Nutritional biochemistry of the vitamins, 2nd ed

List of Figures page xvii List of Tables xxi Preface xxiii 1 The Vitamins 1 1.1 Definition and Nomenclature of the Vitamins 2 1.1.1 Methods of Analysis and Units of Activity 6 1.1.2 Biological Availability 8 1.2 Vitamin Requirements and Reference Intakes 10 1.2.1 Criteria of Vitamin Adequacy and the Stages of Development of Deficiency 10 1.2.2 Assessment of Vitamin Nutritional Status 12 1.2.3 Determination of Requirements 17 1.2.3.1 Population Studies of Intake 17 1.2.3.2 Depletion/Repletion Studies 18 1.2.3.3 Replacement ofMetabolic Losses 18 1.2.3.4 Studies in PatientsMaintained on Total Parenteral Nutrition 19 1.2.4 Reference Intakes of Vitamins 19 1.2.4.1 Adequate Intake 23 1.2.4.2 Reference Intakes for Infants and Children 23 1.2.4.3 Tolerable Upper Levels of Intake 24 1.2.4.4 Reference Intake Figures for Food Labeling 27 2 Vitamin A: Retinoids and Carotenoids 30 2.1 Vitamin A Vitamers and Units of Activity 31 2.1.1 Retinoids 31 2.1.2 Carotenoids 33 2.1.3 International Units and Retinol Equivalents 35 v vi Contents 2.2 Absorption andMetabolism of Vitamin A and Carotenoids 35 2.2.1 Absorption andMetabolism of Retinol and Retinoic Acid 35 2.2.1.1 Liver Storage and Release of Retinol 36 2.2.1.2 Metabolism of Retinoic Acid 38 2.2.1.3 Retinoyl Glucuronide and OtherMetabolites 39 2.2.2 Absorption andMetabolism of Carotenoids 40 2.2.2.1 Carotene Dioxygenase 41 2.2.2.2 Limited Activity of Carotene Dioxygenase 42 2.2.2.3 The Reaction Specificity of Carotene Dioxygenase 43 2.2.3 Plasma Retinol Binding Protein (RBP) 45 2.2.4 Cellular Retinoid Binding Proteins CRBPs and CRABPs 47 2.3 Metabolic Functions of Vitamin A 49 2.3.1 Retinol and Retinaldehyde in the Visual Cycle 49 2.3.2 Genomic Actions of Retinoic Acid 54 2.3.2.1 Retinoid Receptors and Response Elements 55 2.3.3 Nongenomic Actions of Retinoids 58 2.3.3.1 Retinoylation of Proteins 58 2.3.3.2 Retinoids in Transmembrane Signaling 60 2.4 Vitamin A Deficiency (Xerophthalmia) 61 2.4.1 Assessment of Vitamin A Nutritional Status 64 2.4.1.1 Plasma Concentrations of Retinol and β-Carotene 64 2.4.1.2 Plasma Retinol Binding Protein 65 2.4.1.3 The Relative Dose Response (RDR) Test 66 2.4.1.4 Conjunctival Impression Cytology 66 2.5 Vitamin A Requirements and Reference Intakes 66 2.5.1 Toxicity of Vitamin A 68 2.5.1.1 Teratogenicity of Retinoids 70 2.5.2 Pharmacological Uses of Vitamin A, Retinoids, and Carotenoids 71 2.5.2.1 Retinoids in Cancer Prevention and Treatment 71 2.5.2.2 Retinoids in Dermatology 72 2.5.2.3 Carotene 72 3 Vitamin D 77 3.1 Vitamin D Vitamers, Nomenclature, and Units of Activity 78 3.2 Metabolism of Vitamin D 79 3.2.1 Photosynthesis of Cholecalciferol in the Skin 80 3.2.2 Dietary Vitamin D 82 3.2.3 25-Hydroxylation of Cholecalciferol 83 3.2.4 Calcidiol 1α-Hydroxylase 85 3.2.5 Calcidiol 