Vitamins in Endocrine Metabolism

Bath

Preface

This book is intended to bridge the gap between scientists studying nutritional disease problems in the diverse fields of endocrinology, enzymology, pathology and vitamin research. Knowledge in each field is expanding so rapidly that workers in one subject who try to keep up with advances in their own science have very little time to look over their shoulders to see what is happening in the other subjects. In an age when the attention of outstanding scientists is focussed on the infinitely small detail of such matters as the haemoglobin crystal or the insulin molecule, there is still a need for a broad survey of the advancing frontiers of knowledge. The author, a pathologist, is fully aware of the dangers inherent in venturing on to the alien soils of biochemistry, physiology and cognate sciences—there are many pitfalls for the trespasser. However, the risk is well worth taking, if it encourages others to cross the interscience barriers, for there is much to gain from a study of unfamiliar knowledge and techniques.

Scientific papers on the subject of hormones, and on the subject of vitamins are available in vast quantities, quite beyond the power of any single worker to evaluate in a reasonable time. Material which deals directly with vitamin-hormone inter-relationships is exceedingly sparse and difficult to find. The author has been privileged to have the help of the medical literature analysis and retrieval system (MEDLAR) of the National Lending Library for Science and Technology in tracing those papers which span the gap between the various subjects. Nevertheless, a wide computer search of the literature brought forth only twenty-eight references for a five year period ending in 1967—a remarkably small number for such a wide field of research.

This present work therefore is inevitably biassed by the author’s experience in the field of nutritional disease, and by personal selection from the material available in each of the contributary subjects. Further bias has been introduced by the influence of the many scientists who come each year to Cambridge, to discuss advances in their own line of research with the staff and students of this university. To these, and to all the countless scientists whose work is discussed here, I extend my grateful thanks. Had it been possible to mention all these authors individually, the bibliography would have been much longer than the text. The references given at the end of each chapter have been chosen, sometimes because they contain important original work, sometimes because they are difficult to find, but more often because they provide excellent bibliographies in addition to their useful scientific content.

In preparing the text, I have had the invaluable assistance of Alan Wilson, University Lecturer in Chemical Pathology, and my thanks go to him for his careful reading of the manuscript and for many helpful suggestions on the biochemical aspects of the work. I am indebted to my husband for much constructive criticism, and to Mrs. Sally Roberts for typing the final draft. Miss Elizabeth McDowell kindly supplied the electron micrograph illustrating intracellular structures.

Isobel Jennings,     University College, Cambridge, 1970

Introduction

The last twenty years have seen major developments in the sciences of endocrinology and enzymology, but the study of the vitamins has lagged far behind. The golden age of vitamin research took place between the two major world wars, since when there has been little in the way of advancement of knowledge and no major new discoveries, although it seems unlikely that all the essential food factors are known to us at the present time. In the realm of endocrinology there has been the recent discovery of two new hormonal systems, the prostaglandins and calcitonins. Enzymology as an exact science has advanced on a broad front, and large numbers of scientists are specializing in this important subject. As the biological sciences become more and more complex, the relationships between them tend to become forgotten. It is the new science of molecular biology which is drawing these various subjects together, so that workers studying widely separated areas of research are meeting on common ground, in the ultramicroscopic workings of the molecular components of the living cell. In the next few years there must surely be a renaissance in vitamin research, for vitamins are essential for the synthesis of hormones, for permitting their action to proceed and, in the case of the prostaglandins, the fatty acid vitamins are essential biological precursors of the hormones. Although many enzymologists are working with purified enzymes alone, some among them study the combined action of vitamins and enzymes, and it is to these scientists that we must look for advances in the understanding of biological processes.

In the living body, the enzymes are dependant for their action on the presence of the coenzymes, many of which contain vitamins in their complex molecular structure. The vitamins, enzymes and hormones are equal partners in the complex mechanisms which control the working of the cells of the animal body, and maintain the homeostasis which is necessary for health.

Fundamental research on the problem of control and communications within the cell has received a tremendous stimulus from the work of Jacob and Monod, on the way in which genes may be switched on or held in abeyance. Another major advance is the work of Sutherland and his colleagues, which led to the development of the second messenger hypothesis of cellular control. The determination of the structure of the DNA helix and the breaking of the genetic code are two more achievements in biological research which have contributed much to an understanding of the inner workings of the cell.

