterial and viral pathogens
  134. Riboflavin Deficiency
    • Cheilosis- vertical fissuring, redness, swelling & ulceration of the lips
    • Similar skin lesions with B6 deficiency
    • -Impaired collagen formation
    • -Decreased activity of pyridoxine 5’-phosphate oxidase
    • --•Requires FMN
    • --•Converts PMP to PLP
    • May reduce synthesis of niacin from tryptophan
  135. Riboflavin Deficiency: Clinical Symptoms
    • Eborrheic dermatitis
    • Soreness and burning of lips, mouth, tongue
    • Photophobia
    • Burning, itching eyes
    • Superficial vascularization of cornea
    • Cheilosis, angular stomatitis, glossitis, anemia, neuropathy
  136. Riboflavin Defciency: Populations at Risk
    • Reduced dietary intake
    • Congenital heart disease
    • Cancer
    • Excessive alcohol intake
    • Increased excretion - diabetes mellitus.
    • Amish newborns – hyperbilirubinemia
    • -Treated with phototherapy
  137. Riboflavin: Beneficial Deficiency
    • Decreases protection from oxidative stress - malaria
    • Plasmodial growth causes oxidative stress
    • Riboflavin-deficient erythrocytes are susceptible to lipid peroxidation- lyse before the trophozoites mature
  138. Riboflavin: Indicators of Nutriture
    • Erythrocyte glutathione reductase
    • Erythrocyte flavin 
    • Urinary excretion of riboflavin
  139. Riboflavin: Erythrocyte Glutathione Reductase
    • Activity coefficient- ratio of activity in the presence and absence of added FAD
    • < 1.2 = acceptable
    • 1.2 to 1.4 = low
    • > 1.4 = deficient
  140. Riboflavin: Erythrocyte Flavin
    • Measure riboflavin
    • > 400 nmol/L cells = adequate
    • < 270 nmol/L cells = deficient
  141. Riboflavin: Urinary Excretion of Riboflavin
    • Low = 50 to 72 nmol/g creatinine
    • Deficient = <50 nmol/g creatinine
    • Sufficient intake is 1.1 mg/d
  142. Riboflavin: EAR & RDA
    • EAR - clinical deficiency and biochemical values relative to intake
    • Men = 1.1 mg/d; women = 0.9 mg/d
    • RDA - set by using a CV of 10%
    • Men = 1.3 mg/d; women = 1.1 mg/d
  143. Riboflavin: Pregnancy
    0.3 mg/d added to adult EAR
  144. Riboflavin: Lactation
    • 0.3 mg/d is transferred to the milk
    • 70% efficiency of riboflavin usage in milk
    • 0.4 mg/d is added to the EAR
  145. Riboflavin: Tolerable Upper Intake Levels
    • No reported adverse effects from riboflavin consumption
    • Up to 400 mg/d with meals for 3 months
    • Limited capacity for absorption, rapid excretion
    • -Max absorbed from a single dose is 27 mg
    • -Oral riboflavin is used as a fecal marker in clinical studies
    • No UL has been set
  146. Biotin Food Sources
    • Liver
    • Soybeans
    • Egg yolk
    • Cereals
    • Legumes
    • Nuts
    • Protein bound
    • -Biocytin or biotinyllysine
    • Also produced by colonic bacteria
    • -Can get a small amount
    • Avidin
  147. Biotin: Avidin
    • Glycoprotein in raw eggs
    • Binds irreversibly to biotin
    • Heat labile
    • Can be used to follow certain molecules around
    • Used to bind to cell surfaces
  148. Biotin Digestion
    • Requires proteolytic digestion
    • Yields free biotin, biocytin, biotinyl peptides
    • Biotinidase functions on the intestinal brush border
    • Will cleave the lyicine and remove 
  149. Biotin Absorption
    • Primarily from small intestine
    • -Duodenum > jejunum > ileum
    • Some absorption from the proximal & midtransverse colon
    • Na+-dependent multivitamin transporter
  150. Biocytin
    • Absorbed in the small intestine by passive diffusion
    • Slower than biotin/Na+-dependent multivitamin transporter
  151. Biotin Transport
    • Free (80%) or protein-bound biotin in plasma
    • Albumin
    • α- & β-globulins
    • Plasma biotinidase
  152. Biotin Storage
    A small amount is stored in muscle, liver, brain
  153. Biotin Tissue Uptake
    • Na+-dependent multivitamin transporter