24-Hydroxylase 85 3.2.6 Inactivation and Excretion of Calcitriol 86 3.2.7 Plasma Vitamin D Binding Protein (Gc-Globulin) 87 Contents vii 3.2.8 Regulation of Vitamin DMetabolism 87 3.2.8.1 Calcitriol 88 3.2.8.2 Parathyroid Hormone 88 3.2.8.3 Calcitonin 88 3.2.8.4 Plasma Concentrations of Calcium and Phosphate 89 3.3 Metabolic Functions of Vitamin D 89 3.3.1 Nuclear Vitamin D Receptors 91 3.3.2 Nongenomic Responses to Vitamin D 92 3.3.3 Stimulation of IntestinalCalcium andPhosphateAbsorption 93 3.3.3.1 Induction of Calbindin-D 93 3.3.4 Stimulation of Renal Calcium Reabsorption 94 3.3.5 The Role of Calcitriol in BoneMetabolism 94 3.3.6 Cell Differentiation, Proliferation, and Apoptosis 96 3.3.7 Other Functions of Calcitriol 97 3.3.7.1 Endocrine Glands 98 3.3.7.2 The Immune System 98 3.4 Vitamin D Deficiency – Rickets and Osteomalacia 98 3.4.1 Nonnutritional Rickets and Osteomalacia 99 3.4.2 Vitamin D-Resistant Rickets 100 3.4.3 Osteoporosis 101 3.4.3.1 Glucocorticoid-Induced Osteoporosis 102 3.5 Assessment of Vitamin D Status 103 3.6 Requirements and Reference Intakes 104 3.6.1 Toxicity of Vitamin D 105 3.6.2 Pharmacological Uses of Vitamin D 106 4 Vitamin E: Tocopherols and Tocotrienols 109 4.1 Vitamin E Vitamers and Units of Activity 109 4.2 Metabolism of Vitamin E 113 4.3 Metabolic Functions of Vitamin E 115 4.3.1 Antioxidant Functions of Vitamin E 116 4.3.1.1 Prooxidant Actions of Vitamin E 118 4.3.1.2 Reaction of Tocopherol with Peroxynitrite 119 4.3.2 Nutritional Interactions Between Selenium and Vitamin E 120 4.3.3 Functions of Vitamin E in Cell Signaling 121 4.4 Vitamin E Deficiency 122 4.4.1 Vitamin E Deficiency in Experimental Animals 122 4.4.2 Human Vitamin E Deficiency 125 4.5 Assessment of Vitamin E Nutritional Status 125 4.6 Requirements and Reference Intakes 127 4.6.1 Upper Levels of Intake 128 4.6.2 Pharmacological Uses of Vitamin E 128 4.6.2.1 Vitamin E and Cancer 129 4.6.2.2 Vitamin E and Cardiovascular Disease 129 viii Contents 4.6.2.3 Vitamin E and Cataracts 129 4.6.2.4 Vitamin E and Neurodegenerative Diseases 129 5 Vitamin K 131 5.1 Vitamin K Vitamers 132 5.2 Metabolism of Vitamin K 133 5.2.1 Bacterial Biosynthesis ofMenaquinones 135 5.3 TheMetabolic Functions of Vitamin K 135 5.3.1 The Vitamin K-Dependent Carboxylase 136 5.3.2 Vitamin K-Dependent Proteins in Blood Clotting 139 5.3.3 Osteocalcin andMatrix Gla Protein 141 5.3.4 Vitamin K-Dependent Proteins in Cell Signaling – Gas6 142 5.4 Vitamin K Deficiency 142 5.4.1 Vitamin K Deficiency Bleeding in Infancy 143 5.5 Assessment of Vitamin K Nutritional Status 143 5.6 Vitamin K Requirements and Reference Intakes 145 5.6.1 Upper Levels of Intake 145 5.6.2 Pharmacological Uses of Vitamin K 146 6 Vitamin B1 – Thiamin 148 6.1 Thiamin Vitamers and Antagonists 148 6.2 Metabolism of Thiamin 150 6.2.1 Biosynthesis of Thiamin 153 6.3 