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The Vitamins
This page intentionally left blank
The Vitamins
Fundamental Aspects in Nutrition and Health
Sixth Edition

Gerald F. Combs, Jr.

Professor Emeritus, Cornell University, Ithaca, NY, United States
Senior Scientist, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University,
Boston, MA, United States

James P. McClung
Westborough, MA, United States
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To the students and professionals who will use this book, to those
who have used previous editions, and to those whose insights
have helped us produce this sixth edition;
To Mr. Cooper; and
To Papa, the original ‘Dr. McClung’

dthe Authors
This page intentionally left blank
Contents

Preface to the Sixth Edition xix Two lines of inquiry 15

The lines converge 15
Funk's theory 15
Impact of the new concept 17
Part I More than one accessory factor 17
Perspectives on the vitamins in Accessory factors prevent disease 17
nutrition Accessory factors the same as
vitamines 18
1. What is a vitamin? Elucidation of the vitamines 18
Crooked paths to discovery 18
Anchoring concepts 3 6. Elucidation of the vitamins 18
Learning objectives 3 New animal model reveals new
Vocabulary 3 vitamin: “C” 18
1. Thinking about vitamins 3 Fat-soluble A: actually two factors 19
2. Vitamin: a revolutionary concept 4 Vitamin A prevents rickets? 19
Everyday word or revolutionary concept? 4 New vitamin: “D” 19
Vitamin or vitamine? 4 β-Carotene, a provitamin 19
3. An operating definition 4 Vitamin a linked to vision 19
Some caveats 4 The nature of vitamin D 20
4. The recognized vitamins 5 Vitamers D 20
5. Chapter quiz 6 Multiple identities of water-soluble B 20
Vitamin B2: a complex of several
2. Discovery of the vitamins factors 21
Anchoring concepts 7
Vitamin B2 complex yields riboflavin 21
Learning objectives 7
Vitamin B2 complex yields niacin 21
Vocabulary 7
Pellagra: an infectious disease? 22
1. Emergence of nutrition as a science 8
Impact of an animal model for pellagra 22
2. Processes of discovery in nutritional science 8
B2 complex yields pyridoxine 23
3. The empirical phase of vitamin discovery 8
B2 complex yields pantothenic acid 23
Diseases linked to diet 9
A fat-soluble, antisterility factor:
Ideas prevalent by 1900 12
vitamin E 23
Limitations of empirical observations 12
A classic Touch in coining tocopherol 24
4. The experimental phase of vitamin Antihemorrhagic factor: vitamin K 24
discovery 12
Vitamers K 25
Requirements of nutrition science 13
Bios yields biotin 25
Defined diets provided repeatability 13
Antianemia factors 26
Animal models provided relevance 13
Vitamin M? 26
An animal model for beriberi 13
Factors U and R, and vitamin Bc 26
Serendipity or a keen eye? 14
Yeast growth related to anemia? 26
Antiberiberi factor is announced 14
Who's on first? 26
5. The vitamine theory 14
Derivatives of pteroylglutamic acid 27
Defined diets revealed needs for accessory Antipernicious anemia factor 27
factors 14
Intrinsic and extrinsic factors 27

vii
viii Contents

Animal protein factors 27 Part II

Vitamin B12 isolated 28
Vitamins discovered in only five
The individual vitamins
decades 28
7. Vitamin terminology 28
5. Vitamin A
8. Other factors sometimes called vitamins 28 Anchoring concepts 77
9. Modern history of the vitamins 30 Learning objectives 77
10. Chapter quiz 31 Vocabulary 77
Recommended reading 32 1. Significance of vitamin A 78
Key papers of historical significance 32 2. Properties of vitamin A 79
Chemical properties of vitamin A 79
3. General properties of vitamins 3. Sources of vitamin A 80
Foods 80
Anchoring concepts 35
Microbiome 83
Learning objectives 35
Bioavailability 83
Vocabulary 35
Expressing vitamin A biological activity 84
1. Vitamin nomenclature 36
4. Vitamin A absorption 84
2. Chemical and physical properties of the
Enteric absorption of retinoids 84
vitamins 39
Enteric absorption of provitamin A
Vitamin stability 39
carotenoids 85
3. Physiological utilization of the vitamins 39
Mucosal metabolism of retinol 87
Vitamin absorption 39
5. Vitamin A transport 88
Vitamin transport 49
Mucosal secretion to chylomicra 88
Tissue distribution of the vitamins 51
Vitamin A storage 88
4. Metabolism of the vitamins 52
Transport of vitamin A to peripheral
Some vitamins have limited biosynthesis 52
tissues 89
Most vitamins require metabolic
Cellular uptake of retinol 92
activation 52
Vitamin A in critical tissues 93
Vitamin binding to proteins 52
6. Vitamin A metabolism 94
Vitamin excretion 53
Metabolic fates of retinol 94
5. Metabolic functions of the vitamins 54
Metabolic fates of retinal 95
Vitamins serve five basic functions 54
Metabolic fates of retinoic acid 95
6. Vitamin bioavailability 55
Vitamin A excretion 99
7. Vitamin analysis 58
7. Metabolic functions of vitamin A 99
8. Chapter quiz 58
Function of vitamin A in vision 99
Recommended reading 60
Regulation of gene transcription 101
Nontranscriptional functions of
4. Vitamin deficiency vitamin A 104
Anchoring concepts 61 Antioxidant protection 104
Learning objectives 61 Physiological effects of vitamin A 105
Vocabulary 61 8. Biomarkers of vitamin A status 108
1. The concept of vitamin deficiency 62 Serum retinol 108
What is meant by the term vitamin RBP4 108
deficiency? 62 Doseeresponse tests 108
Vitamin deficiencies involve cascades of Potential confounders 109
progressive changes 62 9. Vitamin A requirements 109
2. Clinical manifestations of vitamin 10. Vitamin A deficiency 112
deficiencies 64 General deficiency signs 113
3. Biochemical lesions of vitamin Ocular signs of vitamin A deficiency 113
deficiencies 64 11. Other deficiency signs in humans 115
4. Diagnosing vitamin deficiencies 67 Signs in animals 117
5. Contexts of vitamin deficiencies 68 Treatment of vitamin A deficiency 117
6. Effective interventions 73 12. Other roles of vitamin A in health
7. Chapter quiz 74 and disease 119
Recommended reading 74 Infections 119
 Contents ix

Skin health 122 11. Other roles of vitamin D in health and

Cardiovascular health 123 disease 182
Obesity 123 Psoriasis 182
Cancer 124 Multiple sclerosis 183
13. Vitamin A toxicity 125 Type 2 diabetes 183
Hypervitaminosis A 125 Asthma 183
Signs of toxicity 127 Graft acceptance 184
Adverse effects of topical vitamin A 128 Cancer 184
Embryotoxic potential of high levels 12. Vitamin D toxicity 187
of vitamin A 128 13. Case studies 188
Recommended upper limits of exposure 128 14. Chapter quiz 190
14. Case studies 128 Recommended reading 190
15. Chapter quiz 131
Recommended reading 131 7. Vitamin E
Anchoring concepts 193
6. Vitamin D
Learning objectives 193
Anchoring concepts 133 Vocabulary 193
Learning objectives 133 1. Significance of vitamin E 194
Vocabulary 133 2. Properties of vitamin E 195
1. Significance of vitamin D 134 Vitamin E structure 195
2. Properties of vitamin D 135 Vitamin E chemistry 196
Chemical properties of vitamin D 135 Vitamin E stability 197
3. Sources of vitamin D 136 Vitamin E biopotency 197
Endogenous biosynthesis of vitamin D3 136 Expressing vitamin E biological activity 197
Food sources of vitamin D 140 3. Sources of vitamin E 198
Vitamin D analogs 144 Distribution in foods 198
Vitamin D bioavailability 144 4. Vitamin E absorption 199
Expressing vitamin D activities 144 Micellar absorption requires fat 200
4. Vitamin D absorption 145 Uptake from micelles 201
Dermal absorption 145 5. Vitamin E 202
Enteric absorption 145 Transport 202
5. Vitamin D transport 145 Roles of lipoproteins 202
Cellular uptake 146 Cellular uptake 203
Tissue distribution 147 Tissue vitamin E 205
6. Vitamin D metabolism 147 6. Vitamin E metabolism 207
Metabolic activation 147 7. Oxidative shortening of the phytyl side
Catabolism 149 chain 207
Regulation of vitamin D metabolism 149 β-Oxidation of the chroman ring 209
7. Metabolic functions of vitamin D 151 Redox cycling 209
Vitamin D3 as a steroid hormone 151 Other metabolism 210
Genomic pathways of vitamin D action 151 Excretory metabolites 210
Physiological functions of vitamin D 157 8. Metabolic functions of vitamin E 210
8. Biomarkers of vitamin D status 168 Vitamin E as a biological antioxidant 210
9. Vitamin D requirements 170 Antioxidant functions of vitamine E 212
10. Vitamin D deficiency 172 Nonantioxidant metabbolic functions of
Causes of vitamin D deficiency 172 vitamin E 215
Signs of vitamin D deficiency 173 9. Biomarkers of vitamin E status 224
Nonskeletal effects of hypovitaminosis D 177 Other biomarkers of vitamin E status 224
Vitamin D deficiency in animals 179 10. Vitamin E requirements 225
Responses to treatment 181 11. Vitamin E deficiency 225
x Contents