    • Actively transported across the blood-brain barrier
    • 2.5-times the plasma concentration
    • Renal reabsorption
  154. Biotin Functions
    • Activated biotin - biotinyladenylate
    • -Activated in order for it to bind to carboxylated enzymes
    • Biotin-dependent enzymes - carboxylases 
    • -Substrate picks up CO2 to produce a carboxylated product
  155. Biotin Functions: Carboxylases
    • Acetyl CoA carboxylase
    • Pyruvate carboxylase
    • Propionyl CoA carboxylase
    • β-methylcrotonyl CoA carboxylase
  156. Biotin: Acetyl CoA Carboxylase
    • Forms malonyl CoA from acetate
    • Commits acetate units to fatty acid synthesis
  157. Biotin: Genetic Disorders
    • Holocarboxylase synthetase deficiency
    • Biotinidase deficiency
  158. Biotin: Acetyl CoA Carboxylase Activation
    • Citrate increases polymerization
    • CoA lowers the Km for acetyl CoA
    • High insulin:glucagon favors dephosphorylation
    • The substrate for the formation of malonyl CoA 
    • Increase insulin will activate enzyme
  159. Biotin: Acetyl CoA Carboxylase Inhibition
    • Products of fatty acid synthesis depolymerize
    • Will cause the dissociation of units
    • Low insulin:glucagon favors phosphorylation (inactivates)
  160. Biotin: Pyruvate Carboxylase
    • Converts pyruvate to oxaloacetate
    • Replenishes OAA for Krebs cycle necessary for gluconeogenesis
    • Role in maintaining OAA and other intermediates for energy metabolism
    • Anaplerosis
    • Activated by pyruvate and acetyl CoA 
    • Increased in the liver due to diabetes and hyperthyroidism
  161. Anaplerosis
    Replenishmentof intermediates in a metabolic cycle that may be depleted by removal from the cycle
  162. Biotin: Pyruvate Carboxylase Genetic Deficiency
    • Accumulation of pyruvate
    • Elevated lactate in blood
    • Elevated alanine in bood
    • Transamination
    • A form
    • B form
  163. Pyruvate Carboxylase Genetic Deficiency: A Form
    • Presents postpartum (months)
    • Mild to moderate psychomotor retardation, lactic acidemia
    • Causes severe mental retardation
    • Most die within first few years
    • Majority of cases in Algonkian linguistic group of Native Americans
  164. Pyruvate Carboxylase Genetic Disorder Deficiency: B Form
    • Presents postpartum
    • Severe lactic acidemia, elevated blood ammonium
    • Death within 3 months
  165. Biotin: Propionyl CoA Carboxylase
    • Converts propionate to succinate
    • Provides mechanism for metabolism of some amino acids and odd-numbered chain fatty acids
    • Succinate formed enters Krebs cycle
    • Formation of methymalonyl CoA will ulitmately form succinyl CoA and enter the citric acid cycle
    • Enzyme activity not regulated by substrate/product
    • Not altered by dietary or hormonal changes
  166. Propionyl CoA Carboxylase: Genetic Diseases
    • Propionic acidemia
    • Severe ketosis
    • Metabolic acidosis
    • Neurological complications
    • -Seizures
    • -Developmental delay
    • -EEG abnormalities
    • Elevated causes elevation of other metabolites
    • Causes loss of carnitine
    • In equilibrium with propionylcarnitine (excreted in urine)
    • Elevated blood ammonium
  167. Propionyl CoA Carboxylase: Genetic Diseases Treatment
    • Exogenous Carnitine
    • -Bind to propionyl CoA
    • -Promote conversion of propionyl CoA to propionylcarnitine
    • -Facilitate excretion of propionate
    • Restriction of dietary protein
    • -Low levels of isoleucine, valine, methionine, threonine
  168. Biotin: β-methylcrotonyl CoA Carboxylase
    • Converts β-methylcrotonyl CoA to β-methylglutaconyl CoA
    • Allows catabolism of leucine and certain isoprenoid compounds
    • Not regulated by dietary or hormonal factors
  169. β-methylcrotonyl CoA Carboxylase: Genetic Diseases
    • Elevated methylcrotonyl CoA
    • Severe metabolic acidosis