Metabolic Functions of Thiamin 153 6.3.1 Thiamin Diphosphate in the Oxidative Decarboxylation of Oxoacids 154 6.3.1.1 Regulation of Pyruvate Dehydrogenase Activity 155 6.3.1.2 Thiamin-Responsive Pyruvate Dehydrogenase Deficiency 156 6.3.1.3 2-OxoglutarateDehydrogenase and the γ -Aminobutyric Acid (GABA) Shunt 156 6.3.1.4 Branched-Chain Oxo-acid Decarboxylase andMaple SyrupUrine Disease 158 6.3.2 Transketolase 159 6.3.3 The Neuronal Function of Thiamin Triphosphate 159 6.4 Thiamin Deficiency 161 6.4.1 Dry Beriberi 161 6.4.2 Wet Beriberi 162 6.4.3 Acute Pernicious (Fulminating) Beriberi – Shoshin Beriberi 162 6.4.4 TheWernicke–Korsakoff Syndrome 163 6.4.5 Effects of Thiamin Deficiency on CarbohydrateMetabolism 164 6.4.6 Effects of Thiamin Deficiency on Neurotransmitters 165 6.4.6.1 Acetylcholine 165 6.4.6.2 5-Hydroxytryptamine 165 6.4.7 Thiaminases and Thiamin Antagonists 166 Contents ix 6.5 Assessment of Thiamin Nutritional Status 167 6.5.1 Urinary Excretion of Thiamin and Thiochrome 167 6.5.2 Blood Concentration of Thiamin 167 6.5.3 Erythrocyte Transketolase Activation 168 6.6 Thiamin Requirements and Reference Intakes 169 6.6.1 Upper Levels of Thiamin Intake 169 6.6.2 Pharmacological Uses of Thiamin 169 7 Vitamin B2 – Riboflavin 172 7.1 Riboflavin and the Flavin Coenzymes 172 7.2 TheMetabolism of Riboflavin 175 7.2.1 Absorption, Tissue Uptake, and Coenzyme Synthesis 175 7.2.2 Riboflavin Binding Protein 177 7.2.3 Riboflavin Homeostasis 178 7.2.4 The Effect of Thyroid Hormones on RiboflavinMetabolism 178 7.2.5 Catabolism and Excretion of Riboflavin 179 7.2.6 Biosynthesis of Riboflavin 181 7.3 Metabolic Functions of Riboflavin 183 7.3.1 The Flavin Coenzymes: FAD and Riboflavin Phosphate 183 7.3.2 Single-Electron-Transferring Flavoproteins 184 7.3.3 Two-Electron-Transferring Flavoprotein Dehydrogenases 185 7.3.4 Nicotinamide Nucleotide Disulfide Oxidoreductases 185 7.3.5 Flavin Oxidases 186 7.3.6 NADPH Oxidase, the Respiratory Burst Oxidase 187 7.3.7 Molybdenum-Containing Flavoprotein Hydroxylases 188 7.3.8 FlavinMixed-Function Oxidases (Hydroxylases) 189 7.3.9 The Role of Riboflavin in the Cryptochromes 190 7.4 Riboflavin Deficiency 190 7.4.1 Impairment of LipidMetabolism in Riboflavin Deficiency 191 7.4.2 Resistance toMalaria in Riboflavin Deficiency 192 7.4.3 Secondary Nutrient Deficiencies in Riboflavin Deficiency 193 7.4.4 Iatrogenic Riboflavin Deficiency 194 7.5 Assessment of Riboflavin Nutritional Status 196 7.5.1 Urinary Excretion of Riboflavin 196 7.5.2 Erythrocyte Glutathione Reductase (EGR) Activation Coefficient 197 7.6 Riboflavin Requirements and Reference Intakes 197 7.7 Pharmacological Uses of Riboflavin 198 8 Niacin 200 8.1 Niacin Vitamers and Nomenclature 201 8.2 NiacinMetabolism 203 8.2.1 Digestion and Absorption 203 8.2.1.1 Unavailable Niacin in Cereals 203 8.2.2 Synthesis of the