Vitamin C, Volume III ( Orthomolecular Medicine ) [1 ed.] 0849348439, 9780849348433

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library *IAY 1 1989 IWiWI Instifiites of ffeolb

Vitamin C Volume III

Author

*C. Alan B. Clemetson ✓ .•

Professor Tulane University School of Medicine New Orleans, Louisiana

CRC Press, Inc. Boca Raton, Florida

Library of Congress Cataloging-in-Publication Data Clemetson , C. Alan B. Vitamin C / C. Alan B. Clemetson. p. cm. Includes bibliographies and index. ISBN 0-8493-4841-2 (v. 1) ISBN 0-8493-4842-0 (v. 2) ISBN 0-8493-4843-9 (v. 3) I. Vitamin C deficiency. 2.Vitamin C—Metabolism. RC627.S36C53 1989

I. Title.

616.3'9-dcl9

88-14735 CIP

This book represents information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Every reasonable effort has been made to give reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. All rights reserved. This book, or any parts thereof, may not be reproduced in any form without written consent from the publisher. Direct all inquiries to CRC Press, Inc., 2000 Corporate Blvd., N.W., Boca Raton, Florida, 33431. © 1989 by CRC Press, Inc.

International Standard Book Number 0-8493-4841-2 (v. 1) International Standard Book Number 0-8493-4842-0 (v. 2) International Standard Book Number 0-8493-4843-9 (v. 3) Library of Congress Card Number 88-14735 Printed in the United States

FOREWORD While frank scurvy is rare nowadays, subclinical vitamin C deficiency is common and is now known to be associated with elevated blood histamine levels, which rapidly return to normal when ascorbic acid is administered. Epidemiological and experimental evidence suggests that our common metabolic defect, the inability to synthesize ascorbic acid from simple sugars, may be largely responsible for the development of subendothelial hemorrhage, thrombosis, atheroma, and degenerative vascular disease. This book is more concerned with factors affecting ascorbic acid metabolism, such as aging, smoking, infection, trauma, surgery, hormone administration, heavy metals, pregnancy, hemolysis, ionizing radiation, aspirin, alcohol, and other drugs which cause a disturbance of ascorbic acid metabolism and may thereby lead to vascular disease, than it is with simple dietary deficiency of ascorbic acid. The clinical, pathological, and chemical changes observed in ascorbic acid deficiency are discussed in detail; several diseases and disorders associated with abnormalities of ascorbic acid metabolism are described. Possible toxic effects resulting from the oxidation of ascorbic acid are noted, and reasons for the use of D-catechin or other chelating fiber to prevent or minimize the release of ascorbate free radical are detailed.

PREFACE About 60 years ago, and before the isolation of ascorbic acid, Mme. L. Randoin (1923)* found the number of research studies on the antiscorbutic vitamin so great as to make it impossible for her to review them all. ' “Jai-maintenant^a parler des recherches de toute nature fades sur lefacteur antiscorbutique. La tdche

Now I must speak of all kinds of studies of the antiscorbutic factor. It is a thankless task because

est bien ingrate, car le nombre de ces recherches est si grand qu’il m’est evidemment impossible de les passer toutes en revue et, au surplus, elles pre-

the number of research studies is so great that it is clearly impossible to review them all; moreover, by failure of agreement, they present such gaps that it is truly difficult to present a consistent thesis.

sentent, par defaut de convergence, de telles lacunes, qu’il est vraiment difficile d’en donner une idee d’ensemble.”

Today, the profusion of the literature on this subject is even more overwhelming. It is growing so fast that it is impossible to do justice to all the work that had been done in this field. Moreover, having written 57 chapters in 36 months, it is inevitable that the chapters written first will not be as up-to-date as those written last. Undoubtedly, some important works have been omitted, either because they have escaped my notice or because they were written in a language that I cannot read. Any workers whose contributions have been omitted must accept my assurance that it was not by intent. It is hoped that this book presents a consistent thesis and that its main message is clear. It does not so much concern the amount of vitamin C in the diet, as it does the factors affecting ascorbic acid metabolism, the diseases that may result from abnormalities of ascorbic acid metabolism, and some suggestions as to what we may be able to do to prevent them. Although the title of this book is Vitamin C, it could equally well have been entitled Vitamin C, Heavy Metals, and Chelating Fiber.