12. Vitamin E deficiency signs in humans 227 11. Other roles of vitamin K in health and
13. Vitamin E deficiency signs in animals 228 disease 265
14. Other roles of vitamin E in health and Obesityediabetes 265
disease 230 COVID-19 265
Antiinflammatory effects 230 12. Vitamin K toxicity 266
Cardiovascular disease 230 13. Case studies 266
Enhancing management of type 2 diabetes 232 14. Chapter quiz 268
Minimizing oxidative damage from air Recommended reading 268
pollution and smoking 232
Protection from ionizing radiation 233 9. Vitamin C
Protection from altitude sickness 233
Anchoring concepts 271
Reducing ischemiaereperfusion injury 233
Learning objectives 271
Benefits in other conditions 234
Vocabulary 271
15. Vitamin E toxicity 234
1. Significance of vitamin C 272
16. Case studies 235
2. Properties of vitamin C 272
17. Chapter quiz 237
Vitamin C chemistry 272
Recommended reading 238
Vitamin C biopotency 273
3. Sources of vitamin C 273
8. Vitamin K Biosynthesis of ascorbic acid 273
Anchoring concepts 239 Evolutionary loss of biosynthetic capacity 274
Learning objectives 239 Food sources of vitamin C 275
Vocabulary 239 Stability in foods 276
1. Significance of vitamin K 240 Vitamin C bioavailability 276
2. Properties of vitamin K 240 4. Vitamin C 276
Vitamin K chemistry 241 Absorption 276
Vitamin K biopotency 242 5. Vitamin C 277
3. Sources of vitamin K 242 Transport 277
Biosynthesis by the gut microbiome 242 Cellular uptake 277
Dietary sources 243 Tissue distribution 279
Breast milk 244 6. Vitamin C 279
Bioavailability 245 Metabolism 279
4. Vitamin K absorption 245 Ascorbate regeneration 280
Micellar solubilization 245 Excretion 280
5. Vitamin K 246 7. Metabolic functions of vitamin C 281
Transport 246 Fundamental roles in metabolism 281
Cellular uptake 246 Interactions with other dietary factors 283
Tissue distribution 247 Enzyme cosubstrate functions 284
6. Vitamin K metabolism 247 Physiological functions of ascorbic acid 287
Side chain modification 247 8. Biomarkers of vitamin C status 293
Redox cycling 248 Vitamin C status can be assessed in
Side-chain catabolism 249 several ways 293
Vitamin K antagonists 250 9. Vitamin C requirements 294
7. Metabolic functions of vitamin K 250 10. Vitamin C deficiency 295
Vitamin K-dependent γ-carboxylations 250 Hypovitaminosis C 296
Vitamin K-dependent Gla proteins 251 Signs of deficiency 296
Physiological functions of Gla proteins 251 Signs in humans 296
8. Biomarkers of vitamin K status 260 Responses to vitamin C treatment 298
9. Vitamin K requirements 261 11. Other roles of vitamin C in health and
10. Vitamin K deficiency 262 disease 298
Signs of vitamin K deficiency 263 Protection against oxidative stress 298
 Contents xi

Antihistamine effects 300 15. Case studies 334

Cardiovascular disease 300 16. Chapter quiz 336
Cancer 301 Recommended reading 336
Fractures 301
Infection 302 11. Riboflavin
Postsurgical healing 305
Anchoring concepts 337
Pain management 305
Learning objectives 337
Hyperpigmentation 305
Vocabulary 337
12. Vitamin C toxicity 306
1. Significance of riboflavin 338
13. Case studies 308
2. Properties of riboflavin 338
14. Chapter quiz 310
Riboflavin chemistry 338
Recommended reading 310
3. Sources of riboflavin 339
Hindgut microbial synthesis 339
10. Thiamin Distribution in foods 339
Anchoring concepts 313 Supplements 340
Learning objectives 313 Stability 341
Vocabulary 313 Bioavailability 341
1. Significance of thiamin 314 4. Riboflavin absorption 341
2. Properties of thiamin 314 Hydrolysis of coenzyme forms 341
3. Thiamin chemistry 314 Enteric absorption of free
4. Sources of thiamin 315 riboflavin 341
Limited hindgut microbial synthesis 315 5. Riboflavin transport 342
Distribution in foods 315 Protein carriers 342
Stability in foods 317 Cellular uptake 342
Thiamin antagonists 317 Tissue distribution 343
5. Thiamin absorption 318 6. Riboflavin metabolism 344
6. Thiamin transport 319 Conversion to coenzyme forms 344
Thiamin bound to proteins 319 Synthesis of flavoenzymes 344
Cellular uptake 319 Catabolism 345
Tissue distribution 319 Excretion 345
7. Thiamin metabolism 320 7. Metabolic functions of riboflavin 345
Phosphorylationedephosphorylation 320 Coenzyme functions 345
Catabolism 321 Key metabolic roles 347
Excretion 321 Genetic and epigenetic regulation 348
8. Metabolic functions of thiamin 322 Physiological functions of riboflavin 349
Cosubstrate functions of thiamin Visual function 350
phosphate esters 322 Erythropoiesis 350
Coenzyme functions of thiamin Neural function 350
pyrophosphate 322 Immune function 350
Physiological functions of thiamin 324 Mineral utilization 350
9. Biomarkers of thiamin status 326 Anticarcinogenesis 350
10. Thiamin requirements 327 8. Biomarkers of riboflavin status 351
11. Thiamin deficiency 327 The eGRac assay 351
General signs 327 Other biomarkers 351
12. Signs in humans 329 9. Riboflavin requirements 351
Deficiency signs in animals 332 10. Riboflavin deficiency 351
Response to treatment 333 Causes 351
13. Other roles of thiamin in health and Subclinical riboflavin deficiency 353
disease 333 General signs 353
14. Thiamin toxicity 334 Signs in humans 355
xii Contents

Signs in animals 356 11. Other roles of niacin in health and

11. Other roles of riboflavin in health and disease 379
disease 357 Cardiovascular health 379
Migraine 357 Type 2 diabetes 381
Multiple sclerosis 357 Nonalcoholic fatty liver disease 382
Cancer 357 Hyperphosphatemia 382
Malaria 357 Skin diseases 382
12. Riboflavin toxicity 358 Lung Health 382
13. Case study 358 Cancer 383
14. Chapter quiz 360 Other effects 383
Recommended reading 360 12. Niacin toxicity 383
Nicotinic acid 383
12. Niacin Nicotinamide 383
13. Case studies 384
Anchoring concepts 361
14. Chapter quiz 386
Learning objectives 361
Recommended reading 386
Vocabulary 361
1. Significance of niacin 362
13. Vitamin B6
2. Properties of niacin 362
Niacin chemistry 362 Anchoring concepts 387
3. Sources of niacin 364 Learning objectives 387
Limited hindgut microbial synthesis 364 Vocabulary 387
De novo synthesis from tryptophan 364 1. Significance of vitamin B6 388
Roles of other dietary factors 365 2. Properties of vitamin B6 388
Food sources of niacin 366 Vitamin B6 chemistry 388
Stability 367 3. Sources of vitamin B6 388
Bioavailability 367 Hindgut microbial synthesis 388
4. Niacin absorption 367 Distribution in foods 389
Digestion of pyridine nucleotides 367 Stability 389
Facilitated absorption 368 Bioavailability 389
5. Niacin transport 369 4. Vitamin B6 absorption 392
Free in plasma 369 Digestion of food forms 392
Cellular uptake 369 Two means of absorption 392
Tissue storage 369 5. Vitamin B6 transport 392
6. Niacin metabolism 369 Portal circulation to the liver 392
NAD salvage 369 Plasma circulation 392
Catabolism 371 Cellular uptake 392
Excretion 371 Tissue distribution 393
7. Metabolic functions of niacin 371 6. Vitamin B6 metabolism 393
Enzyme cosubstrate functions 371 Interconversion of vitamers 393
NADþ as a neurotransmitter 373 Catabolism 394
Genomic stabilization 373 Excretion 394
Signaling 373 7. Metabolic functions of vitamin B6 395
Physiological functions of niacin 374 Modulation of gene expression 395
8. Biomarkers of niacin status 375 Coenzyme function 395
9. Niacin requirements 376 Physiological Functions of
10. Niacin deficiency 377 vitamin B6 399
General signs of deficiency 378 Support of cardiovascular function 400
Signs in humans 378 Support of immune function 401
Response to treatment 378 Support of glycemic control 402
Signs in animals 378 Anticarcinogenesis 402
 Contents xiii

