Unit 5: Biochemistry of Vitamins

Unit 5: Biochemistry of Vitamins

Introduction to Vitamins

Vitamins are a group of organic compounds that are essential in small amounts for normal growth, metabolism, and physiological function. They cannot be synthesized by the human body in sufficient quantities (or at all) and must be obtained from the diet or supplements. Vitamins do not provide energy but act as essential cofactors in enzymatic reactions, hormones, or antioxidants.

Historical Perspective:

• The term "vitamine" was coined in 1912 by Casimir Funk (from "vital amine") as he isolated niacin (thought to contain an amine group).
• Later, when it was found that not all vitamins contain nitrogen, the "e" was dropped to become "vitamin."
• Discovery of vitamins occurred through studies of deficiency diseases: scurvy (vitamin C), beriberi (thiamine), rickets (vitamin D), pellagra (niacin).

General Characteristics of Vitamins:

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1. Classification of Vitamins

Vitamins are classified based on their solubility, which affects their absorption, transport, storage, and excretion.

1.1 Fat-Soluble Vitamins (A, D, E, K)

1.2 Water-Soluble Vitamins (B-Complex and Vitamin C)

Summary of Vitamin Classification:

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2. Fat-Soluble Vitamins

2.1 Vitamin A (Retinoids)

Structure:

• Vitamin A refers to a family of compounds with similar structure: retinol (alcohol), retinal (aldehyde), retinoic acid (acid), and retinyl esters (storage form).
• β-Carotene (provitamin A) is cleaved in intestine to yield two molecules of retinal.

Natural Sources:

• Preformed vitamin A (retinyl esters) : Liver, fish liver oils (cod liver oil), egg yolk, butter, whole milk, fortified dairy products
• Provitamin A carotenoids (β-carotene, α-carotene, β-cryptoxanthin) : Dark green leafy vegetables (spinach, kale), orange and yellow vegetables (carrots, sweet potatoes, pumpkin), orange fruits (mango, papaya, apricots)

Synthetic Sources:

• Retinyl palmitate, retinyl acetate (used in supplements and fortified foods)
• Isotretinoin (13-cis-retinoic acid) for acne
• Tretinoin (all-trans-retinoic acid) for acne and acute promyelocytic leukemia

Recommended Dietary Allowance (RDA) :

• Adult men: 900 μg RAE (retinol activity equivalents)/day
• Adult women: 700 μg RAE/day
• 1 μg RAE = 1 μg retinol = 12 μg β-carotene = 24 μg other provitamin A carotenoids

Metabolic Functions:

Physiological Role in Detail:

A. Visual Cycle:

• In rod cells, 11-cis-retinal is bound to opsin protein forming rhodopsin.
• Light absorption isomerizes 11-cis-retinal to all-trans-retinal → conformational change in opsin → activation of transducin (G protein) → signal cascade → nerve impulse.
• All-trans-retinal is reduced to all-trans-retinol, transported to retinal pigment epithelium, re-isomerized to 11-cis-retinol, oxidized to 11-cis-retinal, and returned to rod cells.

B. Gene Regulation:

• Retinoic acid enters nucleus, binds to retinoic acid receptors (RAR) and retinoid X receptors (RXR) as heterodimers.
• These bind to retinoic acid response elements (RARE) in DNA, regulating transcription of genes involved in differentiation, development, and apoptosis.

Deficiency:

At-risk populations: Children in developing countries (leading cause of preventable blindness), malabsorption syndromes (celiac, Crohn's, cystic fibrosis, pancreatic insufficiency), chronic liver disease, alcoholism.

Toxicity (Hypervitaminosis A) :

Carotenemia: Excessive β-carotene intake causes yellow-orange skin discoloration (especially palms and soles); benign, reversible.