Nicotinamide Nucleotide Coenzymes 203 x Contents 8.2.3 Catabolism of NAD(P) 205 8.2.4 Urinary Excretion of NiacinMetabolites 206 8.3 The Synthesis of Nicotinamide Nucleotides from Tryptophan 208 8.3.1 Picolinate Carboxylase and Nonenzymic Cyclization to Quinolinic Acid 210 8.3.2 Tryptophan Dioxygenase 211 8.3.2.1 Saturation of Tryptophan Dioxygenase with Its Heme Cofactor 211 8.3.2.2 Induction of Tryptophan Dioxygenase by Glucocorticoid Hormones 211 8.3.2.3 Induction Tryptophan Dioxygenase by Glucagon 212 8.3.2.4 Repression and Inhibition of Tryptophan Dioxygenase by Nicotinamide Nucleotides 212 8.3.3 Kynurenine Hydroxylase and Kynureninase 212 8.3.3.1 Kynurenine Hydroxylase 213 8.3.3.2 Kynureninase 213 8.4 Metabolic Functions of Niacin 214 8.4.1 The Redox Function of NAD(P) 214 8.4.1.1 Use of NAD(P) in Enzyme Assays 215 8.4.2 ADP-Ribosyltransferases 215 8.4.3 Poly(ADP-ribose) Polymerases 217 8.4.4 cADP-Ribose and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) 219 8.5 Pellagra – A Disease of Tryptophan and Niacin Deficiency 221 8.5.1 Other Nutrient Deficiencies in the Etiology of Pellagra 222 8.5.2 Possible Pellagragenic Toxins 223 8.5.3 The Pellagragenic Effect of Excess Dietary Leucine 223 8.5.4 Inborn Errors of TryptophanMetabolism 224 8.5.5 Carcinoid Syndrome 224 8.5.6 Drug-Induced Pellagra 225 8.6 Assessment of Niacin Nutritional Status 225 8.6.1 Tissue and Whole Blood Concentrations of Nicotinamide Nucleotides 226 8.6.2 Urinary Excretion of N1-Methyl Nicotinamide andMethyl Pyridone Carboxamide 226 8.7 Niacin Requirements and Reference Intakes 227 8.7.1 Upper Levels of Niacin Intake 228 8.8 Pharmacological Uses of Niacin 229 9 Vitamin B6 232 9.1 Vitamin B6 Vitamers and Nomenclature 233 9.2 Metabolism of Vitamin B6 234 9.2.1 Muscle Pyridoxal Phosphate 236 9.2.2 Biosynthesis of Vitamin B6 236 9.3 Metabolic Functions of Vitamin B6 236 9.3.1 Pyridoxal Phosphate in Amino AcidMetabolism 237 9.3.1.1 α-Decarboxylation of Amino Acids 239 Contents xi 9.3.1.2 Racemization of the Amino Acid Substrate 241 9.3.1.3 Transamination of Amino Acids (Aminotransferase Reactions) 241 9.3.1.4 Steps in the Transaminase Reaction 242 9.3.1.5 Transamination Reactions of Other Pyridoxal Phosphate Enzymes 243 9.3.1.6 Transamination and Oxidative Deamination Catalyzed by Dihydroxyphenylalanine (DOPA) Decarboxylase 243 9.3.1.7 Side-Chain Elimination and Replacement Reactions 244 9.3.2 The Role of Pyridoxal Phosphate in Glycogen Phosphorylase 244 9.3.3 The Role of Pyridoxal Phosphate in Steroid Hormone Action and Gene Expression 245 9.4 Vitamin B6 Deficiency 246 9.4.1 Enzyme Responses to Vitamin B6 Deficiency 247 9.4.2 Drug-Induced Vitamin B6 Deficiency 249 9.4.3 Vitamin B6 Dependency Syndromes 250 9.5 The Assessment of Vitamin B6 Nutritional Status 250 9.5.1 Plasma Concentrations of Vitamin B6 251 9.5.2 Urinary Excretion