Table Of ContentRecent 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
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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.