Pharmacological Interactions with Drugs:

Pharmaceutical Importance:

• Treatment of vitamin A deficiency and xerophthalmia
• Isotretinoin for severe nodular acne
• Tretinoin (all-trans-retinoic acid) for acute promyelocytic leukemia (induces differentiation of leukemic cells)
• Topical retinoids (tretinoin, adapalene) for acne and photoaging
• β-Carotene supplements (controversial; may increase lung cancer risk in smokers)

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2.2 Vitamin D (Calciferol)

Structure:

• Vitamin D is a secosteroid (broken steroid ring). Two major forms:
  • Vitamin D₂ (ergocalciferol) : From plants, yeast (ergosterol irradiated with UV)
  • Vitamin D₃ (cholecalciferol) : Synthesized in skin from 7-dehydrocholesterol upon UVB exposure; also in animal sources

Natural Sources:

• Dietary: Fatty fish (salmon, mackerel, sardines), fish liver oils, egg yolk, beef liver, cheese, UV-exposed mushrooms
• Fortified foods: Milk, orange juice, cereals, margarine (in some countries)
• Endogenous synthesis: Skin exposure to sunlight (UVB, 290-315 nm) converts 7-dehydrocholesterol to previtamin D₃, which isomerizes to vitamin D₃

Synthetic Sources:

• Vitamin D₂ (ergocalciferol) and D₃ (cholecalciferol) supplements
• Calcitriol (1,25-dihydroxyvitamin D₃) for renal failure patients
• Calcipotriol (synthetic analog) for psoriasis

Recommended Dietary Allowance (RDA) :

• Adults 19-70 years: 600 IU (15 μg)/day
• Adults >70 years: 800 IU (20 μg)/day
• Upper level: 4000 IU (100 μg)/day

Metabolic Activation:

7-Dehydrocholesterol (skin)
        │ UVB
        ↓
Vitamin D₃ (cholecalciferol) ──┐ (dietary vitamin D₂/D₃)
                               │
                               ↓
                   Liver (25-hydroxylase, CYP2R1)
                               ↓
               25-Hydroxyvitamin D [25(OH)D] (major circulating form)
                               │
                   Kidney (1α-hydroxylase, CYP27B1)
                    (stimulated by PTH, low Ca, low phosphate)
                               ↓
               1,25-Dihydroxyvitamin D [1,25(OH)₂D] (calcitriol) – active form

• Renal 1α-hydroxylase is tightly regulated.
• 24-Hydroxylase (CYP24A1) inactivates both 25(OH)D and 1,25(OH)₂D to calcitroic acid.

Metabolic Functions:

Physiological Role in Detail:

A. Calcium and Phosphate Homeostasis:

• Intestine: 1,25(OH)₂D binds to VDR in enterocytes, increases expression of TRPV6 (calcium channel), calbindin (calcium-binding protein), and PMCA1b (calcium ATPase) → increased calcium absorption. Also increases phosphate absorption via NaPi-IIb.
• Bone: 1,25(OH)₂D with PTH stimulates osteoclast differentiation (via RANKL on osteoblasts) → bone resorption → release of calcium and phosphate.
• Kidney: Increases calcium reabsorption in distal tubules; increases phosphate reabsorption (but PTH opposes this, net effect increased phosphate excretion with high PTH).

B. Parathyroid Hormone (PTH) Regulation:

• Low serum calcium → increased PTH → increased 1α-hydroxylase → increased 1,25(OH)₂D → increased calcium absorption and bone resorption.
• 1,25(OH)₂D feeds back to inhibit PTH synthesis.

Deficiency:

At-risk populations: Elderly (reduced skin synthesis, dietary intake), dark-skinned individuals (melanin reduces UV synthesis), institutionalized/little sun exposure, malabsorption syndromes, obesity (sequestered in fat), chronic kidney disease (reduced 1α-hydroxylase), anticonvulsant therapy (increased catabolism).

Toxicity (Hypervitaminosis D) :

Causes: Excessive supplementation (>10,000 IU/day for months); rarely from diet or sun exposure (synthesis is regulated).

Pharmacological Interactions with Drugs:

Pharmaceutical Importance:

• Treatment and prevention of vitamin D deficiency, rickets, osteomalacia
• Calcium and vitamin D supplementation for osteoporosis (with bisphosphonates)
• Calcitriol for hypocalcemia in chronic kidney disease (renal osteodystrophy)
• Calcipotriol (topical) for psoriasis (regulates keratinocyte proliferation)
• Vitamin D analogs (paricalcitol, doxercalciferol) for secondary hyperparathyroidism in CKD

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2.3 Vitamin E (Tocopherols and Tocotrienols)

Structure:

• Vitamin E refers to eight naturally occurring compounds: four tocopherols (α, β, γ, δ) and four tocotrienols.
• α-Tocopherol is the most biologically active form (due to preference of α-tocopherol transfer protein in liver).