    • Low plasma glucose
    • Low plasma carnitine
    • Treated with carnitine 
    • Moderate restriction of dietary protein
  170. Holocarboxylase Synthetase Deficiency
    • Single gene defect affects all 4 carboxylases
    • Elevated Km for biotin
    • Have lower biotin affinity
    • Treated with biotin supplementation
    • Diagnosed prenatally
    • Treated in utero with 10 mg biotin per day
  171. Biotinidase Deficiency
    • 1 in 112,000 births
    • Wide variability of symptoms
    • Responsible for cleavage
  172. Biotinidase Deficiency Symptoms
    • Present weeks to years after birth
    • Skin rash
    • Hair loss
    • Seizures
    • Hypotonia
    • Ataxia- problem with balance
    • Developmental delay
    • Hearing loss
    • Optic atrophy
    • Sufficient biotin to fully biotinylate carboxylases in utero
  173. Biotinidase Deficiency Symptoms: Age Range
    • Due to:
    • Differences in dietary free biotin
    • Residual biotinidase activity
  174. Biotinidase Deficiency Treatment
    • 10 mg biotin per day
    • Amelioration/correction of symptoms
    • -Metabolic acidosis
    • -Skin rash
    • -Regrowth of hair
    • -Development
    • No effects on hearing loss and optic atrophy
  175. Biotin Metabolism & Excretion
    • Proteolytic catabolism of biotin holoenzymes or holocarboxylases yields biocytin
    • -Biocytin is degraded by biotinidase to yield biotin
    • -β-oxidation of the valeric side chain yields bisnorbiotin
    • Excretion occurs in the urine
    • Free biotin may be reabsorbed by the kidney
    • Unabsorbed biotin is excreted in the feces
  176. Excretion: Urinary Metabolites
    • Bisnorbiotin (major metabolite)
    • Biotin sulfoxide
    • Biotin sulfone
    • Biocytin
    • All lack side chains
  177. Biotin Deficiency Symptoms
    • Depression
    • Hallucinations
    • Muscle pain
    • Anorexia
    • Hair loss
    • Scaly dermatitis
  178. Biotin: Populations at Risk for Deficiency
    • Individuals eating raw eggs
    • Individuals with GI disorders
    • Inflammatory bowel disease
    • Achlorhydria
    • Excessive alcohol consumption
    • No toxicity reported
  179. Biotin: Assessment of Nutriture
    • Urinary biotin, bisnorbiotin and 3-hydroxyisovaleric acid
    • -Urinary biotin and bisnorbiotin decreases, and urinary hydroxyisovaleric acid increases with consumption of raw egg whites
    • Plasma biotin is not a sensitive indicator
  180. Biotin DRI
    • An Adequate Intake is established of 30 µg/d for adults 19 y & older
    • Inadequate data to suggest an EAR & RDA
    • No adverse effects
    • No UL established
  181. Pantothenic Acid Food Sources
    • Widely distributed in nature
    • Contained in its various forms
    • Coenzyme A
    • Coenzyme A esters
    • Acyl carrier protein
    • Supplemental form – calcium pantothenate
  182. Pantothenic Acid Digestion
    • 85% is in food as a component of coenzyme A (CoA)
    • Degraded to pantothenic acid for intestinal absorption
    • CoA, phosphopantetheine, dephospho-CoA cannot be absorbed
  183. Pantothenic Acid Absorption
    • Jejunum
    • Saturable Na+-dependent multivitamin transporter
    • Na+-electrochemical gradient
    • Pantetheine 
    • -Hydrolyzed in intestinal cells
  184. Pantothenic Acid Transport
    • Pantothenate in plasma, serum, & RBCs
    • Primarily in RBCs
    • Low concentration in plasma (0.06-0.08 mg/L)
    • May be the form available for tissue uptake
  185. Pantothenic Acid Tissue Uptake
    • Na+-dependent multivitamin transporter
    • Blood-brain barrier – saturable but not Na+-dependent
  186. Pantothenic Acid: CoA Synthesis
    • All biosynthetic enzymes reside in the cytosol
    • Most of CoA is in mitochondria
    • Pantothenate kinase
    • Fatty acid synthase ACP domain
  187. Pantothenic Acid: CoA Synthesis- Pantothenate Kinase
    • Pantothenate -> 4′-phosphopantothenate