of Vitamin B6 and 4-Pyridoxic Acid 251 9.5.3 Coenzyme Saturation of Transaminases 252 9.5.4 The Tryptophan Load Test 252 9.5.4.1 Artifacts in the Tryptophan Load Test Associated with Increased Tryptophan Dioxygenase Activity 253 9.5.4.2 Estrogens and Apparent Vitamin B6 Nutritional Status 254 9.5.5 TheMethionine Load Test 255 9.6 Vitamin B6 Requirements and Reference Intakes 256 9.6.1 Vitamin B6 Requirements Estimated fromMetabolic Turnover 256 9.6.2 Vitamin B6 Requirements Estimated from Depletion/ Repletion Studies 257 9.6.3 Vitamin B6 Requirements of Infants 259 9.6.4 Toxicity of Vitamin B6 259 9.6.4.1 Upper Levels of Vitamin B6 Intake 260 9.7 Pharmacological Uses of Vitamin B6 261 9.7.1 Vitamin B6 and Hyperhomocysteinemia 261 9.7.2 Vitamin B6 and the Premenstrual Syndrome 262 9.7.3 Impaired Glucose Tolerance 262 9.7.4 Vitamin B6 for Prevention of the Complications of DiabetesMellitus 263 9.7.5 Vitamin B6 for the Treatment of Depression 264 9.7.6 Antihypertensive Actions of Vitamin B6 264 9.8 Other Carbonyl Catalysts 265 9.8.1 Pyruvoyl Enzymes 266 9.8.2 Pyrroloquinoline Quinone (PQQ) and Tryptophan Tryptophylquinone (TTQ) 266 9.8.3 Quinone Catalysts inMammalian Enzymes 268 xii Contents 10 Folate and Other Pterins and Vitamin B12 270 10.1 Folate Vitamers and Dietary Folate Equivalents 271 10.1.1 Dietary Folate Equivalents 271 10.2 Metabolism of Folates 273 10.2.1 Digestion and Absorption of Folates 273 10.2.2 Tissue Uptake andMetabolism of Folate 274 10.2.2.1 Poly-γ -glutamylation of Folate 275 10.2.3 Catabolism and Excretion of Folate 276 10.2.4 Biosynthesis of Pterins 276 10.3 Metabolic Functions of Folate 279 10.3.1 Sources of Substituted Folates 279 10.3.1.1 Serine Hydroxymethyltransferase 279 10.3.1.2 Histidine Catabolism 281 10.3.1.3 Other Sources of One-Carbon Substituted Folates 283 10.3.2 Interconversion of Substituted Folates 283 10.3.2.1 Methylene-Tetrahydrofolate Reductase 284 10.3.2.2 Disposal of Surplus One-Carbon Fragments 286 10.3.3 Utilization of One-Carbon Substituted Folates 286 10.3.3.1 Thymidylate Synthetase and Dihydrofolate Reductase 287 10.3.3.2 Dihydrofolate Reductase Inhibitors 288 10.3.3.3 The dUMP Suppression Test 289 10.3.4 The Role of Folate inMethionineMetabolism 289 10.3.4.1 TheMethyl Folate TrapH ypothesis 291 10.3.4.2 Hyperhomocysteinemia and Cardiovascular Disease 292 10.4 Tetrahydrobiopterin 294 10.4.1 The Role of Tetrahydrobiopterin in Aromatic Amino Acid Hydroxylases 294 10.4.2 The Role of Tetrahydrobiopterin in Nitric Oxide Synthase 296 10.5 Molybdopterin 297 10.6 Vitamin B12 Vitamers and Nomenclature 298 10.7 Metabolism of Vitamin B12 300 10.7.1 Digestion and Absorption of Vitamin B12 300 10.7.2 Plasma Vitamin B12 Binding Proteins and Tissue Uptake 301 10.7.3 Bacterial Biosynthesis of Vitamin B12 303 10.8 Metabolic Functions of Vitamin B12 303 10.8.1 