Natural Sources:

• Vegetable oils (soybean, sunflower, corn, olive), nuts (almonds, peanuts), seeds (sunflower), wheat germ, green leafy vegetables, fortified cereals

Synthetic Sources:

• All-rac-α-tocopherol (synthetic; half the activity of natural RRR-α-tocopherol)
• Tocopheryl acetate, tocopheryl succinate (esterified forms for stability in supplements)

Recommended Dietary Allowance (RDA) :

• Adults: 15 mg (22.4 IU) of α-tocopherol/day
• Upper level: 1000 mg/day (from supplements; toxicity risk)

Metabolic Functions:

Physiological Role in Detail:

A. Antioxidant Mechanism:

• Lipid peroxidation is a chain reaction: initiation (ROS abstracts H from PUFA) → lipid radical → reacts with O₂ → lipid peroxyl radical → abstracts H from another PUFA, propagating chain.
• Vitamin E (α-tocopherol) donates H to lipid peroxyl radical, forming lipid hydroperoxide and tocopheroxyl radical.
• Tocopheroxyl radical is relatively stable and can be reduced back to tocopherol by vitamin C (ascorbate) or glutathione.

B. Protection of LDL:

• Vitamin E in LDL particles prevents oxidative modification of LDL, which is implicated in atherosclerosis.

Deficiency:

Causes: Severe malabsorption (cystic fibrosis, cholestasis, abetalipoproteinemia – defect in lipoprotein assembly, leading to vitamin E malabsorption), genetic defects in α-tocopherol transfer protein (ataxia with isolated vitamin E deficiency, AVED).

At-risk populations: Premature infants (low stores, rapid growth), malabsorption syndromes, abetalipoproteinemia.

Toxicity (Hypervitaminosis E) :

• Relatively low toxicity compared to A and D.
• High doses (>1000 mg/day) may:
  • Increase bleeding risk (antagonizes vitamin K, inhibits platelet aggregation)
  • Interfere with vitamin K metabolism (enhances anticoagulant effect of warfarin)
  • Nausea, diarrhea, headache, fatigue (rare)

Pharmacological Interactions with Drugs:

Pharmaceutical Importance:

• Treatment of vitamin E deficiency (especially in malabsorption, AVED)
• Antioxidant in formulations (protects labile drugs)
• Topical preparations for skin protection
• Supplements for cardiovascular health (controversial efficacy; meta-analyses show no clear benefit)
• Used in some neurological disorders (tardive dyskinesia, Alzheimer's – limited evidence)

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2.4 Vitamin K (Phylloquinone, Menaquinones, Menadione)

Structure:

• Vitamin K₁ (phylloquinone) : From plants; contains phytyl side chain
• Vitamin K₂ (menaquinones) : From bacteria (gut flora); multiple forms (MK-4 to MK-13) with varying isoprenoid side chains; MK-4 also synthesized from K₁ in some tissues
• Vitamin K₃ (menadione) : Synthetic, water-soluble prodrug (alkylated to menaquinone-4 in vivo)

Natural Sources:

• Vitamin K₁: Green leafy vegetables (spinach, kale, broccoli, Brussels sprouts), vegetable oils (soybean, canola)
• Vitamin K₂: Fermented foods (natto – rich in MK-7), cheese, egg yolk, meat; also synthesized by gut bacteria (but contribution to human needs is debated)

Synthetic Sources:

• Menadione (vitamin K₃) – used in animal feed; not recommended for humans (toxicity risk)
• Phytonadione (vitamin K₁) for human supplements and injection

Recommended Dietary Allowance (RDA) :

• Adult men: 120 μg/day
• Adult women: 90 μg/day
• Adequate intake (AI) rather than RDA, as deficiency is rare except in specific conditions

Metabolic Functions:

Physiological Role in Detail:

A. Blood Coagulation Cascade:

• Clotting factors are synthesized in liver as inactive precursors.
• Vitamin K-dependent γ-carboxylation adds a second carboxyl group to specific Glu residues → Gla residues bind calcium → factors can bind to phospholipid surfaces (platelet membranes) and participate in coagulation complexes.
• Without carboxylation, factors are inactive (PIVKA – proteins induced by vitamin K absence).
• Warfarin anticoagulants inhibit vitamin K epoxide reductase (VKOR), preventing recycling of vitamin K.