With all this new knowledge available we are now in a position to make a fresh evaluation of the complex interrelationships between hormones, vitamins and enzymes. In the pages which follow, it is proposed to describe first of all the general principles governing the actions of the members of this triad, and then to examine in more detail the influence of variations in vitamin status on the various endocrine systems. The concluding chapters will deal with the interactions of vitamins and hormones in the initiation and control of tumours and in foetal dysmorphogenesis. It is hoped that this treatment of the subject will throw some light on the many deficiency diseases which are assuming greater importance in public health, as the major epidemic diseases are brought under control. The cure of a cretinous infant or an adult suffering from some obscure nervous disease by a simple alteration in the diet is a dramatic event, but the really important work lies in the field of preventive medicine, where so much can be done to improve the health of the population. Overt deficiency disease is all too common in the underdeveloped countries. Marginal deficiency disease is likely to increase as more and more of the food of the highly civilised nations is processed for convenience and storage. It is the marginal deficiencies which are so difficult to diagnose—they come in many guises and are often unrecognised. Scurvy, for example, is common enough in infants and old people in this country, and yet to our ears the very word sounds as old-fashioned as rabies and glanders, two of the many diseases which have been eliminated from our islands.

The pressing necessity then, is for automated estimation of the circulating vitamin and hormone levels in small samples of blood, or in biopsy specimens. Microtechniques for the estimation of metabolites are being developed in many laboratories and the day will surely come when these are all gathered together in one autoanalyser. We may look too for future developments in the preparation of nutrient media containing the correct vitamins and hormones, not only for cell and tissue growth, but also for organ growth for ‘spare part’ surgery. Such a concept lies in the realm of science fiction at the moment, but in perhaps ten or twenty years we may have sufficient knowledge to take primitive undifferentiated cells and apply to them the correct hormonal and nutritional stimuli, and the correct contact stimuli, to enable them to develop into a strand of muscle, a layer of skin, or even, dare one hope, a heart.

A not unimportant part of nutritional research for the future will be the provision of adequate diets for the astronauts who will eventually take off for journeys into space lasting a year or more. In such circumstances, a supply of material for the replacement of hormones, enzymes and vitamins is literally vital. These substances, although resembling inorganic catalysts in many ways, are not everlasting—they are continually being lost to the bodily economy in the normal turnover of cells, and by inactivation and excretion. In space travel, too, a knowledge of the complex interactions between parathyroid hormone, calcitonin and vitamin D is essential in understanding and coping with the interference with calcium metabolism arising from weightlessness, which deprives living bone of one of the stimuli required for calcification. At the present moment, the control of calcium metabolism still holds many mysteries for the enquiring mind.

If this book provides greater understanding for the unravelling of such problems as prenatal death or deformity, or postnatal disease caused by nutritional deficiency, if it should in any way help to alleviate the human suffering associated with malnutrition, then it will have amply served its purpose.

Chapter 1

The Vitamins

Publisher Summary

Vitamins are a heterogenous group of organic compounds required by most living organisms for normal growth and health. This chapter discusses only those vitamins that are required by the higher animals. Vitamins are essential food factors, of very high biological activity, and required in exceedingly small amounts. Nevertheless, these minute quantities are able to maintain the normal structure and function of all the tissues of the animal body. In the absence of vitamins, metabolic defects arise that may be expressed as anatomical lesions, as mental disturbances with personality changes, or as biochemical changes, which may prove difficult to detect, particularly in the numerous cases of marginal deficiency. Vitamins normally must be provided in the diet either in their active form or in the form of their precursors. The status of certain substances as vitamins may vary with the species of animal for which it is required. Great advances made in determining the chemical structures of the vitamins has led to a better appreciation of their mode of action and to a deeper understanding of the pathological changes that occur in their absence. Broadly, they may be classified into two types: (1) the fat-soluble vitamins and (2) the coenzymatic vitamins. The chapter discusses these two types of vitamins. It further discusses physical and mental stress factors of animals that have a common primary effect of depleting bodily stores of vitamins and a secondary effect of reducing the capacity of the endocrine organs to respond adequately to physiological requirements.

In animal tissues vitamins function, both in the structural parts of cells and in the fluid medium, in close collaboration with enzymes and hormones. Understanding of the complicated interactions of these substances is not yet at a very advanced stage, but an examination of our present knowledge of the subject may help to mark out the considerable areas in the field which are still available for exploration.