8. Biomarkers of vitamin B6 status 403 6. Metabolic functions of biotin 422

Plasma metabolites 403 Coenzyme function 422
Erythrocyte tests 404 Modulation of gene expression 425
Urine tests 404 Other biotin-containing proteins 426
Load tests 404 Physiological functions of biotin 426
Potential confounders 404 7. Biomarkers of biotin status 427
9. Vitamin B6 requirements 405 Carboxylase assays 427
10. Vitamin B6 deficiency 405 Blood and urinary metabolites 427
Privational causes 405 8. Biotin requirements 428
Nonprivational causes 405 9. Biotin deficiency 428
Vitamin B6edependent hereditary Privational causes 429
disorders 405 Nonprivational causes 429
General signs of vitamin B6 deficiency 407 Signs of biotin deficiency 429
Signs in humans 407 Signs in humans 429
Signs in animals 409 Signs in animals 430
11. Other roles of vitamin B6 in health 10. Other roles of biotin in health and
and disease 409 disease 431
Sickle cell anemia 409 Multiple sclerosis 431
Iron storage disease 410 Sudden infant death syndrome 432
Adverse drug effects 410 Valproic acid side effects 432
Carpal tunnel syndrome 410 Muscle cramps in hemodialysis patients 432
Type 2 diabetes 410 11. Biotin toxicity 432
Monosodium glutamate sensitivity 410 12. Case studies 432
Premenstrual syndrome 410 13. Chapter quiz 434
Nausea and vomiting of pregnancy 411 Recommended reading 434
12. Vitamin B6 toxicity 411
13. Case studies 411 15. Pantothenic acid
14. Chapter quiz 412
Anchoring concepts 435
Recommended reading 413
Learning objectives 435
Vocabulary 435
14. Biotin 1. Significance of pantothenic acid 436
Anchoring concepts 415 2. Properties of pantothenic acid 436
Learning objectives 415 Pantothenic acid chemistry 436
Vocabulary 415 3. Sources of pantothenic acid 436
1. Significance of biotin 416 Hindgut microbial synthesis 436
2. Properties of biotin 417 Distribution in foods 436
Biotin chemistry 417 Stability 438
3. Sources of biotin 417 Bioavailability 438
Hindgut microbial synthesis 417 4. Pantothenic acid absorption 438
Distribution in foods 417 Hydrolysis of coenzyme forms 438
Stability 419 Two means of absorption 438
Bioavailability 419 5. Pantothenic acid transport 439
4. Biotin absorption 419 Plasma and erythrocytes 439
Digestion of protein-bound biotin 419 Cellular uptake 439
Two general means of absorption 419 Tissue distribution 440
Biotin can also be absorbed by passive 6. Pantothenic acid metabolism 440
diffusion 420 Coenzyme A synthesis 440
Biotin transport 420 Acyl-CoA synthesis 441
5. Biotin 421 Acyl carrier protein synthesis 441
Metabolism 421 Recycling 441
xiv Contents

Excretion 442 6. Folate metabolism 463

Disorders of pantothenic acid metabolism 442 Reduction of the pteridine ring 463
7. Metabolic functions of pantothenic acid 443 Reaction of the side chain 464
Coenzyme functions 443 Acquisition of single-C moieties 464
Physiological functions of pantothenic Catabolism 465
acid 446 Excretion 465
8. Biomarkers of pantothenic acid status 446 Polymorphisms of enzymes in folate
9. Pantothenic acid requirements 446 metabolism 465
10. Pantothenic acid deficiency 446 Effects of drugs 467
Privational causes 446 7. Metabolic functions of folate 467
Nonprivational causes 447 Single-carbon metabolism 468
Signs of pantothenic acid deficiency 447 The methyl-folate trap 471
Signs in humans 447 Nucleotide metabolism 471
Signs in animals 448 Physiological functions 473
11. Other roles of pantothenic acid in 8. Biomarkers of folate status 478
health and disease 449 Approaches for the assessment of folate
Reduced serum cholesterol level 449 status 479
Rheumatoid arthritis 449 9. Folate requirements 480
Wound healing 449 10. Folate deficiency 481
Facial acne 450 Privational causes 481
Lupus 450 Nonprivational causes 481
Pantothenic acid inhibitors as Metabolic impairments 481
antibiotics 450 General signs of folate deficiency 482
Unverified claims 450 Signs in humans 482
12. Pantothenic acid toxicity 450 Low folate status 482
13. Case studies 450 Signs in animals 485
14. Chapter quiz 452 11. Other roles of folate in health and
Recommended reading 452 disease 486
Pernicious anemia 486
16. Folate Homocysteinemia 486
Sickle cell disease 488
Anchoring concepts 453
Hyperuricemia 488
Learning objectives 453
Malaria 488
Vocabulary 453
Arsenicosis 488
1. Significance of folate 454
12. Folate toxicity 488
2. Properties of folate 455
13. Case studies 489
Folate nomenclature 455
14. Chapter quiz 492
Folate chemistry 455
Recommended reading 492
3. Sources of folate 456
Synthesis by the gut microbiome 456
17. Vitamin B12
Distribution in foods 456
Folate fortification and Anchoring concepts 493
supplementation 457 Learning objectives 493
Stability 458 Vocabulary 493
Bioavailability 459 1. Significance of vitamin B12 494
4. Folate absorption 460 2. Properties of vitamin B12 494
5. Folate transport 461 Vitamin B12 nomenclature 494
Erythrocytes 461 Vitamin B12 chemistry 494
Free in plasma 461 3. Sources of vitamin B12 495
Protein bound in plasma 462 Synthesis by microbes 495
Cellular uptake 462 Distribution in foods 495
Tissue distribution 463 Vegetarian Diets 498
 Contents xv

Breast milk 498 18. Quasi-vitamins

Stability 498
Bioavailability 498 Anchoring concepts 523
4. Vitamin B12 absorption 499 Learning objectives 523
Digestion 499 Vocabulary 524
Protein binding 499 1. Is the list of vitamins complete? 525
Mechanisms of absorption 499 Conditionally essential nutrients 525
5. Vitamin B12 transport 500 2. Choline 525
Transport proteins 500 Recognition of a role of choline in nutrition 525
Cellular uptake 501 Chemical properties of choline 525
Intracellular protein binding 501 Choline biosynthesis 526
Congenital disorders of vitamin B12 Conditions of need for dietary choline 526
absorption and transport 501 Dietary sources of choline 527
Distribution in tissues 502 Absorption and transport of choline 528
6. Vitamin B12 metabolism 503 Choline metabolism 529
Intracellular trafficking 503 Genetic disorders of choline metabolism 530
Activation to the coenzyme Metabolic functions of choline 530
forms 503 Physiological functions of choline 531
Catabolism 504 Choline deficiency 533
Excretion 504 Recommended choline intakes 533
Enterohepatic circulation of Biomarkers of choline status 534
vitamin B12 504 Choline toxicity 534
Congenital disorders of vitamin B12 3. Carnitine 535
metabolism 504 Recognition of a nutritional role of
7. Metabolic functions of vitamin B12 504 carnitine 535
Coenzyme functions 504 Chemical properties of carnitine 536
Interrelationships with folate 506 Carnitine biosynthesis 536
Physiological functions of Conditions of need for dietary carnitine 536
vitamin B12 506 Dietary sources of carnitine 538
8. Biomarkers of vitamin B12 status 509 Absorption and transport of carnitine 538
Serum/plasma vitamin B12 509 Carnitine metabolism 539
Serum/plasma HoloTC 510 Metabolic functions of carnitine 539
Serum/plasma/urine methylmalonic Physiological functions of carnitine 540
acid 510 Biomarkers of carnitine status 544
Distinguishing deficiencies of Carnitine safety 544
vitamin B12 and folate 511 4. myo-Inositol 544
9. Vitamin B12 requirements 511 Recognition of a nutritional role of
10. Vitamin B12 deficiency 511 myo-inositol 544
Privational causes 511 Chemical nature 545
Nonprivational causes 513 Biosynthesis of myo-inositol 545
General signs of deficiency 515 Conditions of need for dietary
Signs in humans 516 myo-inositol 545
Low vitamin B12 status 516 Dietary sources of myo-inositol 546
Signs in animals 517 Absorption and transport of
Response to treatment 518 myo-inositol 547
11. Other roles of vitamin B12 in health Metabolism of myo-inositol 548
and disease 518 Congenital defects in myo-inositol
Neuropathic pain therapy 518 metabolism 548
Cyanide binding 518 Metabolic functions of myo-inositol 548
12. Vitamin B12 toxicity 519 Physiological effects of myo-inositol 549
13. Case studies 519 Support of neurological function 550
14. Chapter quiz 521 Support of healthy pregnancy 550
Recommended reading 521 Biomarkers of myo-inositol status 551
Safety of myo-inositol 551
xvi Contents