C. Alan B. Clemetson, M.D. Pineville, Louisiana February, 1987

THE AUTHOR C. Alan B. Clemetson, M.D., was bom in England. He attended the King’s School, Canterbury, Magdalen College, Oxford, and Oxford University School of Medicine, grad¬ uating as a physician (B.M., B.Ch.) in 1948. He is an obstetrician and gynecologist, with fellowships in British, Canadian, and American colleges (F.R.C.O.G., F.R.C.S.C., and F.A.C.O.G.), but he has devoted most of his life to research and has published papers on many diverse subjects. His career has included academic positions at Fondon University, the University of Sas¬ katchewan, the University of California at San Francisco, the State University of New York, and at Tulane University in Louisiana, where he is currently Professor at the School of Medicine. He has challenged many conventional ideas and believes that, “certainty of knowledge is the antithesis of progress.” Thus, every statement in this book is backed by reference to experiments and observations in the literature; contrary findings are cited, weighed, and given due credence.

VITAMIN C Volume I \

Vitamin C Deficiency Classical Scurvy: A Historical Review Chronic Subclinical Ascorbic Acid Deficiency Factors Affecting the Economy of Ascorbic Acid Inadequate Ascorbic Acid Intake Smoking Aging Sex Menstrual Cycle, Estrus Cycle, Ovulation Infection Trauma, Surgery, and Bums Heavy Metals, Water Supplies: Copper, Iron, Manganese, Mercury, and Cobalt Bioflavonoids Dietary Protein Hormone Administration: Birth Control Pills Pregnancy Hemolysis Stress and the Pituitary-Adrenal System Lack of Sleep Time of Day Season Achlorhydria Ionizing Radiation Aspirin and Salicylates Alcohol Other Factors Affecting Ascorbic Acid Needs Volume II Clinical and Pathological Findings in Ascorbic Acid Deflciency Vascular Changes Diabetes Mellitus Anemia Defective Wound Healing Bone Changes Joint Lesions Dental and Periodontal Changes Atherosclerosis Mental Depression Amyloid Venous Thrombosis Decreased Resistance to Infection Liver, Bile, and Gallstones

Volume III Chemical Changes Associated with Vitamin C Deficiency Histamine Metabolism Proline and Lysine Metabolism Carbohydrate Metabolism Folic Acid Metabolism Cholesterol Metabolism Tyrosine and Phenylalanine Metabolism Tryptophan Metabolism Adrenal Corticoid Metabolism Uric Acid Clearance Clinical Conditions Associated with Disorders of Ascorbic Acid Metabolism Rheumatic Fever Menorrhagia Wound Dehiscence Habitual Abortion Abruptio Placentae Prematurity and Premature Rupture of the Fetal Membranes Megaloblastic Anemia of Infancy, Pregnancy, and Steatorrhea Gastrointestinal Ulcers and Hemorrhage Ocular Lesions Cerebral Hemorrhage and Thrombosis Coronary Thrombosis and Myocardial Infarction

TABLE OF CONTENTS CHEMICAL CHANGES ASSOCIATED WITH VITAMIN C DEFICIENCY Chapter 1 Histamine Metabolism.... 1 I. Introduction. 1 II. Guinea Pigs. 1 III. Humans.3 A. Pregnancy.•.4 B. Age.:.4 C. Sex.5 D. Subsequent Work.5 IV. Implications.11 References.11 Chapter 2 Proline and Lysine Metabolism.15 References. 29 Chapter 3 Carbohydrate Metabolism.33 References.39 Chapter 4 Folic Acid Metabolism.43 References.47 Chapter 5 Cholesterol Metabolism.49 I. Guinea Pig Studies.49 II. Other Animals.59 III. Human Studies.60 IV. Summary .70 V. Conclusions.70 References.70 Chapter 6 Tyrosine and Phenylalanine Metabolism.75 I. Introduction.75 II. Hydroxy phenyluria.75 III. Dopa, Dopamine, Norepinephrine, and Epinephrine.84 IV. Tyrosine Oxidation to Dopa and Melanin.87 V. Tyrosine lodination and Conversion to Thyroxine.88 VI. Conclusions Concerning Clinical Relevance.88 References.89 Chapter 7 Tryptophan Metabolism.93 References.99