B. Bone Metabolism:

• Osteocalcin: Synthesized by osteoblasts; γ-carboxylated osteocalcin binds calcium and hydroxyapatite, regulating bone mineralization. Undercarboxylated osteocalcin may act as hormone (increases insulin secretion, testosterone production).
• Matrix Gla protein (MGP) : Inhibits vascular calcification; requires vitamin K-dependent carboxylation for activity.

C. Vitamin K Cycle:

Vitamin K (quinone)
      │ (NAD(P)H-dependent reductase, also sensitive to warfarin)
      ↓
Vitamin K hydroquinone (active cofactor for γ-glutamyl carboxylase)
      │ (carboxylates Glu to Gla)
      ↓
Vitamin K epoxide
      │ (vitamin K epoxide reductase, VKOR – warfarin-sensitive)
      └───────────────────┘

Deficiency:

Causes: Newborns (prophylactic vitamin K given), malabsorption (celiac, cystic fibrosis, short bowel, biliary obstruction), chronic liver disease, long-term antibiotic use (reduces gut flora – though contribution of gut K₂ is debated), anticoagulant therapy (warfarin), nutritional deficiency (rare in adults due to wide distribution).

Toxicity (Hypervitaminosis K) :

• Vitamin K₁ and K₂: No known toxicity; excess excreted.
• Menadione (K₃) : Can cause hemolytic anemia, jaundice (oxidative stress), especially in G6PD deficiency; not used in humans.

Pharmacological Interactions with Drugs:

Pharmaceutical Importance:

• Prevention and treatment of vitamin K deficiency bleeding (VKDB) in newborns (intramuscular vitamin K₁ at birth)
• Reversal of warfarin overdose (oral or intravenous vitamin K₁)
• Treatment of coagulopathy due to malabsorption, liver disease, or antibiotic use
• Phytonadione injection for hemorrhagic disease
• Potential role in bone health and vascular calcification (under investigation)

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3. Water-Soluble Vitamins

3.1 Vitamin B₁ (Thiamine)

Structure: Thiamine consists of a pyrimidine ring and a thiazole ring linked by a methylene bridge. It is phosphorylated to thiamine pyrophosphate (TPP), the active coenzyme form.

Natural Sources: Pork, whole grains, legumes, nuts, seeds, yeast, fortified cereals, brown rice

Synthetic Sources: Thiamine hydrochloride, thiamine mononitrate (in supplements and fortified foods)

Recommended Dietary Allowance (RDA) :

• Adult men: 1.2 mg/day
• Adult women: 1.1 mg/day

Metabolic Functions (as TPP) :

Physiological Role:

• TPP is essential for oxidative decarboxylation of α-ketoacids.
• Transketolase in PPP generates NADPH and pentoses for nucleotide synthesis.
• Thiamine triphosphate (TTP) may have role in nerve conduction.

Deficiency (Beriberi) :

Causes: Alcoholism (most common in developed countries; impaired absorption, storage, and phosphorylation), polished rice diet (in developing countries), hyperemesis gravidarum, malabsorption, bariatric surgery, chronic dialysis.

Pharmacological Interactions with Drugs:

Pharmaceutical Importance:

• Treatment of beriberi and Wernicke-Korsakoff syndrome (high-dose thiamine IV/IM before glucose infusion to prevent acute deficiency)
• Supplementation in alcoholics, malabsorption, bariatric surgery patients
• Fortification of foods

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3.2 Vitamin B₂ (Riboflavin)

Structure: Riboflavin consists of isoalloxazine ring (yellow) attached to ribitol (sugar alcohol). Active coenzyme forms: flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD).