5. Ubiquinones 551 Absorption and transport of flavonoids 576

Recognition of nutritional roles of Metabolism of flavonoids 576
ubiquinones 551 Metabolic effects of flavonoids 577
Chemical nature of the ubiquinones 551 Enzyme modulation. flavonoids can
Conditions of need for dietary affect the activities of many enzymes 577
ubiquinones 552 Physiological effects of flavonoids 578
Conditions limiting ubiquinone Biomarkers of flavonoid status 583
biosynthesis 552 Flavonoid safety 583
Conditions increasing ubiquinone need 553 9. Unidentified factors 584
Dietary sources of ubiquinones 553 10. Case studies 584
Absorption and transport of ubiquinones 553 11. Chapter quiz 587
Metabolism of ubiquinones 554 Recommended reading 587
Metabolic functions of ubiquinones 555
Physiological effects of ubiquinones 555
Biomarkers of ubiquinone status 557 Part III
Safety of ubiquinones 557 Using current knowledge of the
6. Lipoic acid 557
Chemical nature of lipoic acid 557
vitamins
Conditions limiting lipoic acid
biosynthesis 558
19. Sources of the vitamins
Dietary sources of lipoic acid 558 Anchoring concepts 593
Absorption and transport of lipoic acid 558 Learning objectives 593
Metabolism of lipoic acid 559 Vocabulary 593
Metabolic functions of lipoic acid 559 1. Vitamins in foods and feedstuffs 594
Physiological functions of lipoic acid 560 Vitamin content data 594
Biomarkers of lipoic acid status 561 Core foods for vitamins 594
Safety of lipoic acid 561 Vitamins in staple foods 595
Beneficial bioactive factors 561 2. Vitamin bioavailability 600
7. Nonprovitamin A carotenoids 561 Extrinsic factors 600
Benefits of nonprovitamin A carotenoids 561 Intrinsic factors 600
Chemical properties of nonprovitamin A 3. Vitamin losses in foods 601
carotenoids 561 4. Adding vitamins to foods 603
Dietary sources of nonprovitamin A Purified vitamins 603
carotenoids 562 Vitamin formulations 604
Absorption and transport of Vitamin markets 605
nonprovitamin A carotenoids 562 Addition of vitamins to foods 605
Metabolism of nonprovitamin A carotenoids 565 Stabilities of vitamins added to foods 606
Metabolic functions of nonprovitamin A 5. Biofortification 606
carotenoids 566 6. Vitamin labeling of foods 609
Physiological functions of nonprovitamin A 7. Vitamins in human diets 609
carotenoids 566 Vitamin intakes from foods 610
Biomarkers of nonprovitamin A carotenoid Vitamins in breast milk and formula
status 571 foods 611
Recommended intakes 571 8. Vitamin supplementation 615
Safety of nonprovitamin A carotenoids 572 Guidelines for supplement use 615
8. Flavonoids 572 9. Vitamins in livestock feeding 617
Recognition of nutritional roles of Vitamins in animal feeds 617
flavonoids 572 Losses of vitamins from feedstuffs and
Benefits of dietary flavonoids 573 finished feeds 618
Chemical properties of flavonoids 573 Vitamin premixes for animal feeds 619
Dietary sources 574 Stabilities of vitamins in feeds 620
 Contents xvii

10. Case study 621 DRIs 651

11. Chapter quiz 622 International standards 654
Recommended reading 622 3. Vitamin allowances for animals 654
Public versus private data 654
20. Assessing vitamin status 4. Case study 654
5. Chapter quiz 659
Anchoring concepts 625 Recommended reading 659
Learning objectives 625
Vocabulary 625 22. Vitamin safety
1. Nutritional assessment 625
Approaches to nutritional assessment 626 Anchoring concepts 661
Methods of nutritional assessment 626 Learning objectives 661
2. Biomarkers of vitamin status 628 Vocabulary 661
Biomarkers 628 1. Uses of vitamins above required
Reserve capacities of vitamins 632 levels 661
3. Vitamin status of human populations 632 Typical uses exceed requirements 661
National nutrition surveillance 632 2. Safe intakes of vitamins 662
4. Global undernutrition 637 Quantifying safe intakes 662
Case study 641 Safe vitamin intakes 663
5. Chapter quiz 641 3. Hypervitaminoses 663
Recommended reading 641 Factors affecting vitamin toxicity 663
Signs and symptoms of hypervitaminoses 665
4. Case studies 672
21. Vitamin needs 5. Chapter quiz 673
Anchoring concepts 643 Recommended reading 673
Learning objectives 643
Vocabulary 643
1. Dietary standards for vitamins 644 Appendix A Current and Obsolete Designations
Purposes of dietary standards 644 of Vitamins and Vitamin-Like Factors
Determining nutrient requirements 644 (Designations in current use are bolded) 675
Factors affecting vitamin needs 645 Appendix B Original reports used for case studies 679
Developing vitamin allowances 645 Appendix C A core of current vitamin literature 683
Differences between requirements and Appendix D Vitamin contents of foods
allowances 647 (units per 100 g edible portion) 691
The RDA concept 647 Appendix E Vitamin contents of feedstuffs
Considering nonclassical functions of (units per kg) 725
nutrients 649 Appendix F 20 Questions to examine vitamin
New paradigms for nutrition 649 knowledge 729
Reconstructing the RDA 650
2. Vitamin allowances for humans 650
History of dietary standards 650 Index 731
This page intentionally left blank
Preface to the Sixth Edition
Understanding the vitamins is fundamental to understanding
nutrition. The history of their discovery and the continuing
elucidation of their roles in health is the history of the
emergence of nutritional science out of the areas of physi-
ology, biochemistry, medicine, and agriculture. The practical
application of that knowledge draws on food science,
medicine, public health, economics, sociology, and agricul-
ture. Capturing the understanding and contemporary rele-
vance that was produced by that history and available for
contemporary application is a formidable challenge. It is also
a privilege. For us as authors, that task has involved years of
reviewing thousands of publications, and months of looking
for ways to present that complex information clearly and
with neither oversimplification nor overstatement.
Producing this sixth edition of “The Vitamins”
benefitted from the combined perspectives of an academic
who conceived the project more than 30 years ago and used
the book in his teaching at Cornell University, with those of
research scientist who studied the first first edition as a
graduate student at the University of New Hampshire and,
then, later editions as a student and teaching assistant at
Cornell University. We believe that the dynamic relation-
ship we have enjoyed for many yearsdas student/mentor,
colleagues, friends, and coauthorsdhas facilitated our
producing the most complete and up-to-date edition of this
text, such that it will be useful as a contemporary reference
as well as a teaching/learning aid.
In writing this sixth edition of “The Vitamins,” we were
aided by helpful insights from users of previous editions.
Those prompted us to make several changes that we believe
enhance its utility: reorganization of some chapters; expanded
discussions of the physiological functions of vitamins, and on
the quasi-vitamins; increased focus on the current knowledge
of the vitamin contents of breast milk; increased numbers of
citations to recent scientific publications; and double the
number of case studies. We have also added features to
facilitate self/on-line study: “key point” highlights, chapter
quizzes, and an appended list of examination-type questions.
We are grateful for the help of our friends and colleagues,
Dr. Dan Raiten, Dr. J. Thomas Brenna, and Dr. Xingen Lei.
We also appreciate the professional assistance of Ms. Kumar
Anabazhagan, Ms. Lindsay Lawrence, and Ms. Megan Ball of
Elsevier, Inc.
We enjoyed writing this sixth edition of The Vitamins.
We hope you will enjoy reading it and, most of all, find it
useful.
Gerald F. Combs, Jr.
Topsham, Maine
James P. McClung
Westborough, Massachusetts
June 10, 2021
HOW TO USE THIS BOOK
The Vitamins is intended as both a reference book and a
teaching text. In writing it, we had two audiences in mind.
TO THE HEALTH PROFESSIONAL
The Vitamins is designed as a one-stop source of compre-
hensive contemporary information about the vitamins
suited for a professional’s bookshelf. In it, you will find
information on the following:
l the History of Vitamin Discovery, which reveals the
disparate activities of people with the tools and under-
standings of an earlier time who were able to see in
diet-related phenomena possibilities that others had
missed;
l Chemical Properties of the Vitamins, their isomers
and metabolites, which provides a basis for understand-
ing their functions in animals and their foods;
l Utilization and Metabolism of the Vitamins, which
informs their varying potencies and biological activities;
l Consequences of their Deficient and Excessive
Intakes, which informs the physiological import of
achieving healthful intake;
l available Biomarkers, which provide tools for
diagnosing vitamin status; and
l Other Health Roles of Vitamins beyond prevention of
their traditional deficiency disorders, some of which
may surprise you.
Throughout the book, you will also find examples of
both classical and current research findings as well as
footnoted citations to key publications in the scientific
literature. In this sixth edition, we included complete
xix
xx Preface to the Sixth Edition
citations to make it easier for the reader to determine
whether to search those original reports or reviews.
The Appendices will be as easy references to the vitamin
contents of a foods and feedstuffs.
We are at your service for questions regarding this
edition and welcome your insights that may enhance future
editions of The Vitamins. We would also be grateful to
learn about ways you have used this volume to extend and
share your personal knowledge of the vitamins.
TO STUDENTS AND INSTRUCTORS
The Vitamins is also intended as a teaching text for an
upper-level/graduate study within Nutrition or Health-
related curricula. It will be useful in both traditional and
virtual classroom, as well as self-paced learning formats. It
has several features designed to enhance its utility for
teachers and learners:
l Advance Organizers: Each chapter opens with state-
ments of Anchoring Concepts, Learning Objectives,
and Vocabulary to look for (as they are defined in
context).
l Scannable Layout: The extensive use of section head-
ings and subheaders is designed to facilitate scanningd
to prepare the reader for the material and to help her/
him find material of special interest.
l Planned Redundancy: To enhance retention, cross-
cutting issues are addressed in multiple formats
throughout the book.
l Key Points: Concise summaries of major issues occur
throughout each chapter.
l Case Studies: Presentations of relevant cases from the
clinical literature, followed by Discussion Questions
to provoke thinking and discussion about vitamin
function.
l Extensive Footnotes: Citations to key research papers
and reviews, useful in pursuing information at deeper
levels than covered in the text.
l Chapter Quizzes: Summary questions to direct
thinking/discussion about key learnings from each
chapter.
l Recommended Reading: Useful reviews to facilitate
follow-up study of the chapter subject matter.
l Final Exam Questions: A slate of questions of the type
used in a final exam testing knowledge of the roles of
vitamins in nutrition and health.
To the student. When you use this text, make sure to
have by your side a notebook, pencil (not pendyou may
want to make changes in the notes you take). Before
reading each chapter, take a few moments to go over the
Anchoring Concepts and Learning Objectives on the
chapter title page. Those in the first several chapters should
already be familiar to you; if not, then it will be necessary
for you to do some background reading or discussion until
you feel comfortable in your understanding of these basic
ideas. You will find that most chapters build upon the
understanding gained through previous chapters; in most
cases, the Anchoring Concepts of a chapter relate to the
Learning Objectives of previous chapters. Pay attention to
the Learning Objectives; they are the key elements of un-
derstanding that the chapter is intended to support. Keeping
them in mind as you go through each chapter will help you
maintain focus on those elements. Next, read through the
Vocabulary list and mark any terms that are unfamiliar or
about which you feel unsure. Then, make a list of your own
questions about the topic of the chapter.
As you read through the text, look for items related to
your questions and for unfamiliar terms. You will be able to
find key terms in bold-face type, and you should be able
to get a good feel for their meanings from the contexts of
their uses. If this is not sufficient for any particular term,
then look it up in a medical dictionary. Don’t wait to do
this. Cultivate the habit of being bothered by not under-
standing somethingdthis will help you enormously in
years to come.
As you proceed through the text, note what information
the layout is designed to convey. First, note that the major
sections of each chapter are indicated with a bold heading.
This is done to help you scan for particular information.
Also note that the footnoted information is largely sup-
plementary and not essential to the understanding of the
key concepts presented. Therefore, the text may be read at
two levels: at the basic level, one should be able to ignore
the footnotes and still get the key concepts; at the more
detailed level, one should be able to pick up more back-
ground, particularly key citations to the primary literature,
from the footnotes. Refer back frequently to your own list
of questions and “target” vocabulary words; when you find
an answer or can make a deduction, make a note. Don’t
hesitate to write in the book, particularly to put a concept
into your own words, or to note something you find
important or don’t fully understand. Studies show that to be
an effective learning technique. When you have completed
a chapter, take some time to list what you see as the
key pointsdthose that you would cover in a formal
presentation. Then, skim back over the chapter.
You’ll find that Chapters 5e22 each have one or more
case studies based on actual clinical case reports abstracted
from the scientific literature. For each, use the associated
questions to focus your thinking on the features that relate
to vitamin functions. As you do so, try to ignore the
obvious connection with the subject of the chapter; put
yourself in the position of someone called upon to diagnose
the problem without prior knowledge of it involving a
nutrient. The Case Study in Chapter 19 is different; it is a
fictional but highly plausible scenario that calls for
a nonobvious decision.

