VitaminsTheir Role in the Human Body

G.F.M. BallConsultant, London, UK

BlackwellScience

Vitamins: Their Role in the Human Body

VitaminsTheir Role in the Human Body

G.F.M. BallConsultant, London, UK

BlackwellScience

© 2004 by Blackwell Publishing Ltd, a Blackwell Publishing company

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To the memory of Mariah Margaret Ball

Foreword xiii

Preface xv

1 Historical Events Leading to the Establishment of Vitamins 1

1.1 Introduction 11.2 Early studies of nutritionally related diseases 21.3 Experiments on formulated diets 61.4 Naming of the vitamins 7 Further reading 7 References 7

2 Nutritional Aspects of Vitamins 8

2.1 Defi nition and classifi cation of vitamins 82.2 Nutritional vitamin defi ciency 82.3 Stability and bioavailability of vitamins 102.4 Vitamin requirements 11 Further reading 11 References 11

3 Background Physiology and Functional Anatomy 12

3.1 Movement of solutes across cell membranes and epithelia 133.2 The blood–brain, blood–cerebrospinal fl uid and placental barriers 263.3 Functional anatomy of the small and large intestine, liver and kidney 293.4 Digestion and absorption 363.5 Glucose transport 393.6 Digestion, absorption and transport of dietary fat 443.7 Neural and endocrine communication systems 473.8 Structure of bone and its growth and development 553.9 Cell proliferation 62 Further reading 64 References 64

4 Background Biochemistry 67

4.1 Major degradation pathways in which B-group vitamins are involved as coenzymes 68

Contents

viii Contents

4.2 Amino acid utilization 714.3 Defences against free radicals and other reactive species 754.4 Haemostasis 764.5 Atherosclerosis 80 Further reading 90 References 90

5 Background Immunology 94

5.1 General features of the immune system 945.2 Innate immunity 955.3 Infl ammation 1015.4 Acquired immunity 1035.5 Cytokines 1065.6 Hypersensitivity 1075.7 Immune suppression 1085.8 Neuroendocrine modulation of immune responses 108 Further reading 108 References 108

6 The Genetic Control of Protein Synthesis and its Regulation by Nuclear Hormone Receptors 110

6.1 Functional structure of DNA 1106.2 Role of RNA in protein synthesis 1136.3 Gene expression 1166.4 Mutation and polymorphism 1166.5 Basal transcription 1186.6 Regulated transcription 1206.7 Jun, Fos and the AP-1 complex 1256.8 Nuclear hormone receptors as regulators of protein synthesis 126 Further reading 131 References 131

7 Vitamin A: Retinoids and Carotenoids 133

7.1 Historical overview 1347.2 Chemistry and biological functions 1347.3 Dietary sources 1367.4 Absorption, transport and metabolism 1367.5 Nutritional factors that infl uence vitamin A status 1507.6 The role of vitamin A in vision 1517.7 Retinoids as regulators of gene expression 1557.8 Effects of vitamin A on the immune system 1717.9 Role of vitamin A in bone metabolism and embryonic development 1747.10 Vitamin A and cancer 1767.11 Vitamin A defi ciency and toxicity 178 Further reading 180 References 180

Contents ix

8 Vitamin D 188

8.1 Historical overview 1898.2 Chemistry and biological functions 1908.3 Dietary sources 1918.4 Cutaneous synthesis, intestinal absorption, transport and metabolism 1918.5 Molecular action of the vitamin D hormones 1988.6 Calcium and phosphate homeostasis 2088.7 Immunoregulatory properties 2188.8 Effects of vitamin D on insulin secretion 2218.9 Vitamin D-related diseases 2218.10 Therapeutic applications of vitamin D analogues 2228.11 Toxicity 2238.12 Dietary requirement 224 Further reading 224 References 224

9 Vitamin E 234

9.1 Historical overview 2359.2 Chemistry, biopotency and units of activity 2359.3 Dietary sources 2369.4 Absorption, transport and delivery to tissues 2369.5 Antioxidant role 2399.6 Effect upon the ageing immune responses 2409.7 Vitamin E and atherosclerosis 2419.8 Vitamin E defi ciency 2479.9 Dietary intake 251 Further reading 252 References 252

10 Vitamin K 256

10.1 Historical overview 25610.2 Chemistry 25710.3 Dietary sources 25810.4 Absorption, transport and metabolism 25810.5 Biochemical and physiological functions 26310.6 Vitamin K defi ciency 268 Further reading 269 References 269

11 Thiamin (Vitamin B1) 273

11.1 Historical overview 27411.2 Chemistry and biological activity 27411.3 Dietary sources and bioavailability 27411.4 Absorption, transport and metabolism 27511.5 Biochemical functions 27711.6 Neurophysiological functions 28011.7 Vitamin B1 defi ciency 282

x Contents

11.8 Nutritional aspects 286 Further reading 287 References 287

12 Flavins: Ribofl avin, FMN and FAD (Vitamin B2) 289

12.1 Historical overview 28912.2 Chemistry 29012.3 Dietary sources and bioavailability 29112.4 Absorption, transport and metabolism 29112.5 Biochemical functions 29712.6 Vitamin B2 defi ciency 29812.7 Nutritional aspects 298 Further reading 299 References 299

13 Niacin: Nicotinic Acid and Nicotinamide 301

13.1 Historical overview 30113.2 Chemistry 30113.3 Dietary sources and bioavailability 30213.4 Absorption, transport and metabolism 30313.5 Biochemical functions 30613.6 Niacin defi ciency 30813.7 Nutritional aspects 308 Further reading 309 References 309