Chapter 8 Adrenal Corticoid Metabolism .101 I. Introduction..101 II. Human Observations.101 III. Guinea Pigs.102 IV. Rats.;.108 V. In Vitro Studies.108 References. 109 Chapter 9 Uric Acid Clearance.113 References.114 CLINICAL CONDITIONS ASSOCIATED WITH DISORDERS OF ASCORBIC ACID METABOLISM Chapter 10 Rheumatic Fever.117 I. Experimental Production in the Guinea Pig.117 A. Controls.117 B. Infection.117 C. Scurvy.117 D. Combined Scurvy and Infection.118 E. Scurvy and Exotoxin.119 II. Rheumatic Rurpura.120 III. Epidemiology of Rheumatic Fever.121 IV. Ascorbate Status in Rheumatic Fever.121 A. Urinary Excretion Tests.122 B. Blood Values.123 V. Ascorbic Acid Supplements in Rheumatic Fever.124 VI. Use of Ascorbic Acid in Prophylaxis Against Rheumatic Fever.125 VII. Other Prophylactic and Therapeutic Measures.125 VIII. The Hyperimmune Response.127 IX. The Effect of Cortisone on Ascorbic Acid Metabolism in Rheumatic Fever.127 X. Conclusions.127 XI. Future Research.130 References.130 Chapter 11 Menorrhagia. 133 References.143 Chapter 12 Wound Dehiscence.145 References. Chapter 13 Habitual Abortion References.

Chapter 14 Abruptio Placentae.. .159 References.166 Chapter 15 Prematurity and Premature Rupture of the Fetal Membranes..169 References.173 Chapter 16 Megaloblastic Anemia of Infancy, Pregnancy, and Steatorrhea.175 I. Introduction. 175 II. Infancy.175 III. Pregnancy.176 IV. Steatorrhea, Malabsorption Syndrome.176 References.178 Chapter 17 Gastrointestinal Ulcers and Hemorrhage.179 I. Human Observations.179 II. Studies of Monkeys.190 III. Guinea Pig Studies. 190 IV. Rat Studies.193 V. Dog Studies.193 VI. Observations in Cows and Sheep.194 VII. Discussion.194 References.195 Chapter 18 Ocular Lesions.199 I. Classical Scurvy.199 II. Experimental Human Scurvy.199 III. Hypovitaminosis C in Monkeys and Guinea Pigs.200 IV. Normal Ascorbate Levels.200 V. Value of Ascorbic Acid and Bioflavonoids in Various Eye Diseases.204 A. Hemorrhagic Lesions.204 B. Eye Infections.208 C. Wounds of the Eye.209 D. Corneal Bums.209 E. Alkali Bums.209 F. Comeal Ulcers .212 G. Cataracts.212 H. Glaucoma.214 I. Toxic Retinopathy.216 J. Retinal Detachment.216 K. Osteogenesis Imperfecta.217 L. Oscular Palsies.217 VI. Summary .217 VII. Conclusions.218 References.218

Chapter 19 Cerebral Hemorrhage and Thrombosis. 223 I. Vascular Fragility Due to Ascorbic Acid Deficiency.223 II. Hypertension.242 References.243 Chapter 20 Coronary Thrombosis and Myocardial Infarction.247 I. Clinical and Pathological Observations .247 II. Animal Experiments.249 III. Human Experiments.249 IV. Demographic and Nutritional Surveys.250 V. Ascorbic Acid Levels.252 VI. Blood Cholesterol Levels.253 VII. Aging.255 References.255 INDEX.259

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Chemical Changes Associated with Vitamin C Deficiency

Volume III Chapter

1

1

HISTAMINE METABOLISM

I. INTRODUCTION Since the original observation of Parrot and Richet (1945) that scurvy increases the sensitivity of guinea pigs to histamine, several workers, including Dawson and West (1965), Dawson et al. (1965), and Lewis and Nicholls (1973), have investigated the relationship between ascorbic acid and histamine metabolism. During the same period other workers, including Sayers and Sayers (1947), Hicks (1965), Csaba and Toth (1966), Kovacs and Suffiad (1968), Freeman (1968), Muszbek et al. (1969), Porter et al. (1970), Latif and Sultan (1971), Reilly and Schayer (1972), Hirose et al. (1976), and Bruce et al. (1976), were working on the related problem of histamine and the adrenocortical system in rats, mice, chicks, guinea pigs, dogs, and asthmatic human subjects.