Natural Sources: Milk and dairy products, eggs, meat (liver), green leafy vegetables, almonds, fortified cereals

Synthetic Sources: Riboflavin supplements; riboflavin-5'-phosphate (FMN) for injection

Recommended Dietary Allowance (RDA) :

• Adult men: 1.3 mg/day
• Adult women: 1.1 mg/day

Metabolic Functions (as FMN/FAD) :

Physiological Role:

• FAD and FMN are prosthetic groups for numerous oxidoreductases involved in energy production, detoxification, and biosynthesis.
• Riboflavin is also involved in vitamin B₆ activation and niacin formation from tryptophan.

Deficiency (Ariboflavinosis) :

Causes: Poor diet (alcoholism, elderly), malabsorption, phototherapy for neonatal jaundice (light degrades riboflavin), chronic use of certain drugs.

Pharmacological Interactions with Drugs:

Pharmaceutical Importance:

• Treatment of ariboflavinosis
• Part of multivitamin supplements
• Used in phototherapy for neonatal jaundice (riboflavin as photosensitizer – experimental)

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3.3 Vitamin B₃ (Niacin, Nicotinic Acid, Nicotinamide)

Structure: Niacin refers to both nicotinic acid (pyridine-3-carboxylic acid) and nicotinamide (niacinamide). Active coenzyme forms: NAD⁺ (nicotinamide adenine dinucleotide) and NADP⁺ (nicotinamide adenine dinucleotide phosphate).

Natural Sources: Meat (liver, chicken, fish), poultry, peanuts, legumes, whole grains, fortified cereals; also synthesized from tryptophan (60 mg tryptophan → 1 mg niacin)

Synthetic Sources: Nicotinic acid, nicotinamide in supplements; extended-release formulations for dyslipidemia

Recommended Dietary Allowance (RDA) :

• Adult men: 16 mg NE (niacin equivalents)/day
• Adult women: 14 mg NE/day

Metabolic Functions (as NAD⁺/NADP⁺) :

Physiological Role:

• NAD⁺ is essential for hundreds of redox reactions.
• NADPH is crucial for reductive biosynthesis and antioxidant defense.
• Poly(ADP-ribose) polymerase (PARP) uses NAD⁺ for DNA repair; excessive activation depletes NAD⁺ and ATP (cell death).

Deficiency (Pellagra) :

Causes: Corn-based diets (niacin in corn is bound and unavailable; tryptophan low), alcoholism, carcinoid syndrome (tryptophan diverted to serotonin), Hartnup disease (tryptophan malabsorption), isoniazid therapy (competes with tryptophan)

Pharmacological Uses of Niacin:

Pharmacological Interactions with Drugs:

Pharmaceutical Importance:

• Treatment and prevention of pellagra
• Nicotinic acid (niacin) for dyslipidemia (prescription formulations)
• Nicotinamide in multivitamins (no flushing effect)
• Topical nicotinamide for acne (anti-inflammatory)
• NAD⁺ precursors (nicotinamide riboside, NMN) as anti-aging supplements (experimental)

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3.4 Vitamin B₅ (Pantothenic Acid)

Structure: Pantothenic acid consists of pantoic acid linked to β-alanine. Active coenzyme form: Coenzyme A (CoA) and acyl carrier protein (ACP).

Natural Sources: Widely distributed in foods: meat (liver), chicken, egg yolk, whole grains, legumes, avocados, broccoli, mushrooms ("pantothen" means "from everywhere")

Synthetic Sources: Calcium pantothenate, panthenol (provitamin used in topical products)

Recommended Dietary Allowance (RDA) :

• Adults: 5 mg/day (adequate intake)

Metabolic Functions (as CoA) :

Physiological Role:

• CoA is essential for acyl transfer reactions.
• ACP is integral to fatty acid synthesis.

Deficiency:

• Extremely rare due to wide distribution.
• Experimental deficiency (with antagonist) causes: fatigue, headache, paresthesias (burning feet syndrome), insomnia, nausea, abdominal cramps, hypoglycemia.

Causes: Severe malnutrition, alcoholism (may contribute to "burning feet syndrome").

