Ebook Handbook of vitamins (4th edition) Part 1

Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page i

5.5.2007 2:33pm Compositor Name: BMani

F O U RT H
EDITION

Handbook of

VITAMINS


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page ii 5.5.2007 2:33pm Compositor Name: BMani


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page iii

5.5.2007 2:33pm Compositor Name: BMani

F O U RT H
EDITION

Handbook of

VITAMINS
Edited by

Janos Zempleni
Robert B. Rucker
Donald B. McCormick

John W. Suttie

Boca Raton London New York

CRC Press is an imprint of the
Taylor & Francis Group, an informa business


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page iv 5.5.2007

2:33pm Compositor Name: BMani

CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2007 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Printed in the United States of America on acid-free paper
10 9 8 7 6 5 4 3 2 1
International Standard Book Number-10: 0-8493-4022-5 (Hardcover)
International Standard Book Number-13: 978-0-8493-4022-2 (Hardcover)
This book contains 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. Reasonable efforts have been made to
publish 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.
No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or
other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://

www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923,
978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for
identification and explanation without intent to infringe.
Library of Congress Cataloging-in-Publication Data
Handbook of vitamins / editors, Robert B. Rucker ... [et al.]. -- 4th ed.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-0-8493-4022-2 (hardcover : alk. paper)
ISBN-10: 0-8493-4022-5 (hardcover : alk. paper)
1. Vitamins. 2. Vitamins in human nutrition. I. Rucker, Robert B.
[DNLM: 1. Nutrition Physiology--Handbooks. 2. Vitamins--Handbooks. QU 39 H361 2007]
QP771. H35 2007
612.3’99--dc22
Visit the Taylor & Francis Web site at

and the CRC Press Web site at


2006100138


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page v 5.5.2007 2:33pm Compositor Name: BMani

Table of Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Editors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Chapter 1

Vitamin A: Nutritional Aspects of Retinoids and Carotenoids . . . . . . . . . . . . 1

A. Catharine Ross and Earl H. Harrison
Chapter 2

Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Anthony W. Norman and Helen L. Henry
Chapter 3

Vitamin K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

John W. Suttie
Chapter 4

Vitamin E. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

Maret G. Traber
Chapter 5

Bioorganic Mechanisms Important to Coenzyme Functions. . . . . . . . . . . . 175

Donald B. McCormick
Chapter 6

Niacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

James B. Kirkland
Chapter 7

Riboflavin (Vitamin B2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

Richard S. Rivlin
Chapter 8

Thiamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

Chris J. Bates
Chapter 9

Pantothenic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

Robert B. Rucker and Kathryn Bauerly
Chapter 10

Vitamin B6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

Shyamala Dakshinamurti and Krishnamurti Dakshinamurti

v


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page vi 5.5.2007

2:33pm Compositor Name: BMani

vi

Chapter 11

Table of Contents

Biotin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

Donald M. Mock
Chapter 12

Folic Acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

Lynn B. Bailey
Chapter 13

Vitamin B12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413

Ralph Green and Joshua W. Miller
Chapter 14

Choline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459

Timothy A. Garrow
Chapter 15

Ascorbic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489

Carol S. Johnston, Francene M. Steinberg, and Robert B. Rucker
Chapter 16

Vitamin-Dependent Modifications of Chromatin: Epigenetic Events
and Genomic Stability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521

James B. Kirkland, Janos Zempleni, Linda K. Buckles, and Judith K. Christman
Chapter 17

Accelerator Mass Spectrometry in the Study of Vitamins and
Mineral Metabolism in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545

Fabiana Fonseca de Moura, Betty Jane Burri, and Andrew J. Clifford
Chapter 18

Dietary Reference Intakes for Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . 559

Suzanne P. Murphy and Susan I. Barr
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page vii 5.5.2007 2:33pm Compositor Name: BMani