Take some time and go through the Chapter Quiz at the
end of each chapter. These questions, too, are designed to
direct your thinking back to the key concepts of the
respective chapter, and to facilitate integration of those
concepts with those you already have. We have made a
point in Chapter 1 of using the technique of concept
mapping to illustrate the integration of complex subject
matter. We have found the concept map to be a powerful
teaching/learning tool. If you have had no previous
experience with this device, then it will be worth your while
to consult Learning How to Learn.1
When you have done all of this for a chapter, then
reconsider your questions. Discuss them with other students
and colleagues; consult the Recommended Reading list at
the end of each chapter; search PubMed2 for relevant
research papers and review. With the exception of Chapter 2,
which lists publications of landmark significance to the
discovery of the vitamins, the reading lists consist of key
reviews in prominent scientific journals. These reviews and
the papers cited in the footnotes will help you find primary
research papers on topics of specific interest.
Last, reread the chapter. You will find this last step to
be extraordinarily useful in gaining a command of the
material, and . Have fun with this fascinating and
important aspect of the field of nutrition!
To the instructor. The format of this text reflects the
way GFC taught “The Vitamins” course for nearly 27 years
at Cornell University, and JPMs experiences as both stu-
dent and teaching assistant. Some of our experiences in
using The Vitamins in teaching may be of interest. We
believe that you will find these approaches useful whether
you teach in a traditional or and virtual classroom. In fact,
the features identified before will make The Vitamins
particularly useful for online or self-paced learning, as they
will facilitate a logical progression on topical discussions
based on guided readings. Here are general principles we
have found useful in teaching and learning with The
Vitamins:
l Build on Existing Knowledge. Every student comes to
the study of the vitamins with some background knowl-
edge of the subject, although those backgrounds are
generally incomplete and frequently include some
misinformation. This is true for upper-level nutrition
majors and for students from other fields, the difference
being largely one of magnitude. This is also true for
instructors, most of whom come to the field with spe-
cific expertise that relates to only a subset of the subject
matter. You can demonstrate this with the following
1. Novak, J.D., Gowin, D.B., 1984. Learning How to Learn. Cambridge,
University Press, New York, NY, 199 pp.
2. A free search engine maintained by the US National Library of
Medicine accessing w32 million biomedical citations primarily the
MEDLINE database.
Preface to the Sixth Edition xxi
exercise, best done of the first day of class. Raise
your index finger (a bit of dramatic flair is always
good) and say “vitamin A.” Hold that pose for 10
seconds and then ask “What came to mind when I
said ‘vitamin A’?” Without fail, most in a group
will hesitate; but then, someone will say “vision” or
“carrots,” and then a more senior graduate student
may add “toxic” or “beta-carotene.” When it looks
safe to chime in, others will add what will build to an
array of descriptors that, collectively, are more relevant
to vitamin A than any is individually. Most of the
answers, by far, will relate to the clinical symptoms of
vitamin A deficiency and the sources of vitamin A in
diets. Catch each answer by dashing it on to a large
sticky note, and then post the note haphazardly to a
blackboard or wall. If you hear something complex or
a cluster of concepts, question the contributor until
you hear one or more individual concepts which you
can record on individual sticky notes. This approach
never fails to stimulate further answers, and it is
common that a group of 15e20 students will generate
a list of twice that number of concepts before the
momentum fades. Having used sticky notes, it is easy
to move them into clusters and, thus, to use the activity
to construct a concept map of “vitamin A” based solely
on the knowledge that the students, collectively,
brought into the room. This exercise can demonstrate
an empowering idea: that, having at least some back-
ground on the subject and being motivated (by any of
a number of reasons) to learn more, every learner brings
to the study of the vitamins a unique perspective which
may not be readily apparent.
l Create a Learning Community. Meaningful learning
is served when both instructor and students come to
understand one another’s perspectives. This has two
benefits in teaching the vitamins. First, it is in the
instructor’s interest to know the students’ ideas and
levels of understanding concerning issues of vitamin
need, function, etc., such that these can be built upon
and modified as may be appropriate. Second, many
upper-level students have interesting experiences
(through personal or family histories, their own
research, information from other courses, etc.) that
can be valuable contributions to classroom discussions.
These experiences are assets that can reduce the tempta-
tion to fall back on the “instructor knows all” notion,
which we all know to be false. To identify student
perspectives, it is useful to assign on the first class for
submission at the second class a written autobiograph-
ical sketch. Distribute your own as a model, and ask
each student to write “as much or as little” as he or
she cares to, recognizing that you will distribute to the
entire class copies of all submissions. The biographical
sketches will range from a few sentences that reveal
xxii Preface to the Sixth Edition
little of a personal nature, to longer ones that provide
many good insights about their authors; every one will
help you to get to know your students personally and
to get a better idea of their understandings of the vita-
mins and their expectations of the course. The exercise
serves the students in a similar manner, promoting a
group dynamic that facilitates classroom discussions.
l Using The Vitamins. The Vitamins can be used as a
typical text from which you can make regular reading
assignments as preparation for each class. This will
free you of the need to lecture and, instead, use an
open discussion format. In fact, this approach allows
more information to be covered, as even a brilliant
lecturer simply cannot cover the vitamins in any real
depth within the limits of traditional class periods and
term lengths. This was the original motivation for
writing this text, which allows shifting responsibility
for learning to the learner. This also allows class time
to be used to facilitate learning through discussions of
issues of student interest or concern. Often, this means
clarifying points were not clear upon reading, and
pursuing questions stimulating by the reading but not
satisfactorily addressed in the text. Usually, these
questions are nicely handled by eliciting the views
and understandings of other students and by the
instructor providing supplementary information.With
this approach, the instructor’s preparation involves
collating pertinent research data from the scientific
literature that can supplement the text, developing
topic-related questions that can stimulate student discus-
sions. In developing those questions, it may be useful to
prepare your own concept maps of the subject matter
and to focus questions on the linkages between con-
cepts, e.g.: “How does the mode of enteric absorption
of the tocopherols relate to what we know about its
physiochemical properties?” If you are unfamiliar
with concept mapping, then consult “Learning How to
Learn”1 and experiment with the technique to deter-
mine whether/how it can assist you.The Chapter Quiz
questions and/or Case Studies can be used as weekly
written assignments to keep students focused on the
topic and prevent them from letting the course slide
until exam time. More importantly, there is learning
associated with the thought that necessarily goes into
such written assignments. To support that learning,
make a point of going over each assignment briefly at
the beginning of the class at which it is due, and return
it by the next class with your written comments. You
will find that the Case Studies are abstracted from actual
clinical reports; students enjoy and do well on these
assignments.
l Course Management. The model used in teaching The
Vitamins at Cornell was to evaluate student performance
on the basis of class participation, weekly written assign-
ments, a review of a recent research paper, and either one
or two written examinations. To allow each student to
pursue a topic of specific individual interest, students
were asked to review a research paper published within
the last year, using the style of Nutrition Reviews.
Students were asked to make a short (10 min) oral,
in-class presentation of their review. Their reviews
were evaluated on the basis of critical analysis and on
the importance of the paper to the field. This assignment
was well received. Because many students are inexperi-
enced in research and will, thus, feel uncomfortable
in criticizing it, it is helpful to conduct in advance a
discussion of the general principles of experimental
design and statistical inference. Exams were also
concept-oriented: students were given brief case descrip-
tions and actual experimental data, and were asked to lay
out diagnostic strategies, develop hypotheses, design
means of hypothesis testing and interpretation of results,
etc. Many students may prefer the more familiar short-
answer test, which has less learning value; such inertia
can be overcome by using examples in class discussions
and/or homework assignments.
We found The Vitamins to be of great value as a
ready desk reference and as a guide in teaching of the
subject at Cornell. It is our wish that it will assist you
similarly in your work. Please let us know how it meets
your needs, and how we might enhance it for that pur-
pose.
Gerald F. Combs, Jr.
James P. McClung
Part I