    • Inhibited by intermediates and end products
    • 4’-phosphopantothenate, dephospho-CoA
    • CoA, acetyl-, propionyl-, malonyl-CoA
  188. Pantothenic Acid: CoA Synthesis- Fatty Acid Synthase ACP Domain
    • Covalent attachment of phosphopantetheine by a transferase
    • ACP hydrolase releases ACP from fatty acid synthase
  189. Pantothenic Acid: Function of Fatty Acid Synthesis
    • Regulated by malonyl CoA concentration
    • Regulated by activity of acetyl CoA carboxylase (biotin)
    • As malonyl CoA increases, it’ll affect this
  190. Pantothenic Acid: Function of Oxidative Decarboxylation
    • Pyruvate dehydrogenase
    • -TPP, NAD+, FAD+, CoA 
    • α-ketoglutarate dehydrogenase complex
  191. Pantothenic Acid: Oxidative Decarboxylation- α-Ketoglutarate Dehydrogenase Complex
    • Succinyl CoA and other acyl CoA
    • Catabolic pathways for amino acids
    • Glutamate, proline, arginine, histidine
  192. Pantothenic Acid: Oxidative Decarboxylation- Branched α-Ketoglutarate Dehydrogenase Complex
    • Valine, isoleucine, leucine
    • Form α-keto acids after transamination
    • Oxdatively decarboxylated
    • Form branched chain acyl CoA products
  193. Pantothenic Acid: Function of Fatty Acid β-Oxidation
    • Fatty acids CoA -> acetyl CoA
    • Carnitine palmitoyltransferase-I
    • Carnitine palmitoyltransferase-II
    • Sequential removal of 2-carbon segments as acetyl CoA
    • Controlled by rate of transport of fatty acids into mitochondria
  194. Pantothenic Acid: Fatty Acid Carnitine β-Oxidation: Palmitoyltransferase-I
    • Fatty acyl CoA -> acyl carnitine
    • On outer mitochondrial membrane
    • Inhibited by malonyl CoA
  195. Pantothenic Acid: Fatty Acid Carnitine β-Oxidation: Palmitoyltransferase-II
    • Regenerates fatty acyl CoA
    • On inner mitochondrial membrane
  196. Fatty Acid β-Oxidation: Starvation
    • Increased plasma free fatty acids 
    • Inhibits acetyl CoA carboxylase
    • Decreases malonyl CoA
    • Increases fatty acids into mitochondria
  197. Pantothenic Acid: Function of Ketone Bodies
    • Acetoacetate
    • 3-hydroxybutyrate
  198. Pantothenic Acid: Function of 3-hydroxy-3-methylgutaryl CoA
    • Isoprenoid
    • -Ubiquinone (coenzyme Q)
    • Dolichol (glycoprotein synthesis)
    • Cholesterol
    • Steroid hormones
    • Bile acids
    • Is going to be a substrate for many different products including cholesterol
  199. Pantothenic Acid: Protein Acetylation
    • Protection from proteolysis
    • Compartmentalization
  200. Pantothenic Acid Metabolism & Excretion
    • CoA is dephosphorylated; the final product is pantothenate
    • Pantothenate is excreted in the urine
    • Reflects dietary intake
    • Urinary excretion <1 mg/d - deficiency is suspected
    • -Thought to correspond to an intake of <4mg/d
  201. Pantothenic Acid Deficiency
    • Associated with severe malnutrition, impaired absorption
    • Abnormal skin sensations
    • Burning feet syndrome
    • Vomiting
    • Fatigue
    • Weakness
  202. Pantothenic Acid: Populations at Risk for Deficiency
    • Alcoholics (low intake)
    • Diabetes mellitus (increased excretion)
    • Inflammatory bowel disease (impaired absorption)
  203. Pantothenic Acid Toxicity
    • None reported to date
    • Intake of 100 mg may increase niacin excretion
    • Intake 20 g - mild intestinal stress & diarrhea
  204. Pantothenic Acid: Assessment of Nutriture
    • Plasma pantothenic acid concentrations <100 mg/dL reflects low pantothenate intakes
    • Urine pantothenate concentrations <1 mg/d is considered low
  205. Pantothenic Acid DRIs
    • Adequate Intake is 5 mg/d for adults 19 y & older
    • Not enough data to establish an estimated average requirement (EAR) or an RDA
    • AI’s were set for all age groups
    • No UL established
    • No reports of adverse effects from oral pantothenic acid

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