Preface
In keeping with the tradition of previous editions, the fourth edition of the Handbook of
Vitamins was assembled to update and provide contemporary perspectives on dietary accessory factors commonly classified as vitamins. One of the challenges in assembling this volume
was to maintain the clinical focus of previous editions, while addressing important concepts
that have evolved in recent years owing to the advances in molecular and cellular biology as
well as those in analytical chemistry and nanotechnology. The reader will find comprehensive
summaries that focus on chemical, physiological, and nutritional relationships and highlights
of newly described and identified functions for all the recognized vitamins. Our goal was to
assemble the best currently available reference text on vitamins for an audience ranging from
basic scientists to clinicians to advanced students and educators with a commitment to better
understanding vitamin function.
As examples, apparent vitamin-dependent modifications that are important to epigenetic
events and genomic stability are described, as well as new information on the role and

importance of maintaining optimal vitamin status for antioxidant and anti-inflammatory
defense. Important analytical advances in vitamin analysis and assessment are discussed in a
chapter dealing with accelerated mass spectrometry (AMS) applications. Recent AMS applications have provided the basis for studies of vitamin metabolism and turnover in humans at
levels corresponding to physiological concentrations and fluxes. It is also important to
underscore that much of the interest in vitamins stems from an appreciation that there
remains regrettably sizable populations at risk for vitamin deficiencies. In this regard, classic
examples are included along with examples of vitamin-related polymorphisms and genetic
factors that influence the relative needs for given vitamins.
This volume is written by a group of authors who have made major contributions to our
understanding of vitamins. Over half of the authors are new to this series; each chapter is
written by individuals who have made clearly important contributions in their respective
areas of research as judged by the scientific impact of their work. In addition, Dr. Janos
Zempleni joins the group of editors who assembled the third edition. Dr. Zempleni adds a
molecular biology perspective to complement the biochemical and physiological expertise of
the other editors. We also wish to note that we miss the input of Dr. Lawrence Machlin, a
renowned researcher on vitamin E, who was sole editor of the first two editions in this series
and who died shortly after the release of the third edition. We know that he would be pleased
with the progress and advances in vitamin research summarized in the fourth edition.
This volume comes at an important time and represents a new treatment of this topic.
With the possible exception of the earlier days of vitamin discovery, this period of vitamin
research is particularly exciting because of the newly identified roles of vitamins in cellular
and organismal regulation and their obvious and continuing importance in health and
disease.
Janos Zempleni
Robert B. Rucker
Donald B. McCormick
John W. Suttie

vii

Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page viii 5.5.2007 2:33pm Compositor Name: BMani


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page ix 5.5.2007

2:33pm Compositor Name: BMani

Editors
Janos Zempleni received his undergraduate and graduate training in nutrition at the University of Giessen in Germany. He received postdoctoral training in nutrition, biochemistry, and
molecular biology at the University of Innsbruck (Austria), Emory University, and Arkansas
Children’s Hospital Research Institute. Janos Zempleni is currently an assistant professor of
molecular nutrition at the University of Nebraska at Lincoln. He has published more than
100 manuscripts and books and is the recipient of the 2006 Mead Johnson Award by the
American Society for Nutrition. Zempleni’s research focuses on roles of the vitamin biotin in
chromatin structure.
Robert B. Rucker received his PhD in biochemistry from Purdue University in 1968 and
worked for two years as a postdoctoral fellow at the University of Missouri, before joining the
faculty of nutrition at the University of California (UC), Davis, in 1970. He currently holds
the title of distinguished professor. He serves as vice chair of the department of nutrition in
the College of Agriculture and Environmental Sciences and holds an appointment in endocrinology, nutrition, and vascular medicine, department of internal medicine, UC Davis,
School of Medicine.
Dr. Rucker’s research focuses on cofactor function. His current research addresses
problems associated with extracellular matrix assembly, the role of copper in early growth
and development, and the physiological roles of quinone cofactors derived from tyrosine,
such as pyrroloquinoline quinone.
Honors and activities include serving as a past president, American Society for Nutrition;
appointment as a fellow in the American Association for the Advancement of Science and the
American Society for Nutrition; service as chair or cochairperson for FASEB Summer and
Gordon Conferences; service on Program and Executive Committees for American Society