Pharmaceutical Importance:

• Part of multivitamin supplements
• Panthenol in topical preparations (wound healing, moisturizer) – converted to pantothenic acid in skin
• Calcium pantothenate in hair and skin products

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3.5 Vitamin B₆ (Pyridoxine, Pyridoxal, Pyridoxamine)

Structure: Three naturally occurring forms: pyridoxine (alcohol), pyridoxal (aldehyde), pyridoxamine (amine). All are converted to active coenzyme: pyridoxal-5'-phosphate (PLP).

Natural Sources: Meat (liver, poultry), fish, potatoes, bananas, chickpeas, nuts, whole grains, fortified cereals

Synthetic Sources: Pyridoxine hydrochloride (most common supplement form)

Recommended Dietary Allowance (RDA) :

• Adults 19-50 years: 1.3 mg/day
• Older adults: 1.5-1.7 mg/day

Metabolic Functions (as PLP) :

Physiological Role:

• PLP is cofactor for >140 enzymes, primarily in amino acid metabolism.
• Essential for neurotransmitter balance, heme production, and one-carbon metabolism.

Deficiency:

Causes: Alcoholism (acetaldehyde displaces PLP), isoniazid, hydralazine, penicillamine (form hydrazones with PLP, inactivate it), oral contraceptives (may increase requirement), malabsorption, chronic kidney disease (increased PLP loss in dialysis)

Pharmacological Interactions with Drugs:

Toxicity (from supplements) :

Pharmaceutical Importance:

• Treatment and prevention of B₆ deficiency (isoniazid therapy, alcoholism)
• Management of homocystinuria (high-dose B₆ responsive forms)
• Treatment of sideroblastic anemia (some forms respond to B₆)
• Premenstrual syndrome (controversial, low-dose)
• Nausea in pregnancy (pyridoxine with doxylamine – Diclegis)

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3.6 Vitamin B₇ (Biotin)

Structure: Biotin is a ureido ring fused with a tetrahydrothiophene ring with a valeric acid side chain.

Natural Sources: Liver, egg yolk (but raw egg white contains avidin, which binds biotin and prevents absorption), nuts, seeds, legumes, mushrooms, bananas, cauliflower

Synthetic Sources: D-biotin in supplements

Recommended Dietary Allowance (RDA) :

• Adults: 30 μg/day (adequate intake)

Metabolic Functions:

Mechanism:

• Biotin is covalently bound to carboxylases via amide linkage to lysine (biocytin).
• It carries activated CO₂ as carboxybiotin, transferring it to substrates.

Deficiency:

Causes: Raw egg white consumption (avidin), long-term parenteral nutrition without biotin, malabsorption, biotinidase deficiency (genetic disorder impairs biotin recycling), anticonvulsant therapy.

Pharmacological Interactions with Drugs:

Pharmaceutical Importance:

• Treatment of biotin deficiency and biotinidase deficiency (high-dose biotin, 5-20 mg/day)
• Supplements for hair, skin, nails (limited evidence)
• Multiple carboxylase deficiency (biotin-responsive)

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3.7 Vitamin B₉ (Folate, Folic Acid)

Structure: Folate consists of pteridine ring, p-aminobenzoic acid (PABA), and glutamic acid (usually polyglutamate in food). Folic acid (pteroylmonoglutamic acid) is the synthetic form used in supplements and fortified foods.

Natural Sources: Dark green leafy vegetables (spinach, kale), legumes (beans, lentils), liver, asparagus, Brussels sprouts, oranges, fortified grains and cereals

Synthetic Sources: Folic acid (pteroylmonoglutamic acid); folinic acid (5-formyltetrahydrofolate, leucovorin) for rescue after methotrexate

Recommended Dietary Allowance (RDA) :

• Adults: 400 μg DFE (dietary folate equivalents)/day
• Pregnancy: 600 μg DFE/day
• Lactation: 500 μg DFE/day
• 1 μg DFE = 1 μg food folate = 0.6 μg folic acid with food = 0.5 μg folic acid on empty stomach

Metabolic Functions:

Physiological Role:

• Folate is essential for DNA synthesis, repair, and methylation.
• Rapidly dividing cells (bone marrow, intestinal epithelium, fetus) have high folate requirement.
• Folate deficiency causes megaloblastic anemia (impaired DNA synthesis → large, immature RBC precursors).

