Recent Vitamin Research Editor Michael H. Briggs, D.Sc., Ph.D. Professor of Human Biology Dean of Sciences Deakin University Geelong, Victoria, Australia First published 1984 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-27 42 Reissued 2018 by CRC Press © 1984 by Taylor & Francis CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. A Library of Congress record exists under LC control number: 83007093 Publisher's Note The publisher has gone to great lengths to ensure the quality of this reprint but points out that some imperfections in the original copies may be apparent. Disclaimer The publisher has made every effort to trace copyright holders and welcomes correspondence from those they have been unable to contact. ISBN 13: 978-1-138-50617-6 (hbk) ISBN 13: 978-0-203-71056-2 (ebk) Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http:/ /www.crcpress.com PREFACE Recently, CRC Press published Vitamins in Human Biology and Medicine, a series of reviews summarizing modern aspects of the medical uses of various vitamins. The current volume is a continuation of that theme, presenting the results of recent research into vitamin biochemistry, physiology, and nutrition. The book opens with a survey by Dr. Morton Cowan of biotin-responsive metabolic disorders of children. A group of Japanese researchers then present their latest data on the complex interactions between vitamin D and parathyroid hormone (PTH) in bone calcifi­ cation. Dr. Maxine Briggs reviews the prolific published information relating vitamin C to infectious diseases and presents the results of an 8-year study into the prophylactic value of high-dose ascorbic acid (AA) and the common cold. Professor Kristoffersen and Dr. Rolschau review the effects of vitamin supplements during pregnancy and intrauterine growth. Possible protective effects of vitamin A and other retinoids against cancer are discussed by Dr. Jill Blunck, while Dr. Sue Tonkin describes her results on the interaction between oral contra­ ceptives and riboflavin. Finally, the possible prevention of neural tube defects by vitamin supplements is described by Professor Laurence. It is hoped that this collection of papers on the frontiers of vitamin research will be of wide interest to medical and scientific workers interested in the exciting and controversial uses and functions of vitamins. Mdchael H. Briggs THE EDITOR Michael H. Briggs, D.Sc., Ph.D., F.R.S.C., F.I. Biol., F.R.C. Path., is Professor of Human Biology at Deakin University, Geelong, Victoria, Australia. Currently he is Dean of Sciences. Bom in Manchester, England in 1935, Dr. Briggs was educated at the University of Liverpool, then undertook postgraduate studies in biochemistry and nutrition at Cornell University and the University of New Zealand. He is a Fellow of the Royal Society of Chemistry, a Fellow of the Royal Institute of Biology, and a Fellow of the Royal College of Pathologists. Dr. Briggs is also a member of a wide range of national and international scientific and medical societies. Since 1970, he has been a Consultant to the World Health Organization, and in this capacity has visited 15 different countries. Immediately prior to his present position, Dr. Briggs was Director of Biochemistry at the Alfred Hospital, Melbourne, a major teaching hospital of Monash University. In 1971 and 1972, Dr. Briggs was at the University of Zambia as Head of the Department of Biochemistry, where a Food and Agriculture Organization nutrition survey team formed part of his unit. Dr. Briggs also spent 7 years in the pharmaceutical industry working as a research and development director on the therapeutic substances and nutrient additives for humans and farm animals. Among his more than 200 publications are contributions to textbooks, monographs, and encyclopedias, as well as articles in scientific and medical periodicals on biochemistry, pathology, toxicology, pharmacology, enzymology, and reproductive biology. Dr. Briggs was editor of seven volumes of Advances in Steroid Biochemistry and Pharmacology and is co-editor of the new series Progress in Hormone Pharmacology and Biochemistry. Among other recent volumes he has written or edited are Oral Contraceptives (six volumes, 1977— 1982, Eden Press), Biochemical Contraception (Academic Press, 1975), Chemistry and Metabolism of Drugs and Toxins (Heinemann Medical, 1974), Pharmacological Models in Contraceptive Development (WHO, 1974), Implications of Steroid Hormones in Cancer (Heinemann Medical, 1971), Steroid Biochemistry and Pharmacology (Academic Press, 1970), Advances in the Study of the Prostate (Heinemann Medical, 1970), and Urea as a Protein Suppliment (Pergamon Press, 1968). Dr. Briggs is married to a medical practitioner, Dr. Maxine Briggs, who has been