Methionine Synthetase 304 10.8.2 Methylmalonyl CoAMutase 305 10.8.3 Leucine Aminomutase 306 10.9 Deficiency of Folic Acid and Vitamin B12 307 10.9.1 Megaloblastic Anemia 308 10.9.2 Pernicious Anemia 308 10.9.3 Neurological Degeneration in Vitamin B12 Deficiency 309 10.9.4 Folate Deficiency and Neural Tube Defects 310 10.9.5 Folate Deficiency and Cancer Risk 311 10.9.6 Drug-Induced Folate Deficiency 312 10.9.7 Drug-Induced Vitamin B12 Deficiency 313 Contents xiii 10.10 Assessment of Folate and Vitamin B12 Nutritional Status 313 10.10.1 Plasma and Erythrocyte Concentrations of Folate and Vitamin B12 314 10.10.2 The Schilling Test for Vitamin B12 Absorption 315 10.10.3 Methylmalonic Aciduria andMethylmalonic Acidemia 316 10.10.4 HistidineMetabolism – the FIGLU Test 316 10.10.5 The dUMP Suppression Test 317 10.11 Folate and Vitamin B12 Requirements and Reference Intakes 318 10.11.1 Folate Requirements 318 10.11.2 Vitamin B12 Requirements 318 10.11.3 Upper Levels of Folate Intake 319 10.12 Pharmacological Uses of Folate and Vitamin B12 321 11 Biotin (Vitamin H) 324 11.1 Metabolism of Biotin 324 11.1.1 Bacterial Synthesis of Biotin 327 11.1.1.1 The Importance of Intestinal Bacterial Synthesis of Biotin 329 11.2 TheMetabolic Functions of Biotin 329 11.2.1 The Role of Biotin in Carboxylation Reactions 330 11.2.1.1 Acetyl CoA Carboxylase 330 11.2.1.2 Pyruvate Carboxylase 331 11.2.1.3 Propionyl CoA Carboxylase 331 11.2.1.4 Methylcrotonyl CoA Carboxylase 332 11.2.2 Holocarboxylase Synthetase 332 11.2.2.1 Holocarboxylase Synthetase Deficiency 332 11.2.3 Biotinidase 334 11.2.3.1 Biotinidase Deficiency 335 11.2.4 Enzyme Induction by Biotin 335 11.2.5 Biotin in Regulation of the Cell Cycle 336 11.3 Biotin Deficiency 337 11.3.1 Metabolic Consequences of Biotin Deficiency 338 11.3.1.1 Glucose Homeostasis in Biotin Deficiency 338 11.3.1.2 Fatty Liver and Kidney Syndrome in Biotin-Deficient Chicks 338 11.3.1.3 Cot Death 339 11.3.2 Biotin Deficiency In Pregnancy 340 11.4 Assessment of Biotin Nutritional Status 340 11.5 Biotin Requirements 341 11.6 Avidin 341 12 Pantothenic Acid 345 12.1 Pantothenic Acid Vitamers 345 12.2 Metabolism of Pantothenic Acid 346 12.2.1 The Formation of CoA from Pantothenic Acid 348 12.2.1.1 Metabolic Control of CoA Synthesis 349 xiv Contents 12.2.2 Catabolism of CoA 350 12.2.3 The Formation and Turnover of ACP 350 12.2.4 Biosynthesis of Pantothenic Acid 351 12.3 Metabolic Functions of Pantothenic Acid 352 12.4 Pantothenic Acid Deficiency 353 12.4.1 Pantothenic Acid Deficiency in Experimental Animals 353 12.4.2 Human Pantothenic Acid Deficiency – The Burning Foot Syndrome 354 12.5 Assessment of Pantothenic Acid Nutritional Status 355 12.6 Pantothenic Acid Requirements 355 12.7 Pharmacological Uses of Pantothenic Acid 356 13 Vitamin C (Ascorbic Acid) 357 13.1 Vitamin C Vitamers and Nomenclature 