Perspectives on the vitamins

in nutrition
This page intentionally left blank
Chapter 1
What is a vitamin?
Imagination is more important than knowledge.
Chapter Outline
Anchoring concepts
Learning objectives
Vocabulary
1. Thinking about vitamins
Anchoring concepts
1. Certain factors, called nutrients, are necessary for
normal physiological function of animals, including
humans. Some nutrients cannot be synthesized
adequately by the host and must therefore be obtained
from the external chemical environment; these are
referred to as dietary essential nutrients.
2. Diseases involving physiological dysfunction, often
accompanied by morphological changes, can result
from insufficient intakes of dietary essential nutrients.
Learning objectives
1. To understand the classic meaning of the term vitamin
as it is used in the field of nutrition.
2. To understand that the term vitamin describes both a
concept of fundamental importance in nutrition and
any member of a rather heterogeneous array of nutri-
ents, any one of which may not fully satisfy the classic
definition.
3. To understand that some compounds are vitamins for
one species and not another, and that some are vitamins
only under specific dietary or environmental conditions.
4. To understand the concepts vitamer and provitamin.
Vocabulary
Nutriome
Provitamin
Vitamer
Vitamin
The Vitamins. https://doi.org/10.1016/B978-0-323-90473-5.00028-8
Copyright © 2022 Elsevier Inc. All rights reserved.
A. Einstein.
3 2. Vitamin: a revolutionary concept 4
3 3. An operating definition 4
3 4. The recognized vitamins 5
3 5. Chapter quiz 6
1. Thinking about vitamins
Among the nutrients required for the many physiologic
functions essential to life are the vitamins. Unlike other
nutrients, the vitamins do not serve structural functions, nor
does their catabolism provide significant energy. Instead,
the physiologic functions of vitamins are highly specific,
and, for that reason, they are required in only small
amounts in the diet. The common food forms of most vi-
tamins require some metabolic activation to their functional
forms.
Although the vitamins share these general characteris-
tics, they show few close chemical or functional similar-
ities; their categorization as vitamins is strictly empirical.
Consider also that, whereas several vitamins function as
enzyme cofactors (vitamins A, K, and C, thiamin,1 niacin,
riboflavin, vitamin B6, biotin, pantothenic acid, folate, and
vitamin B12), not all enzyme cofactors are vitamins.2 Some
vitamins function as biological antioxidants (vitamins E
and C), and several function as cofactors in metabolic
oxidationereduction reactions (vitamins E, K, and C,
niacin, riboflavin, and pantothenic acid). Two vitamins
(vitamins A and D) function as hormones; one of them
(vitamin A) also serves as a photoreceptive cofactor in
vision.
1. The name of this vitamin is sometimes spelled with a terminal “e,” i.e.,
“thiamine.”
2. Other enzyme cofactors are biosynthesized, e.g., heme, coenzyme Q,
and lipoic acid.
3
4 PART | I Perspectives on the vitamins in nutrition
2. Vitamin: a revolutionary concept
Everyday word or revolutionary concept?
The term vitamin, today a common word in everyday lan-
guage, was born of a revolution in thinking about the in-
terrelationships of diet and health that occurred at the
beginning of the twentieth century. That revolution
involved the growing realization of two phenomena that are
now taken for granted, even by the nonscientist:
l Diets are sources of many important nutrients.
l Insufficient intakes of specific nutrients can cause
certain diseases.
In today’s world, each of these concepts may seem self-
evident, but in a world still responding to and greatly
influenced by the important discoveries in microbiology
made in the 19th century, each represented a major de-
parture from contemporaneous thinking in the area of
health. 19th-century physiologists perceived foods and di-
ets as sources of only four types of nutrients: protein, fat,
carbohydrate, ash,3 and water. After all, these accounted for
very nearly 100% of the mass of most foods. With this
view, it is understandable that, at the turn of the 20th
century, experimental findings that now can be seen as
indicating the presence of unrecognized nutrients were
interpreted, instead, as substantiating the presence of nat-
ural antidotes to unidentified disease-causing microbes.
Important discoveries in science have ways of directing,
even entrapping, one’s view of the world; resisting this ten-
dency calls for critical thinking and constant questioning.
That such minds were involved in early nutrition research is
evidenced by the spirited debates and frequent polemics that
ensued over discoveries of apparently beneficial new dietary
factors. Still, the systematic development of what emerged as
nutrition science depended on a new intellectual construct for
interpreting such experimental observations. Today, the field
of nutrition addresses a wide array of dietary essential and
beneficial nutrientsdthe nutriome.4
Vitamin or vitamine?
The elucidation of the nature of what was later to be called
thiamin occasioned the proposition of just such a new
construct in physiology.5 Aware of the impact of what was
3. The residue from combustion, i.e., minerals.
4. Multiple nutrients interacting withing the metabolic systems of an or-
ganism (Raiten, D.J., Combs, Jr., G.F., Steiber, A.L., et al., 2021.
Perspective: nutritional status as a biological variabale [NABV]: inte-
grating nutritional science into basic and clinical research and care. Adv.
Nutr. 2021 (00), 1e11).
5. This is a clear example of what T. H. Kuhn called a “scientific revo-
lution” (Kuhn, T.H., 1968. The Structure of Scientific Revolutions, Uni-
versity of Chicago Press, Chicago, 200 pp.), i.e., the discarding of an old
paradigm with the invention of a new one.
a departure from prevailing thought, its author, the Polish
biochemist Casimir Funk, chose to generalize from his
findings on the chemical nature of that “vital amine” to
suggest the term vitamine as a generic descriptor for many
such accessory factors associated with diets. That the
factors soon to be elucidated comprised a somewhat
chemically heterogeneous group, not all of which were
nitrogenous, does not diminish the importance of the
introduction of what was first presented as the vitamine
theory, later to become a key concept in nutrition: the
vitamin.
The term vitamin has been defined in various ways.
While the very concept of a vitamin was crucial to progress
in understanding human physiology and nutrition, the
actual definition of a vitamin has evolved in consequence of
that understanding.
3. An operating definition
For the purposes of the study of this aspect of nutrition, a
vitamin is defined as follows (Fig. 1.1). A vitamin
l is an organic compound distinct from fats, carbohy-
drates, and proteins;
l is a natural component of foods in which it is usually
present in minute amounts;
l is essential, also usually in minute amounts, for normal
physiological function (i.e., maintenance, growth,
development, and/or production);
l prevents a specific deficiency syndrome, which occurs
when it is absent or underutilized; and
l is not synthesized by the host in amounts adequate to
meet normal physiological needs.
This definition is captured in the concept map shown in
Fig. 1.1. It will be useful in the study of vitamins, as it
effectively distinguishes this class of nutrients from others
(e.g., proteins and amino acids, essential fatty acids, and
minerals) and indicates the needs in various normal phys-
iological functions. It also denotes the specificity of defi-
ciency syndromes by which the vitamins were discovered.
Furthermore, it places the vitamins in that portion of the
external chemical environment on which animals
(including humans) must depend for survival, thus dis-
tinguishing vitamins from hormones.
Some caveats
It will quickly become clear, however, that, despite its
utility, this operating definition has limitations, notably
with respect to the last clause. Many species can, indeed,
synthesize at least some of the vitamins, although not al-
ways at the levels required to prevent deficiency disorders.
Four examples illustrate this point:
 What is a vitamin? Chapter | 1 5

