Gloanne C. Adolor, RPh, MD, FPCP, MSc, MBA

1. Metabolic Roles of VITAMINS AND MINERALS Gloanne C. Adolor, RPh, MD, FPCP, MSc, MBA

2. Objectives • To determine the role of selected vitamins and minerals in metabolism • To identify clinical abnormalities associated with vitamin/mineral excesses and deficiencies

3. Vitamins Organic nutrients that are required in small quantities in the diet and serve specialized functions in the body Water-soluble Fat-soluble

4. In 1912, Casimir Funk coined the term “vitamines” because these substances were required for life (“vita”) and contained nitrogen (“amine”). Future studies showed that not all vitamins contained nitrogen so the “e” was dropped. Background Information

6. Recommended Daily Allowances (RDAs) • Defines a dietary intake that is considered optimal under ordinary conditions • NOT a minimal requirement • Depends on sex, age, body weight, diet, and physiologic status • Increase during pregnancy and lactation

7. Classification of Vitamins

8. Thiamine or Vitamin B1 part of coenzyme thiamine pyrophosphate (TPP): needed for CHO metabolism part of thiamine diphosphate (TDP): needed for glucose oxidation and transketolation reactions (conversion of glucose to fat) helps maintain good appetite, good muscle tonus in GIT, normal nerve functioning

9. About 30mg are present in the body, 80% of this is in the form of TPP.

10. Aldehyde transfers Oxidative decarboxylation of alpha-ketoacids Transketolase reactions TPP-dependent reactions Cytoplasm Mitochondria

11. TPP-dependent catalytic mechanisms • Pyruvate dehydrogenase • Alpha-keto glutarate dehydrogenase • Branched-chain alpha-ketoacid dehydrogenase • Alpha-ketobutyrate dehydrogenase

13. TPP and PDH

16. In general, the major catabolic, energy-producing pathways are most dependent on TPP.

17. Thiamin or Vitamin B1 found in the intestinal lumen in its free form its phophoesters being completely hydrolyzed by different phosphatases mostly absorbed in the jejunum and ileum of the small intestine Adult male RDA = 1.2 mg

18. 1/2 within muscle tissue with much of the remainder in the heart, liver, kidneys and nervous tissue, including brain, which contains most of the triphosphate form excreted from the body as thiamin-acetic acid and as various other metabolites produced by its degradation Thiamin or Vitamin B1

19. Thiamin or Vitamin B1 Effects of Deficiency Early stage: loss of appetite, weakness, easily fatigued, GIT disturbances, poor reflexes, irritability, retarded growth, numbness in extremities Later stage: beriberi or nutritional polyneuritis: changes in GI, cardiovascular and nervous systems infantile beriberi: in infants 2-5 months whose main nourishment is milk from a mother with beri-beri

20. Thiamin or Vitamin B1 Types of Beri-beri (full-blown deficiency) Wet: aphonia (loss of voice), whining cry, cyanosis (bluish discoloration), difficulty of breathing, even death within a few hours Dry: edema of lower extremities which progresses to body cavities as abdomen and chest, enlarged heart, arryhthmias, breathing difficulty involves peripheral nerves: paresthesias

21. Thiamin or Vitamin B1 Effects of Deficiency Wernicke-Korsokoff or Wernicke’s Syndrome: seen in alcoholics and pregnant women with excessive vomiting: memory loss, mental deterioration, abnormal perception, loss of eye control, sudden heart failure if untreated Korsakoff psychosis, a severely debilatating anterograde amnesia,is the most common form of amnesia in most countries.

23. Dimethylisoaloxazine ring Sugar alcohol ribitol

24. Riboflavin or Vitamin B2 precursor of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) (prosthetic groups of the flavoproteins) ATP ADP ATP PPi FAD (oxidized form) FMN Riboflavin In the Respiratory Chain, FMN or FAD can transfer one or two electrons at a time; they accept hydrogen/electrons from NADH and donate it to the cytochromes.

26. Adult male RDA = 1.3mg/day Deficiency: Itchy eyes with burning sensation Glossitis (magenta tongue) Angular stomatitis Sore throat Seborrheic dermatitis of the scrotum and nose Normocytic normochromic anemia Riboflavin or Vitamin B2

28. In Infants… • Riboflavin deficiency can occur when receiving phototherapy for hyperbilirubinemia. • Riboflavin supplements are given routinely in this situation.