358 13.1.1 Assay of Vitamin C 359 13.2 Metabolism of Vitamin C 359 13.2.1 Intestinal Absorption and Secretion of Vitamin C 361 13.2.2 Tissue Uptake of Vitamin C 361 13.2.3 Oxidation and Reduction of Ascorbate 362 13.2.4 Metabolism and Excretion of Ascorbate 363 13.3 Metabolic Functions of Vitamin C 364 13.3.1 Dopamine β-Hydroxylase 365 13.3.2 Peptidyl Glycine Hydroxylase (Peptide α-Amidase) 366 13.3.3 2-Oxoglutarate–Linked Iron-Containing Hydroxylases 367 13.3.4 Stimulation of Enzyme Activity by Ascorbate In Vitro 369 13.3.5 The Role of Ascorbate in Iron Absorption and Metabolism 369 13.3.6 Inhibition of Nitrosamine Formation by Ascorbate 370 13.3.7 Pro- and Antioxidant Roles of Ascorbate 371 13.3.7.1 Reduction of the Vitamin E Radical by Ascorbate 371 13.3.8 Ascorbic Acid in Xenobiotic and CholesterolMetabolism 371 13.4 Vitamin C Deficiency – Scurvy 372 13.4.1 Anemia in Scurvy 373 13.5 Assessment of Vitamin C Status 374 13.5.1 Urinary Excretion of Vitamin C and Saturation Testing 374 13.5.2 Plasma and Leukocyte Concentrations of Ascorbate 374 13.5.3 Markers of DNA Oxidative Damage 376 13.6 Vitamin C Requirements and Reference Intakes 376 13.6.1 TheMinimum Requirement for Vitamin C 376 13.6.2 Requirements Estimated from the Plasma and Leukocyte Concentrations of Ascorbate 378 13.6.3 Requirements Estimated fromMaintenance of the Body Pool of Ascorbate 378 13.6.4 Higher Recommendations 379 13.6.4.1 The Effect of Smoking on Vitamin C Requirements 380 Contents xv 13.6.5 Safety and Upper Levels of Intake of Vitamin C 380 13.6.5.1 Renal Stones 380 13.6.5.2 False Results in Urine Glucose Testing 381 13.6.5.3 Rebound Scurvy 381 13.6.5.4 Ascorbate and Iron Overload 382 13.7 Pharmacological Uses of Vitamin C 382 13.7.1 Vitamin C in Cancer Prevention and Therapy 382 13.7.2 Vitamin C in Cardiovascular Disease 383 13.7.3 Vitamin C and the Common Cold 383 14 Marginal Compounds and Phytonutrients 385 14.1 Carnitine 385 14.1.1 Biosynthesis andMetabolism of Carnitine 386 14.1.2 The Possible Essentiality of Carnitine 388 14.1.3 Carnitine as an Ergogenic Aid 388 14.2 Choline 389 14.2.1 Biosynthesis andMetabolism of Choline 389 14.2.2 The Possible Essentiality of Choline 391 14.3 Creatine 392 14.4 Inositol 393 14.4.1 Phosphatidylinositol in Transmembrane Signaling 394 14.4.2 The Possible Essentiality of Inositol 394 14.5 Taurine 396 14.5.1 Biosynthesis of Taurine 396 14.5.2 Metabolic Functions of Taurine 398 14.5.2.1 Taurine Conjugation of Bile Acids 398 14.5.2.2 Taurine in the Central Nervous System 398 14.5.2.3 Taurine and HeartMuscle 399 14.5.3 The Possible Essentiality of Taurine 399 14.6 Ubiquinone (Coenzyme Q) 400 14.7 Phytonutrients: Potentially Protective Compounds in Plant Foods 401 14.7.1 Allyl Sulfur Compounds 401 14.7.2 Flavonoids and Polyphenols 402 14.7.3 Glucosinolates 403 14.7.4 Phytoestrogens