his research collaborator for many years and is co-author of many of their publications. CONTRIBUTORS Jill M. Blunck, M.B., B.S., Ph.D. Kohtaro Kawashima, Ph.D. Senior Lecturer in Pathology and Associate Professor of Physiological Toxicology Chemistry Deakin University Faculty of Pharmaceutical Sciences Geelong, Victoria, Australia Teikyo University Sagamiko, Kanagawa, Japan Maxine Briggs, M.B., Ch.B., D.P.H., Mamoru Kiyoki, Ph.D. D.O.H., F.R.A.C.M.A. Teijin Institute for Bio-Medical Research Director of Rehabilitation Services Hino, Tokyo, Japan Geelong Hospital Victoria, Australia K. Michael Laurence, M.A., D.Sc., M.B., Ch.B., F.R.C.P., F.R.C. Path Morton J. Cowan, M.D. Professor of Pediatric Research Assistant Professor of Pediatrics Honorary Consultant Clinical Geneticist University of California Welsh National School of Medicine San Francisco, California University of Wales Cardiff, Wales Hiroyoshi Endo, Ph.D. John Rolschau, M.D. Professor of Physiological Chemistry Lecturer and Senior Registrar Faculty of Pharmaceutical Sciences Obstetrics and Gynecology Teikyo University Odense University Hospital Sagamiko, Kanagawa, Japan Odense, Denmark Karl Kristoffersen, M.D. Suzanne Y. Tonkin, B.Sc.(Hons), Professor and Senior Chief of Obstetrics M.Sc., Ph.D. and Gynecology Biochemist Odense University Hospital Deakin University Odense, Denmark Geelong, Victoria, Australia TABLE OF CONTENTS Chapter 1 Biotin-Responsive Metabolic Disorders in Early Childhood................................................. 1 Morton J. Cowan Chapter 2 Synergistic Stimulatory Effects of Vitamin D3 Metabolites and Parathyroid Hormone (PTH) Upon Bone Calcification In Vitro..........................................................................................27 Mamoru Kiyoki, Kohtaro Kawashima, and Hiroyoshi Endo Chapter 3 Vitamin C and Infectious Disease: A Review of the Literature and the Results of a Randomized, Double-Blind, Prospective Study Over 8 Years..........................................39 Maxine Briggs Chapter 4 Vitamin Supplements and Intrauterine Growth.....................................................................83 Karl Kristoffersen and John Rolschau Chapter 5 Modification of Neoplastic Processes byV itamin A and Retinoids....................................103 Jill M. Blunck Chapter 6 Application of the Erythrocyte Glutathione Reductase Test to the Evaluation of Vitamin B2 Status in Normal Female Subjects and in Females Taking Oral Contraceptive Agents.......................................................................................................................................127 Suzanne Y. Tonkin Chapter 7 Causes of Neural Tube Malformation and Their Prevention by Dietary Improvement and Preconceptional Supplementation with Folic Acid and Multivitamins...............................177 K. M. Laurence Index...........................................................................................................................................203 1 Chapter 1 BIOTIN-RESPONSIVE METABOLIC DISORDERS IN EARLY CHILDHOOD Morton J. Cowan TABLE OF CONTENTS I. Introduction........................................................................................................................2 II. Biotin Chemistry and Metabolism .................................................................................2 A. Chemistry..............................................................................................................2 B. Biotin-Dependent Enzymes.................................................................................4 C. Biotin-Dependent C02 Fixation in Mammalian Cells.....................................4 D. Biotin Synthesis, Absorption and Transport....................................................6 E. Biotin Binding to Apoenzyme and Carboxylation Processes.........................7 F. Biotin Catabolism and Excretion.......................................................................7 III. Clinical and Laboratory Manifestations of Biotin-Deficient and Biotin-Dependent States..................................................................................................................................7 A. Biotin Deficiency..................................................................................................7 B. Inborn Errors of Biotin-Dependent Enzymes...................................................9 1. Propionyl-CoA Carboxylase Deficiency...............................................9 2. ß-Methylcrotonyl-CoA Carboxylase (MCC) Deficiency...................11 3. Pyruvate Carboxylase (PC) Deficiency...............................................11 4. Acetyl-CoA Carboxylase (ACC) Deficiency.....................................12 C. Inborn Errors of Biotin