Folate Cycle and Methionine Synthase:

                    Homocysteine
                         │ (methionine synthase, requires B12, 5-methyl-THF)
                         ↓
                    Methionine
                         │ (ATP)
                         ↓
                    S-Adenosylmethionine (SAM) – universal methyl donor
                         ↓ (methyltransferase reactions)
                    S-Adenosylhomocysteine (SAH)
                         ↓
                    Homocysteine (regenerated)

Deficiency:

Causes: Poor dietary intake (alcoholism, elderly, poverty), increased requirement (pregnancy, lactation, hemolytic anemias), malabsorption (celiac, Crohn's, atrophic gastritis), drugs (methotrexate, phenytoin, sulfasalazine, trimethoprim), alcohol (impairs absorption and metabolism)

Pharmacological Interactions with Drugs:

Pharmaceutical Importance:

• Prevention of neural tube defects (folic acid supplementation before and during early pregnancy) – 400-800 μg/day
• Treatment of folate deficiency anemia (1 mg/day folic acid)
• Adjunct to methotrexate therapy (leucovorin rescue)
• Fortification of grains (in many countries) to reduce NTD risk
• Management of hyperhomocysteinemia (with B12 and B6)
• Folate antagonists (methotrexate) for cancer, autoimmune diseases

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3.8 Vitamin B₁₂ (Cobalamin)

Structure: Complex corrin ring with central cobalt atom. Forms: cyanocobalamin (synthetic, stable), hydroxocobalamin, methylcobalamin, adenosylcobalamin (active coenzymes).

Natural Sources: Only from animal products: meat (liver), fish (shellfish), eggs, milk and dairy products; not found in plants (vegans at risk)

Synthetic Sources: Cyanocobalamin, hydroxocobalamin, methylcobalamin in supplements; hydroxocobalamin injection

Recommended Dietary Allowance (RDA) :

• Adults: 2.4 μg/day
• Pregnancy: 2.6 μg/day
• Lactation: 2.8 μg/day

Absorption:

1. Food B₁₂ bound to protein – released by gastric acid and pepsin.
2. Binds to R-protein (haptocorrin) from saliva.
3. In duodenum, pancreatic proteases degrade R-protein; B₁₂ binds to intrinsic factor (IF) from gastric parietal cells.
4. IF-B₁₂ complex binds to cubam receptor (cubilin/amnionless) in ileum → endocytosis.
5. In enterocyte, B₁₂ released, bound to transcobalamin II (TCII), enters portal blood.

Metabolic Functions:

Physiological Role:

• Methylmalonyl-CoA mutase: Deficiency leads to methylmalonic aciduria (elevated methylmalonic acid in urine and plasma) – clinical marker of B12 deficiency.
• Methionine synthase: Traps folate as 5-methyl-THF (methylfolate trap hypothesis) – B12 deficiency causes functional folate deficiency (megaloblastic anemia) despite normal folate levels.

Deficiency:

Causes: Pernicious anemia (autoimmune destruction of gastric parietal cells → lack of intrinsic factor), gastrectomy, ileal resection or disease (Crohn's), vegan diet (no animal products), chronic proton pump inhibitor use (reduced acid release), metformin (reduces calcium-dependent absorption), nitrous oxide (oxidizes cobalt, inactivates B12), tropical sprue, fish tapeworm (Diphyllobothrium latum)

Pernicious Anemia:

• Autoimmune gastritis → antibodies against parietal cells or intrinsic factor.
• Achlorhydria, low IF → B12 malabsorption.
• Associated with other autoimmune diseases (thyroid, vitiligo).
• Treatment: lifelong intramuscular B12 (or high-dose oral B12, as some passive absorption occurs).

Pharmacological Interactions with Drugs:

Pharmaceutical Importance:

• Treatment of pernicious anemia and B12 deficiency (IM hydroxocobalamin or cyanocobalamin; high-dose oral for mild deficiency)
• Hydroxocobalamin as antidote for cyanide poisoning (binds cyanide)
• Methylcobalamin supplements for neuropathy (popular in some countries)
• Screening and management of B12 deficiency in at-risk populations (vegans, elderly, metformin users, post-gastrectomy)

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3.9 Vitamin C (Ascorbic Acid)

Structure: Ascorbic acid is a six-carbon lactone with an enediol structure (reducing agent). Dehydroascorbic acid is the oxidized form (still active, can be reduced back).