14 Vitamin B6 310

14.1 Historical overview 31014.2 Chemistry and biological activity 31114.3 Dietary sources and bioavailability 31114.4 Absorption, transport and metabolism 31214.5 Biochemical functions 31514.6 Regulation of steroid hormone action 31914.7 Immune function 32014.8 Vitamin B6 defi ciency 32214.9 Nutritional aspects 322 Further reading 323 References 323

15 Pantothenic Acid and Coenzyme A 326

15.1 Historical overview 32615.2 Chemistry 32715.3 Dietary sources and bioavailability 32715.4 Absorption, transport and metabolism 32815.5 Biochemical functions of coenzyme A and acyl carrier protein in cellular

metabolism 33015.6 Physiological roles of coenzyme A in the modifi cation of proteins 332

Contents xi

15.7 Defi ciency in animals and humans 33415.8 Dietary intake 334 Further reading 335 References 335

16 Biotin 337

16.1 Historical overview 33716.2 Chemistry 33816.3 Dietary sources and bioavailability 33816.4 Absorption, transport and metabolism 33916.5 Biochemical and physiological functions 34116.6 Biotin defi ciency 343 Further reading 345 References 345

17 Folate 347

17.1 Historical overview 34817.2 Chemistry 34817.3 Dietary sources and bioavailability 34817.4 Absorption, transport and metabolism 35117.5 Biochemical functions 35917.6 Homocysteine-related occlusive arterial and thrombotic diseases 36317.7 Folate and neural tube defects 37117.8 Folate defi ciency 37417.9 Dietary intake 376 Further reading 376 References 377

18 Vitamin B12 383

18.1 Historical overview 38318.2 Chemistry 38418.3 Dietary sources and bioavailability 38418.4 Absorption, transport and metabolism 38518.5 Biochemical functions 38718.6 Vitamin B12 defi ciency 38818.7 Dietary intake 390 Further reading 391 References 391

19 Vitamin C 393

19.1 Historical overview 39419.2 Chemistry 39419.3 Dietary sources and bioavailability 39519.4 Absorption, transport and metabolism 39519.5 Effect of ascorbic acid upon absorption of inorganic iron 40019.6 Inhibition of N-nitroso compound formation 40119.7 Biochemical and neurochemical functions 403

xii Contents

19.8 Role of ascorbic acid in mesenchymal differentiation 40619.9 Antioxidant role 40719.10 Immune function 40919.11 Vitamin C and cardiovascular disease 41219.12 Vitamin C defi ciency 41419.13 Dietary intake 415 Further reading 415 References 415

Abbreviations 421

Glossary 423

Index 429

Foreword

cipally vitamins C and E, perhaps better described as ‘redox modulators’, because they can act as pro-oxidants as well as antioxidants. Risk of developing degenerative diseases such as vascular disease, cancers and eye diseases (cataract, macular degeneration) has been linked to these ‘protective’ nutrients via animal and tissue culture model studies and epidemiological associations. The removal of oxygen-derived reactive free radicals seems generally benefi cial and desirable, and is performed effi ciently by these micronutrients. Just how important this is for human health remains controversial, as is the question, how far we now need to go ‘beyond defi ciency’ and ‘toward enhanced and optimal protection’ against noxious agents in the en-vironment and those derived from our own metabolic processes.

The fat-soluble vitamins have likewise proved equally elusive, with respect to the breadth of their functional implications. Thus, until a couple of dec-ades ago, vitamin A was seen as the anti-xerophthal-mia, anti-keratomalacia vitamin, preventing blind-ness in children in poor, developing countries. Then its role in preventing severe morbidity and mortality from infectious diseases was recognized, and this soon assumed dominance. Now, new roles for vitamin A in gap-junction cell–cell communication and on cell-signalling are recognized, revealing a potential role for retinoids in the treatment of cancer. Derivatives of vi-tamin D, the ‘sunshine vitamin’ which prevents rickets and osteomalacia, also have therapeutic potential for cancer. Vitamin K, which is used clinically to prevent haemorrhagic disease in breast-fed babies, now as-sumes important new signifi cance for osteoporosis and arterial calcifi cation.

All these newly discovered roles for individual vita-mins have serious implications for recommended di-etary amounts and for public health food policies. In the UK, government recommendations for ‘reference’

The thirteen vitamins that are essential for an ad-equate human diet are staggeringly diverse in their structures, chemical properties and functions, but they have, by and large, all arrived at a similar juncture in their evolving recognition and understanding. Fifty to a hundred years ago, the main research emphasis was on isolation, structural determination, basic bio-chemical properties and functional signifi cance. As George Ball’s new book demonstrates, the quest for their functional signifi cance is still continuing and is by no means yet complete. However, the recent focus on their public health signifi cance has shifted from a relatively straightforward concern with the preven-tion and cure of overt defi ciency diseases towards more subtle functional properties, often linked to those medical conditions that are not obviously vitamin-dependent.

An example is folate, a generic group of compounds which includes folic acid. When discovered, its medi-cal signifi cance was in the prevention of megaloblastic anaemia in pregnant women in developing countries such as India. Today, the focus has shifted towards the avoidance of neural tube defects (spina bifi da, anencephaly) in western countries and the reduction of hyperhomocysteinaemia, which is considered to be a precursor, predictor, and likely causative agent for vascular diseases, including some dementias. There are recent indications that folate may infl uence can-cer risk, especially for bowel cancers. Paradoxically, whereas anti-folate drugs are frequently used to treat existing cancer, poor folate status may be a risk factor for development of new cancers, perhaps by com-promising DNA repair mechanisms. None of these implications of folate status were recognized before the fi nal decades of the twentieth century, and they are still being researched and refi ned.

Another recently emergent research topic has involved the so-called ‘antioxidant’ vitamins, prin-