II. GUINEA PIGS It was the elegant studies of Subramanian et al. (1973, 1974), Chatterjee et al. (1975a, b), and Subramanian (1978) which clarified the relationship between blood histamine and ascorbic acid levels. These workers demonstrated a progressive rise in the blood histamine levels of guinea pigs on a scorbutogenic diet (Figure lA). It is interesting to note that the histamine level began to rise very early, on the third day of the diet, when the blood ascorbic acid level had only just fallen below 1 mg/100 ml. Moreover, after 2 weeks on the diet, when the blood histamine level was markedly elevated, it could be returned rapidly to normal by the administration of a single dose of ascorbic acid (5 mg/100 g of guinea pig). They obtained very similar results when studying urinary histcunine (Figure IB) and studying tissue histamine levels in guinea pigs on a vitamin C-deficient diet (Figure 2). Subramanian et al. (1973) found that neither ascorbic acid nor dehydroascorbic acid (DHAA) and H2O2, the products of oxidation of ascorbic acid, were able to break down histamine. However, histamine is broken down when it is added to a system in which ascorbic acid is allowed to undergo oxidation in the presence of a catalyst such as Cu+ + or tissue homogenates. Chatterjee et al. (1975b) reported that in a model system of ascorbic acid (5 mmol), Cu'^+ (0.05 mmol as CUSO4, 5H2O), and histamine (1 mmol), in a total volume of 12.5 ml 0.05 M sodium phosphate buffer, pH 7.2, incubated 37°C for 4 h, the histamine is completely broken down to aspartic acid. Hydantoin acetic acid was identified as an intermediate in this conversion (Figure 3). The various intermediates identified at different intervals of incubation were as follows: 0 h, histamine; 2 h, histamine and hydantoin-5-acetic acid; 4 h, aspartic acid. Aspartic acid was identified even after 24 h of incubation, indicating that it was the end product of incubation. These workers suggest that the probable intermediate in the conversion of his¬ tamine to hydantoin acetic acid would be 2,4-dihydroxyimidazole acetic acid, believing it to be another example of an ascorbic acid-mediated hydroxylation of a heterocyclic com¬ pound. Studying the effects of stress, Chatterjee et al. (1975b) observed that the administration of antibiotics, vaccines, heat, cold, and even pregnancy caused an elevation of the blood histamine levels of guinea pigs (Table 1), but ascorbic acid supplements brought their histamine levels down to normal, thus blocking this effect of stress.

2

Vitamin C

DAYS ON SCORBUTIC DIET A

DAYS ON SCORBUTIC DIET B

FIGURE 1.

(A) Ascorbic acid and histamine levels in blood from guinea pigs fed an ascorbic

acid-free diet. ascorbic acid; o-o, histamine, f > i > administration of a single dose of ascorbic acid, 5 mg/100 g body weight guinea pig; A-A, n-o, subsequent ascorbic acid and histamine levels. (B) Ascorbic acid and histamine levels in urine from guinea pigs fed an ascorbic acid-free diet. Symbols f > i , as in Figure lA. In control guinea pigs fed an ascorbic acid-free diet plus a daily oral dose of ascorbic acid 1 mg/100 g guinea pig, the basal value of ascorbic acid and histamine in urine did not change within the experimental period. (From Chatteijee, I. B., Das Gupta, S., Majumder, A. K., Nandi, B. K., and Subramanian, N. [1975a], J. Physiol. (London), 251, 271. With permission.)

Volume III

3

FIGURE 2. Effect of a single administration of ascorbic acid on the tissue histamine contents of guinea pigs fed an ascorbic acid-free diet for 16 d. The values were obtained after killing of the animals, on the 17th day. C, control; S, scorbutic diet; S A, scorbutic diet after administration of ascorbic acid. (Erom Chatterjee, I. B., Majumder, A. K., Nandi, B. K., and Subramanian, N. [1975b], Ann. N.Y. Acad. Sci., 258, 24. With permission.) HC,

5

-CH2CH2NH

OC — CHCH2COOH 1

1

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CH Histamine

NH / CO Hy lantoin -5-acet i c Ac i d

^

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1

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C02,NH3 Aspartic acid

FIGURE 3. Scheme proposed by Chatterjee (1975b) whereby histamine is broken down when it is added to a system in which ascorbic acid is allowed to undergo oxidation in the presence of a catalyst, such as Cu^^ or tissue homogenates.

III. HUMANS The simple plan of analyzing the same blood samples, both for histamine and for ascorbic acid, was adopted by the Department of Obstetrics and Gynecology at the Methodist Hospital of Brooklyn, NY, and has provided much useful information. Blood samples were drawn from pregnant women attending the prenatal clinic and from healthy men and women volunteers, including physicians, nurses, laboratory technicians and medical students, before they had taken any vitamin C-containing food, in the morning. The results of analysis of 437 such human blood samples for histamine by the spectrofluorometric method of Shore et al. (1959) and for reduced ascorbic acid by the method of Roe (1954) were reported by Clemetson (1980) and are shown in Table 2. When the mean blood histamine level for each O.l-mg/100 ml ascorbate group is plotted on a graph, as shown in Figure 4, it becomes evident that plasma ascorbic acid levels below 1.0 mg/100 ml are associated with increasing whole blood histamine levels. Moreover, this increase becomes highly significant (p > ^ ^ .2

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