for Nutrition and FASEB, as well as service on committees of the Society for Experimental
Biology and Medicine. He also currently serves as senior associate editor, American Journal of
Clinical Nutrition and is a past editorial board member of the Journal of Nutrition, Experimental Biology and Medicine, Nutrition Research, and the Annual Review of Nutrition. He is a
past recipient of UC Davis and the American Society for Nutrition Research awards.
Donald B. McCormick earned his bachelor’s degree (chemistry and math, 1953) and doctorate
(biochemistry, 1958) at Vanderbilt University in Nashville, Tennessee. His dissertation was
on pentose and pentitol metabolism. He was then an NIH postdoctoral fellow (1958–1960) at
the University of California-Berkeley, where his research was on enzymes that convert
vitamin B6 to the coenzyme pyridoxal phosphate. He has had sabbatics in the chemistry
departments in Basel University (Switzerland) and in the University of Arizona, and in the
biochemistry department in Wageningen (Netherlands).
Dr. McCormick’s academic appointments have been at Cornell University (1960–1978) in
Ithaca, New York, where he became the Liberty Hyde Bailey Professor of nutritional
biochemistry and at Emory University (1979–present) in Atlanta, Georgia, where he served
as the Fuller E. Callaway professor and chairman of the department of biochemistry and the
executive associate dean for basic sciences in the school of medicine. His research has been on

ix


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page x 5.5.2007 2:33pm Compositor Name: BMani

x

Editors

cofactors with emphases on chemistry, biochemistry, and nutrition of vitamins (especially B6,
riboflavin, biotin, and lipoate), coenzymes, and metal ions.
Dr. McCormick has been a consultant and served on numerous committees that include
service for NIH, NCI, FASEB, IOM=NAS, NASA, FAO=WHO, and several organizing

groups for international symposia on cofactors. He has been on the editorial boards of several
journals of biochemistry and nutrition, and he has served as editor of volumes on vitamins
and coenzymes in the Methods in Enzymology series, Vitamins and Hormones, the Handbook
of Vitamins, and the Annual Review of Nutrition.
Dr. McCormick is a member of numerous scientific societies, including those in biochemistry and nutrition and has received such honors as a Westinghouse Science Scholarship,
Guggenheim Fellowship, Wellcome Visiting Professorships (University of Florida, Medical
College of Pennsylvania), and named visiting professorships (University of California-Davis,
University of Missouri). He has received awards from the American Institute of Nutrition
(Mead Johnson, Osborne and Mendel) and Bristol-Myers Squibb=Mead Johnson Award for
Distinguished Achievement in Nutrition Research. He is a fellow of AAAS and a fellow of the
American Society of Nutritional Sciences.
John W. Suttie is the Katherine Berns Van Donk Steenbock professor emeritus in the
department of biochemistry and former chair of the department of nutritional sciences
at the University of Wisconsin-Madison. He has broad expertise in biochemistry and
human nutrition. Dr. Suttie received his BS, MS, and PhD degrees from the University of
Wisconsin-Madison. He was an NIH postdoctoral fellow at the National Institute for
Medical Research, Mill Hill, England, before joining the University of Wisconsin faculty.
His research activities are directed toward the metabolism, mechanism of action, and nutritional significance of vitamin K. Dr. Suttie has served as president of the American Society
for Nutritional Sciences (ASNS) and recently resigned his position as editor-in-chief of
The Journal of Nutrition. He has received the Mead Johnson Award, the Osborne and Mendel
Award, and the Conrad Elvehjem Award of the ASNS, the ARS Atwater Lectureship, and
the Bristol Myers-Squibb Award for Distinguished Achievement in Nutrition Research. In
1996 Dr. Suttie was elected to the National Academy of Sciences. He has served as chairman
of the Board of Experimental Biology, as president of the Federation of American Societies
for Experimental Biology (FASEB), and as a member of the NRC’s Board on Agriculture
and Natural Resources, the FDA Blood Products Advisory Committee, and the American
Heart Association Nutrition Committee. He presently serves on the Public Policy Committees
of the ASNS and the American Society for Biochemistry and Molecular Biology (ASBMB),
the USDA=NAREEE Advisory Board, the ILSI Food, Nutrition and Safety Committee, and
the Food and Nutrition Board of the Institute of Medicine.

Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page xi 5.5.2007

2:33pm Compositor Name: BMani

Contributors
Lynn B. Bailey
Department of Food Science and
Human Nutrition
University of Florida
Gainesville, Florida
Susan I. Barr
Department of Food, Nutrition,
and Health
University of British Columbia
Vancouver, British Columbia, Canada
Chris J. Bates
MRC Human Nutrition Research
Elsie Widdowson Laboratory
Cambridge, United Kingdom
Kathryn Bauerly
Department of Nutrition
University of California
Davis, California
Linda K. Buckles
Department of Biochemistry and Molecular
Biology
University of Nebraska Medical Center
Omaha, Nebraska

Betty Jane Burri
Department of Nutrition
University of California
Davis, California
Judith K. Christman
Department of Biochemistry and Molecular
Biology and UNMC=Eppley
Cancer Center
University of Nebraska Medical Center
Omaha, Nebraska

Andrew J. Clifford
Department of Nutrition
University of California
Davis, California
Krishnamurti Dakshinamurti
Department of Biochemistry and Medical
Genetics
University of Manitoba
Winnipeg, Manitoba, Canada
Shyamala Dakshinamurti
Department of Pediatrics and Physiology
University of Manitoba
Winnipeg, Manitoba, Canada
Timothy A. Garrow
Department of Food Science and Human
Nutrition
University of Illinois at
Urbana-Champaign
Urbana, Illinois

Ralph Green
Department of Pathology and
Laboratory Medicine
University of California
Davis, California
Earl H. Harrison
Department of Human Nutrition
The Ohio State University
Columbus, Ohio
Helen L. Henry
Department of Biochemistry
University of California
Riverside, California

xi


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C000 Final Proof page xii 5.5.2007 2:33pm Compositor Name: BMani

xii

Carol S. Johnston
Department of Nutrition
Arizona State University
Mesa, Arizona
James B. Kirkland
Department of Human Health and
Nutritional Sciences
University of Guelph
Guelph, Ontario, Canada

Donald B. McCormick
Department of Biochemistry
Emory University
Atlanta, Georgia
Joshua W. Miller
Department of Pathology and
Laboratory Medicine
University of California
Davis, California
Donald M. Mock
Department of Biochemistry and Molecular
Biology
University of Arkansas for Medical Sciences
Little Rock, Arkansas
Fabiana Fonseca de Moura
Department of Nutrition
University of California
Davis, California
Suzanne P. Murphy
Cancer Research Center of Hawaii
University of Hawaii
Honolulu, Hawaii
Anthony W. Norman
Department of Biochemistry
University of California
Riverside, California

Contributors

Richard S. Rivlin

Department of Medicine
Weill Medical College
of Cornell University
New York, New York
A. Catharine Ross
Department of Nutritional Sciences
Pennsylvania State University
University Park, Pennsylvania
Robert B. Rucker
Department of Nutrition
University of California
Davis, California
Francene M. Steinberg
Department of Nutrition
University of California
Davis, California
John W. Suttie
Department of Biochemistry
University of Wisconsin
Madison, Wisconsin
Maret G. Traber
Department of Nutrition and Exercise
Sciences, Linus Pauling Institute
Oregon State University
Corvallis, Oregon
Janos Zempleni
Department of Nutrition and Health
Sciences
University of Nebraska
Lincoln, Nebraska

Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 1 5.5.2007 2:46pm Compositor Name: BMani

1

Vitamin A: Nutritional Aspects
of Retinoids and Carotenoids
A. Catharine Ross and Earl H. Harrison