29. Niacin or Vitamin B3 • Generic term for the vitamin-active pyrimidine derivatives: • Nicotinic acid (Niacin) • Nicotinamide (niacinamide) • Present as a constituent of NAD and NADP

30. Acceptor of H+ and electrons: needed in energy metabolism (aerobic and anaeribic oxidation of glucose); fatty acid synthesis and oxidation; protein synthesis and catabolism Active coenzyme forms: nicotinamide adenine dinucleotide (NAD or Coenzyme I ), nicotinamide adenince dinucleotide phosphate (NADP or Coenzyme II) Niacin or Vitamin B3

33. This pathway is inefficient: 60mg tryptophan is required for the synthesis of 1 mg niacin

35. Adult male RDA = 16 niacin equivalents (NE) 1 NE = 1 mg niacin Deficiency Early stages: anorexia, lassitude, indigestion, skin changes, glossitis Later stages: pellagra: characterized by 4 D’s: dermatitis, dementia, diarrhea, death  dermatitis: bilateral dermatitis: blackish or dark scaly patches appearing symmetrically in area exposed to sunlight Niacin or Vitamin B3 Often associated with corn-based diet.

36. Niacin or Vitamin B3 Toxicity Occurs following or after administration of massive doses: hypermotility and acidity of stomach, paralysis of respiratory center, niacin rash (painful flush and rash)

37. Niacin lowers LDL Cholesterol and increases HDL Cholesterol

38. Niacin-Induced Flushing Pathway: 2 Separate Sites of Action V • 1. Epidermal Langerhans’ Cells • Niacin binds • PGD2 is produced and released • 2. Dermal Blood Vessels • PGD2 binds to DP1 • Vasodilation results • Artistic rendering. PGD2 = prostaglandin D2; DP1 = prostaglandin D2 receptor 1. Benyó Z et al. Mol Pharmacol. 2006;70:1844–1849; Morrow JD et al. J Invest Dermatol. 1992;98:812–815; Cheng K et al. Proc Natl Acad Sci USA. 2006;103:6682–6687; Pike NB et al. J Clin Invest. 2005;115:3400–3403.

39. Pyridoxine or Vitamin B6 Forms: Pyridoxal (aldehyde) Pyridoxamine (amine) Pyridoxal (alcohol) Total body content = 25 mg in adults

41. Pyridoxine or Vitamin B6 part of pyridoxal phosphate: amino acid metabolism: decarboxylation, transamination, dehydration, other amino acid transformations catalyzes urea production, synthesis of essential fatty acids, conversion of tryptophan to niacin

43. Adult male RDA = 1.3mg/day Deficiency rare in adults; induced under experimental conditions; nausea, vomiting, seborrheic or oily dermatitis, glossitis, conjunctivitis, depressive moods in infants: may occur if milk formula is deficient in this vitamin: irritability, poor growth, anemia, convulsions Pyridoxine or Vitamin B6

44. Neurologic derangements may result from impaired activity of the PLP-dependent enzyme glutamate decarboxylase (forms GABA) Sideroblastic anemia - microcytic, hypochromic anemia caused by reduced activity of the PLP-dependent aminolevulinic acid synthase in the bone marrow (heme biosynthesis) Pyridoxine or Vitamin B6

45. Vitamin B6 deficiency is most common in alcoholics.

46. Isoniazid and penicillamine can precipitate Vitamin B6 deficiency by reacting nonenzymatically with the aldehyde group of pyridoxal or pyridoxal phosphate (PLP)

47. Vitamin B6 is toxic in high doses Daily consumption of >500mg for several months leads to peripheral sensory neuropathy. Note: Used for treatment of Carpal Tunnel Syndrome

48. Cobalamin or Vitamin B12

49. Cobalamin or Vitamin B12 • Absorption of dietary B12 requires intrinsic factor - a 50-kD glycoprotein secreted by the parietal cells of the stomach

50. Only two reactions require cobalamin coenzymes in human tissues: 1. Cytoplasmic methylation of homocysteine to methionine requires methylcobalamin 2. Mitochondrial methylmalonyl-CoA mutase reaction requires deoxyadenosylcobalamin