Natural Sources: Citrus fruits (oranges, lemons), strawberries, kiwi, bell peppers, broccoli, tomatoes, potatoes

Synthetic Sources: Ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbyl palmitate (fat-soluble ester) in supplements; added to foods as preservative (antioxidant)

Recommended Dietary Allowance (RDA) :

• Adult men: 90 mg/day
• Adult women: 75 mg/day
• Smokers: +35 mg/day (increased oxidative stress)
• Upper level: 2000 mg/day (to avoid GI distress)

Metabolic Functions:

Physiological Role:

• Collagen: Hydroxyproline and hydroxylysine are essential for collagen triple helix formation and cross-linking. Deficiency impairs wound healing, blood vessel integrity.
• Antioxidant: Vitamin C is a major aqueous-phase antioxidant; protects lipids, proteins, DNA from oxidative damage.
• Iron: Maintains iron in ferrous state for absorption and utilization.

Deficiency (Scurvy) :

Causes: Poor diet (elderly, alcoholics, food insecurity), malabsorption, dialysis, smoking (increased turnover), pregnancy/lactation (increased requirement).

Pharmacological Interactions with Drugs:

Toxicity (from high doses) :

Pharmaceutical Importance:

• Treatment and prevention of scurvy
• Antioxidant in formulations (prevents oxidation of labile drugs)
• Wound healing (topical or systemic, limited evidence)
• Cold prevention/treatment (controversial; may slightly reduce duration)
• Iron supplementation adjunct (enhances absorption)
• Used as preservative in food and pharmaceutical products
• Intravenous high-dose vitamin C in cancer (experimental, controversial)

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4. Summary Tables

Table 1: Fat-Soluble Vitamins Summary

Table 2: Water-Soluble Vitamins Summary

Table 3: Vitamin Deficiencies and Clinical Features

Table 4: Pharmacological Interactions of Vitamins with Drugs

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5. Pharmaceutical Importance of Vitamins

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References

1. Lippincott Williams & Wilkins. (2020). Lippincott's illustrated reviews: Biochemistry. (Chapters on Vitamins)

2. Berg, J. M., Tymoczko, J. L., & Gatto, G. J. (2019). Stryer's biochemistry (8th ed.). W. H. Freeman and Company. (Chapters on Vitamins and Cofactors)

3. Nelson, D. L., & Cox, M. M. (2017). Lehninger principles of biochemistry (7th ed.). W. H. Freeman and Company. (Chapters on Vitamins and Minerals)

4. Rodwell, V. W., Bender, D. A., Botham, K. M., Kennelly, P. J., & Weil, P. A. (2017). Harper's illustrated biochemistry (31st ed.). McGraw-Hill Education. (Chapters on Vitamins)

5. Devlin, T. M. (2016). Textbook of biochemistry with clinical correlations (8th ed.). Wiley-Liss. (Chapters on Vitamins and Their Functions)

6. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. (1998-2011). Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline; Vitamin C, Vitamin E, Selenium, and Carotenoids; Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc; Calcium and Vitamin D. National Academies Press.

7. Kumar, V., Abbas, A. K., & Aster, J. C. (2020). Robbins & Cotran pathologic basis of disease (10th ed.). Elsevier. (Clinical correlations of vitamin deficiencies)

8. Ball, G. F. M. (2004). Vitamins: Their role in the human body. Blackwell Publishing.

9. Combs, G. F., & McClung, J. P. (2017). The vitamins: Fundamental aspects in nutrition and health (5th ed.). Academic Press.

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Recommended Textbooks for Further Reading:

• Lippincott Williams & Wilkins. (2020). Lippincott's illustrated reviews: Biochemistry. (Excellent for visual summaries and clinical notes on vitamins)
• Rodwell, V. W., et al. (2017). Harper's illustrated biochemistry (31st ed.). (Strong clinical emphasis with vitamin chapters)
• Combs, G. F., & McClung, J. P. (2017). The vitamins: Fundamental aspects in nutrition and health (5th ed.). (Comprehensive coverage of all vitamins)