The vitamins are a heterogenous group of organic compounds required by most living organisms for normal growth and health. In this present context, however, only those required by the higher animals will be considered. Vitamins are essential food factors, of very high biological activity, and required in exceedingly small amounts. Nevertheless these minute quantities are able to maintain the normal structure and function of all the tissues of the animal body. In the absence of vitamins, metabolic defects arise which may be expressed as anatomical lesions, as mental disturbances with personality changes, or as biochemical changes, which may prove difficult to detect, particularly in the numerous cases of marginal deficiency. Vitamins normally must be provided in the diet, either in their active form, or in the form of their precursors. The status of certain substances as vitamins may vary with the species of animal for which it is required. For example vitamin C, although essential for domestic animals, is readily synthesized by them from carbohydrate sources, and need not be provided in the diet. For such animals, ascorbic acid is an endogenously synthezised essential metabolite, but is not strictly speaking, a vitamin. For man, subhuman primates and guinea pigs, ascorbic acid is a true vitamin.

Within the last twenty years, great advances have been made in determining the chemical structures of the vitamins. Inevitably this has led to a better appreciation of their mode of action, and to a deeper understanding of the pathological changes which occur in their absence. Broadly, they may be classified into two types, the fat-soluble vitamins and the coenzymatic vitamins. The fat-soluble group includes vitamins A, D, E and K. Of these, the first three are stored in the body in relatively large amounts. In contrast, the coenzymatic, water soluble vitamins B and C are not stored to any great extent in the body, and renewed supplies are required at fairly frequent intervals.

The fat soluble vitamins appear to function as integral parts of cell membranes and variations in availability of, for example vitamins A or E may have a profound effect on the structure and properties of the membranes of cells and their contained organelles. The biochemical make-up of these membranes varies not only from one tissue to another, but also from one intracellular organelle to another. As a result, pathological effects resulting from deficiency or excess of vitamins are highly selective in their situation, whether in the tissues or within the cells themselves. The fat soluble vitamins in general are more akin to the steroid hormones, than to the vitamins which function as enzymic cofactors.

Coenzymes are complicated organic molecules, which, by virtue of their chemical constitution and configuration are able to accelerate enzymatic reactions, often as carriers of some particular chemical grouping. Thiamine, in its active form of thiamine pyrophosphate provides an example of this type of coenzyme. One of its functions is to assist in the transfer of carboxyl groups, and it is therefore known as a cocarboxylase. Other examples are the adenylic acid-containing coenzymes, nicotinamide adenine dinucleotide (NAD) and its phosphate (NADP) and coenzyme A, all of which contain vitamins of the B complex as part of their molecule. In some cases vitamin-containing organic molecules are so firmly attached to enzymes, that their removal from the enzyme results in loss of activity. These integral parts of enzyme molecules are known as prosthetic groups. They act as carriers of chemical groups from one substrate to another. The flavoproteins, which contain vitamin B2 are examples of enzymes with such prosthetic groups. Many essential enzyme systems within the animal body are completely dependent on the presence of the cofactoral vitamins which function as essential parts of coenzymes and prosthetic groups.

Although the general division into fat soluble and cofactoral vitamins is valid in most cases, the distinction must not be taken as absolutely clear cut. Vitamin A, for example, in addition to its role in the activities of membranes, also functions, in the form of its aldehyde retinene, as a cofactor in the visual cycle.

Conditions affecting vitamin requirements

Requirements for vitamins vary from species to species, from one individual to another, and during the lifetime of an individual in accordance with

1. Age

2. Physiological status

3. Inherited enzyme pattern

4. Modifying effect of other food stuffs in the diet

5. Availability of activators

6. Pathological status

1 Age

During periods of rapid growth, requirements for vitamins rise steeply; at some periods an adequate supply of vitamins is literally vital. The most important of these periods occur during prenatal life at the various stages of organogenesis. As each organ is formed it has requirements for essential food factors which must be met during a restricted period of time if malformation or even agenesis is not to occur. The endocrine organs, unlike some other tissues such as the lung, start working before birth. As each endocrine organ swings into action during prenatal life, and starts producing its own hormones, its vitamin requirements for hormone synthesis are in all probability, similar in quality if not in quantity, to those of the post-natal organ. Requirements are drawn from maternal sources, which must be adequate to support two sets of organs as gestation proceeds.

Early post-natal life is another period of rapid growth during which depletion in vitamin status can have a lasting effect, not only in growth but also in the production of irreparable pathological lesions. Of these last, perhaps arterial lesions are the most important in the so-called ‘affluent’ societies, epithelial and bone lesions in the underprivileged societies. Artificially fed infants are greatly at risk at this period, partly because of their predisposition to gastrointestinal disturbances with resulting malabsorption, and partly because dietary formulas may not be adequate. It would be arrogant to assume that we know, at the present day, all the vitamins and trace elements required by man and domestic animals in their first few months of life. The recent discovery of the entirely new series of hormones, known as the prostaglandins, derived from essential food factors, should be sufficient to induce a proper state of humility in the nutritional scientist, and to raise doubts about his ability to imitate