a Vitamin

foods
diet
organic compound

in

but not

but not
small amounts v

not sufficiently
but not

produced by
vitamers fat
protein

essenal roles in
a specific deficiency

which play
carbohydrate
dietary syndrome
biosynthesis
requirement

metabolism
FIGURE 1.1 Concept map of a vitamin.6

l Vitamin D. Individuals exposed to modest amounts of
sunlight can produce cholecalciferol, which functions as
a hormone. Only individuals without sufficient expo-
sure to ultraviolet light (e.g., livestock raised in indoor
confinement, people spending most of their days in-
doors) require dietary sources of vitamin D.
l Vitamin C. Most animal species have the ability to bio-
synthesize ascorbic acid. Only those few that lack the
enzyme L-gulonolactone oxidase (e.g., the guinea pig,
humans) cannot. For those species, ascorbic acid is
properly called vitamin C.
l Niacin. All animal species can synthesize nicotinic acid
mononucleotide from the amino acid tryptophan. Only
those for which this metabolic conversion is particularly
inefficient (e.g., the cat, fishes) and others fed low die-
tary levels of tryptophan require a dietary source of
niacin.
l Choline. Most animal species have the metabolic ca-
pacity to biosynthesize choline; however, some
(e.g., the chick, the rat) may not be able to employ
that capacity if they are fed insufficient amounts of
methyl-donor compounds. In addition, some (e.g., the
chick) do not develop that capacity fully until they are
several weeks of age. Thus, for the young chick and
6. The concept map can be a useful device for organizing thought, as its
discipline can serve to assist in identifying the nature and extent of con-
cepts related to the one in question. A concept map should be laid out as a
hierarchy of related concepts with the superordinate concept at the top and
all relationships between concepts identified with a verb phrase. Thus, it
can be “read” from top to bottom. One of the authors (GFC) has used
concept mapping in graduate-level teaching, both as a group exercise and
testing device. For a useful discussion of the educational value of the
concept map, the reader is referred to Novak, J.D., Gowin, D.B., 1984.
Learning How to Learn, Cornell University Press, Ithaca, NY, 199 pp.
for individuals of other species fed diets providing
limited methyl groups, choline is a vitamin.
With these counterexamples in mind, the definition of a
vitamin has specific connotations for animal species, stage
of development, diet or nutritional status, and physical
environmental conditions.7
Key points
The “vitamin caveat”
l Some compounds are vitamins for one species but not
another.
l Some compounds are vitamins only under specific di-
etary or environmental conditions.
4. The recognized vitamins
Thirteen substances or groups of substances are now
generally recognized as vitamins (Table 1.1); others have
been proposed.8 In some cases, the familiar name is actu-
ally the generic descriptor for a family of chemically related
compounds having qualitatively comparable metabolic ac-
tivities. For example, the term vitamin E refers to those
analogs of tocol or tocotrienol9 that are active in preventing
7. For this reason, it is correct to refer to vitamin C for the nutrition of
humans, but ascorbic acid for the nutrition of livestock.
8. These include such factors as inositol, carnitine, bioflavonoids, pan-
gamic acid, and laetrile, for some of which there is evidence of
vitamin-like activity (see Chapter 19).
9. Tocol is 3,4-dihydro-2-methyl-2-(4,8,12-trimethyltridecyl)-6-chromanol;
tocotrienol is the analog with double bonds at the 30 , 70 , and 110 positions on
the phytol side chain (see Chapter 7).
6 PART | I Perspectives on the vitamins in nutrition

TABLE 1.1 The vitamins: their vitamers, provitamins, and functions.

Group Vitamers Provitamins Physiological functions

Vitamin A Retinol b-Carotene Visual pigments; epithelial cell differentiation
Retinal cryptoxanthin
Retinoic acid
Vitamin D Cholecalciferol (D3) Calcium homeostasis; bone metabolism; transcription factor
Ergocalciferol (D2)
Vitamin E a-Tocopherol Membrane antioxidant
g-Tocopherol
Vitamin K Phylloquinones (K1) Blood clotting; calcium metabolism
Menaquinones (K2)
Menadione (K3)
Vitamin C Ascorbic acid Reductant in hydroxylations in the formation of collagen and carni-
Dehydroascorbic tine, and in the metabolism of drugs and steroids
acid
Vitamin B1 Thiamin Coenzyme for decarboxylations of 2-keto acids (e.g., Pyruvate)
and transketolations
Vitamin B2 Riboflavin Coenzyme in redox reactions of fatty acids and the tricarboxylic
acid (TCA) cycle
Niacin Nicotinic acid Coenzyme for several dehydrogenases
Nicotinamide
Vitamin B6 Pyridoxol Coenzyme in amino acid metabolism
Pyridoxal
Pyridoxamine
Folic acid Folic acid Coenzyme in single-carbon metabolism
Polyglutamyl
folacins
Biotin Biotin Coenzyme for carboxylations
Pantothenic Pantothenic acid Coenzyme in fatty acid metabolism
acid

Vitamin B12 Cobalamin Coenzyme in the metabolism of propionate, amino acids, and
single-carbon units

such syndromes as fetal resorption in the rat and myopa-
thies in the chick. In these cases, the members of the same
vitamin family are called vitamers. Some carotenoids can
be metabolized to yield the metabolically active form of
vitamin A; such a precursor of an actual vitamin is called a
provitamin.
5. Chapter quiz
1. Define “essential nutrient” in your own terms.
2. What key features define a vitamin?
3. What are the fundamental differences between vitamins
and hormones?
4. Are all “micronutrients” considered vitamins? Why or
why not?
5. Describe a situation in which a vitamin may be nutri-
tionally essential for one species but not another.
6. Using keywords and phrases, list briefly what you
already know about each of the recognized vitamins.
7. In your opinion, will contemporary science result in the
discovery of new vitamins? Why or why not?
Chapter 2

Discovery of the vitamins

When science is recognized as a framework of evolving concepts and contingent methods for gaining new knowledge, we see the very
human character of science, for it is creative individuals operating from the totality of their experiences who enlarge and modify the
conceptual framework of science.