Metabolism................................................................12 IV. Pathogenesis of Biotin-Deficient and Biotin-Dependent States..................................16 V. Selected Topics...............................................................................................................17 A. Neurologic Diseases and Biotin Metabolism...................................................17 B. Immunodeficiency and Biotin Metabolism....................................................19 VI. Summary .........................................................................................................................21 Acknowledgments......................................................................................................................22 References....................................................................................................................................23 2 Recent Vitamin Research I. INTRODUCTION Biotin, one of the B vitamins, is a cofactor for at least four carboxylation reactions in mammalian cells.1,2 While it was known as early as the beginning of this century that raw egg white, which contains a biotin-binding protein (avidin), was a toxic nutrient, it was not until 1936 that biotin was characterized as a yeast growth factor.3 It was subsequently shown to be identical to a variety of substances including “protective factor X,“ BIOS II B, vitamin H, and egg white injury factor. Until relatively recently, interest in biotin focused on defining its role as a cofactor for supporting growth of microorganisms and understanding its metabolism and mode of action in eukaryotic and prokaryotic cell systems. It has only been in the last 20 years that the specific role of biotin as a cofactor for C02 transfer (carboxylation) processes has been elucidated. The clinical significance of biotin-deficient and biotin-dependent states was not recognized until the early 1970s. Prior to that time it was felt that the GI flora produced sufficient biotin to prevent a deficient state unless a diet containing raw egg whites (avidin) was consumed.4 A few case reports in the literature supported this assessment.5,6 However, in 1971 the first inborn error of biotin metabolism was reported.7 Subsequently, there have been numerous discoveries of children with either single or multiple deficiencies of biotin-dependent en­ zymes. In addition to the obvious effects of biotin deficiency on the skin and hair, it has become evident that in these affected children there are major disturbances of carbohydrate and amino and fatty acid metabolism involving not only acid-base and glucose homeostasis but CNS and immune system functions as well. The current focus of biotin research remains on its metabolism but its role in humans has acquired a new significance since more biotin-deficient and biotin-dependent disorders have been discovered. The early diagnosis of patients with either acquired or inborn deficiencies in biotin metabolism has resulted in a simple and safe therapy for correcting one of the causes of organic aciduria in childhood. The deleterious metabolic, CNS, and immunologic consequences often can be reversed with pharmacologic doses of biotin and therapy may even begin during gestation following prenatal diagnosis. These biotin-responsive disorders clearly are models which can be used in approaching other vitamin-dependent states. Also, these new inborn errors have generated interest in the role of biotin-dependent metabolism in the immune system and CNS which may result in a better understanding of how biotin- dependent carboxylation selectively affects immune regulation as well as how it is involved in brain cell chemistry. Finally, by focusing attention on these pathways, a better under­ standing of the regulation of carbohydrate and amino and fatty acid metabolism will result and the potential always exists for the discovery of new pathways or metabolites, as yet unreported. The subsequent sections will include: (1) a brief discussion of biotin chemistry and metabolism, (2) clinical and laboratory findings in children with biotin-responsive disorders, (3) the pathogenesis of these disorders, and finally (4) studies which have been done in selected areas on the effects of biotin deficiency. II. BIOTIN CHEMISTRY AND METABOLISM A. Chemistry Biotin is a low molecular weight (M.W. = 244) coenzyme consisting of two fused rings, one of which is a ureido and the other a tetrahydrothiophene (Figure 1). The aliphatic side chain [(-CH2-)4 COOH] is essential for the covalent binding of biotin via the carboxyl group to an epsilon amino group of a lysine residue in the apoenzyme (Figure 2). During the 3 FIGURE 1. Biotin. FIGURE 2. Biotin binding to lysine residue of apocarboxylase.