J. D. Novak1

Chapter Outline
Anchoring concepts 7 6. Elucidation of the vitamins 18
Learning objectives 7 7. Vitamin terminology 28
Vocabulary 7 8. Other factors sometimes called vitamins 28
1. Emergence of nutrition as a science 8 9. Modern history of the vitamins 30
2. Processes of discovery in nutritional science 8 10. Chapter quiz 31
3. The empirical phase of vitamin discovery 8 Recommended reading 32
4. The experimental phase of vitamin discovery 12 General history of the vitamins 32
5. The vitamine theory 14 Key papers of historical significance 32

Anchoring concepts
1. A scientific theory is a plausible explanation for a set of
observed phenomena; because theories cannot be tested
directly, their acceptance relies on the absence of
dispositive evidence and a preponderance of supporting
evidence.
2. A scientific hypothesis is a tentative, falsifiable supposi-
tion that is assumed for the purposes of argument or
testing, and is thus used in the generation of evidence
by which theories can be evaluated.
3. An empirical approach to understanding the world in-
volves the generation of theories strictly by observation,
whereas an experimental approach involves the under-
taking of operations (experiments) to test the truthful-
ness of hypotheses. Physiology is the branch of
biology that seeks to elucidate the processes, activities,
and phenomena of life and living organisms, while
biochemistry seeks to elucidate the molecular bases
for such phenomena.
1. Novak, J.D., 1930 is a prominent American educator known for his
research on human learning, knowledge creation, and knowledge repre-
sentation. Prof. Novak spent most of his career at Cornell University where
he and his colleagues developed the technique of concept mapping as a
means of representing science knowledge.
4. The field of nutrition is derived from both of these dis-
ciplines; it seeks to elucidate the processes by which an-
imals or plants take in and utilize food substances.
Learning objectives
1. To understand the nature of the process of discovery in
the field of nutrition.
2. To recognize the major forces in the emergence of
nutrition science.
3. To understand the impact of the vitamine theory, as an
intellectual construct, on that process of discovery.
4. To understand that the discoveries of the vitamins pro-
ceeded along indirect lines, most often through the
seemingly unrelated efforts of many people.
5. To recognize the key events in the discovery of each of
the vitamins.
6. To become familiar with the basic terminology of the
vitamins and their associated deficiency disorders.
Vocabulary
Accessory factor
Anemia
Animal model
Animal protein factor
Ascorbic acid

The Vitamins. https://doi.org/10.1016/B978-0-323-90473-5.00021-5

Copyright © 2022 Elsevier Inc. All rights reserved. 7
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 THE IGNITION SYSTEM
The ignition system is the name applied to the batteries, coils,
commutator and spark plug which, acting as a whole, produce an
electric spark hot enough and at the right time to fire the charge in
the cylinder. There are three ways in which an electric current may
be obtained which have been found to be of practical use in
automobile construction. First, by a dry battery; second, by a storage
battery; and third, by magneto or dynamo. You can look up the
construction of these things in any good book on electricity, so that I
will not explain them further here. As the object of the whole system
is to produce a sufficiently hot spark to fire the mixture at the right
time, it is sometimes necessary to raise the pressure of the electric
current. When either a dry battery or storage battery or a certain type
of magneto is used, it is necessary to put it through what is known as
an induction coil in order to raise the pressure so it will be high
enough to jump across the two points in the cylinder.
An induction coil consists merely of a bundle of soft wires around
which is wound two separate coils of wire. The first, known as the
primary winding, is of coarse wire, and the second, known as the
secondary winding, is of fine wire. When the current flowing through
the primary coil is rapidly made and broken, another current of very
high voltage is created in the secondary circuit.
 Fig. 23—Wiring Diagram, showing electric circuit for one cylinder.
The sketch is only diagrammatic—not a reproduction of any actual
wiring system.

When the current starts to flow through the primary winding, the
bundle of wires immediately becomes a magnet and attracts the
vibrator. As soon as this occurs, however, the flow of the current is
interrupted and the vibrator resumes its former position and the
action is repeated. Thus you can see that the coil automatically
makes and breaks its own circuit. The rapidity with which this is done
may be changed at will by adjusting the vibrator screw.
 Fig. 24—The Four-cylinder, Four-cycle Diagram,
showing the order in which the various cylinders do
their work.

Having thus obtained an electric current of sufficient strength to

fire the mixture it is necessary to supply a device which will
automatically open and close the electric circuit at the proper time.
Such a device is called a commutator and consists of two parts; one
a rotating part, actuated by the engine, which makes a metallic
contact with one or more points on a stationary part, the points being
so located that contact occurs at the proper time for igniting the
charge in any particular cylinder.
 Fig. 25—Four-cylinder Wiring Diagram.

In the four-cylinder wiring diagram (Fig. 25) various parts of an

ignition system may be easily seen. The electric current is furnished
either by a set of dry cells or by a storage battery. Four individual
coils and a four point commutator are used. The commutator is
driven by means of bevel gears from the engine itself. A single
switch controls the whole circuit, it being provided with two points,
making it possible for either battery to be used at will.
 Fig. 26—Types of Spark Plugs.

Fig. 27—A Single Cylinder Commutator.

Diagrammatic sketch.
 Fig. 29—A Four-cylinder
Commutator.
Fig. 28—A Two-point Switch.

Fig. 30—A Two-cylinder Commutator.

 THE COOLING SYSTEM
In order to prevent the walls of the cylinder from becoming red
hot, it is necessary to cool them by some means, and this is done by
surrounding the cylinder with a water jacket through which the
cooling water is circulated.

Fig. 31—A Diagram showing piping and direction of circulation

in a One-cylinder Water-cooled Motor.

In order to prevent the water from boiling and evaporating, thus

making the constant addition of water necessary, a radiator is
introduced into the system. This radiator is made up of very thin
tubes which give up their heat rapidly, thereby keeping the
temperature of the water below the boiling point. A fan is also used
sometimes to draw the air through between the tubes, thereby
making the process of cooling take place more rapidly. The system is
so arranged that the water is drawn from the lower part of the
radiator where the water is coldest by means of a pump and forced
up through the water jackets and back into the radiator again.
Several different styles of pumps are used, but a very common one
is the gear pump shown in Fig. 32. As you will see by the drawing, it
consists of two gears en mesh with each other which revolve in the
direction indicated by the arrow. The water entering through the inlet
pipe is drawn around the outside and forced out through the outlet at
the top.

Fig. 32—A Gear Water Pump.

 Fig. 33—Front End of Motor,
showing radiator, fan and cam shaft
gears.
Fig. 34—A typical Radiator.
Fig. 35—Valve side of a Four-cylinder Motor.
Fig. 36—Opposite side of same Motor showing
Carburetor and Inlet Pipe.
 Fig. 37—Bottom view of same Motor with oil pan
removed showing Crank Shaft, and Connecting Rods.
 Fig. 38—Top view of same Motor showing Valve Caps
and Holes for Spark Plugs.

NOTE—Both views show motor mounted in ring frames

used for assembling in factory.
 THE TWO-CYCLE MOTOR.
Although the four-stroke cycle type of motor is used by most of
the automobile manufacturers, yet there is another type which has
given such good results that it is destined to become one of the
important forms to be used in gas engine vehicle manufacture.
 Fig. 39.

It therefore merits a brief description. It has the advantage of being

very simple in construction and operation, and for this reason it has
become very popular among the marine engine builders, although
with a few exceptions it has not as yet been accepted by motor car
engineers. It is called a Two-stroke Cycle Motor, so named because
it combines in two strokes the series of changes ordinarily
accomplished in four in the four-stroke cycle type. Its operation may
be seen by referring to the accompanying diagrams. It is first
assumed that the engine is being turned over by hand in the
direction indicated by the arrow. You will note that as the piston
moves up it will uncover a port (H), allowing the gasoline vapor from
the mixing chamber to enter the crank case. As soon as the piston
moves down again, a port (J) will be opened, allowing the mixture
which has just been compressed to rush through a “by-pass” (F), into
the “combustion chamber,” or upper part of the cylinder. Now, as the
piston moves up again on the next stroke, this charge is compressed
still more, then as the piston reaches its uppermost position the
charge is ignited and the engine begins to work under its own power.
The gases continue to act on the piston until nearly the end of the
stroke is reached, when you will notice, by referring to the drawing,
the exhaust port (G) is passed. At this point the burned gases rush
out into the air. You will also notice that in order to aid the discharge
and fill the cylinder again, as the piston travels a little farther down,
the inlet port will be again uncovered, and the next charge, which
has meanwhile been taken into the crank case and compressed, will
enter the cylinder, forcing the exhaust gases out.
 Fig. 40.

In order to prevent the vapor which has just entered the cylinder from
traveling straight across and out through the exhaust port, thus
wasting a portion of the fuel, a “baffle plate” (K) is cast on top of the
piston which deflects the gases toward the top of the combustion
chamber, producing a sort of whirling action which tends to scavenge
the cylinder most thoroughly. In order to prevent the burning gases
from traveling back into the crank case and igniting the gas there,
thus producing a “back explosion,” a wire gauze (S) is placed in the
“by-pass.” You will note that this type of motor has no valves, no
cams and no cam shaft, in fact, its simplicity is such that it practically
cannot get out of adjustment. It therefore is a form of gas engine
which as soon as engineers are able to educate the public to its
peculiarities bids fair to become as popular and practical as the four-
stroke cycle.
 INDEX
Cam shaft 21
Cam 20
Carburetor 28
Commutator 33
Connecting rod 26
Connecting rod—lubrication of 26
Cooling system 37
Crank case 27
Crank shaft 25
Cycle—explanation of four-stroke type 9
Cycle—explanation of two-stroke type 42
Cylinder 16
Electrical ignition 31
Exhaust valve 21
Fan—radiator 39
Float chamber 28
Gasoline valve 30
Ignition 31
Induction coil 32
Inlet valve 21
Piston pin 24
Piston ring 24
Piston 23
Pump—water 38
Radiator 39
Spark plug 35
Switch—electric 36
Valve grinding 21