CONTENTS
Introduction .......................................................................................................................... 2
Nutritional Aspects of Vitamin A and Carotenoids.............................................................. 2
Historical ........................................................................................................................... 2
Definitions of Vitamin A, Retinoids, and Carotenoids ..................................................... 3
Properties, Nutritional Equivalency, and Recommended Intakes ..................................... 3
Properties of Nutritionally Important Retinoids ........................................................... 3
Properties of Nutritionally Important Carotenoids ....................................................... 7
Nutritional Equivalency................................................................................................. 8
Transport and Metabolism.................................................................................................. 10
Transport and Binding Proteins ...................................................................................... 10
Retinol-Binding Protein ............................................................................................... 12
Albumin ....................................................................................................................... 13
Lipoproteins................................................................................................................. 13
Intracellular Retinoid-Binding Proteins ....................................................................... 13
Nuclear Retinoid Receptors......................................................................................... 14
Intestinal Metabolism ...................................................................................................... 15
Conversion of Provitamin A Carotenoids to Retinoids............................................... 15
Intestinal Absorption of Vitamin A............................................................................. 17
Reesterification, Incorporation into Chylomicrons, and Lymphatic Secretion ........... 18

Hepatic Uptake, Storage, and Release of Vitamin A ...................................................... 18
Hepatic Uptake............................................................................................................ 18
Extrahepatic Uptake .................................................................................................... 19
Storage ......................................................................................................................... 19
Release ......................................................................................................................... 20
Plasma Transport ............................................................................................................ 20
Plasma Retinol ............................................................................................................. 20
Conditions in Which Plasma Retinol May Be Low..................................................... 22
Other Retinoids in Plasma ........................................................................................... 23
Plasma Carotenoids ..................................................................................................... 23
Plasma Retinol Kinetics and Recycling ....................................................................... 23
Intracellular Retinoid Metabolism .................................................................................. 23
Hydrolysis .................................................................................................................... 23
Oxidation–Reduction and Irreversible Oxidation Reactions ....................................... 24
Formation of More Polar Retinoids............................................................................ 24

1


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 2 5.5.2007 2:46pm Compositor Name: BMani

2

Handbook of Vitamins, Fourth Edition

Conjugation .................................................................................................................
Isomerization ...............................................................................................................
Vitamin A and Public Health..............................................................................................
Prevention of Xerophthalmia ..........................................................................................
Actions of Vitamin A in the Eye..................................................................................

Morbidity and Mortality .................................................................................................
Subclinical Deficiency ..................................................................................................
Immune System Changes .............................................................................................
Medical Uses of Retinoids...............................................................................................
Dermatology ................................................................................................................
Acute Promyelocytic Leukemia ...................................................................................
Prevention of Hypervitaminosis A of Nutritional Origin................................................
Excessive Consumption of b-Carotene ........................................................................
References ...........................................................................................................................

25
25
25
25
26
27
27
27
28
28
29
29
29
30

INTRODUCTION
Vitamin A (retinol) is an essential micronutrient for all vertebrates. It is required for normal
vision, reproduction, embryonic development, cell and tissue differentiation, and immune
function. Many aspects of the transport and metabolism of vitamin A, as well as its
functions, are well conserved among species. Dietary vitamin A is ingested in two main

forms—preformed vitamin A (retinyl esters and retinol) and provitamin A carotenoids
(b-carotene, a-carotene, and b-cryptoxanthin)—although the proportion of vitamin A
obtained from each of these form varies considerably among animal species and among
individual human diets. These precursors serve as substrates for the biosynthesis of two
essential metabolites of vitamin A: 11-cis-retinal, required for vision, and all-trans-retinoic acid,
required for cell differentiation and the regulation of gene transcription in nearly all tissues.
Research on vitamin A now spans nine decades. Over 34,000 citations to vitamin A, 7,000
to b-carotene, and 20,000 to retinoic acid can be found in the National Library of Medicine’s
PubMed database [1], covering topics related to nutrition, biochemistry, molecular and cell
biology, physiology, toxicology, public health, and medical therapy. Besides the naturally
occurring forms of vitamin A indicated earlier, numerous structural analogs have been
synthesized. Some retinoids have become widely used as therapeutic agents, particularly in
the treatment of dermatological diseases and certain cancers.
In this chapter, we focus first on vitamin A from a nutritional perspective, addressing its
chemical forms and properties, the nutritional equivalency of compounds that provide
vitamin A activity, and current dietary recommendations. We then cover the metabolism
of carotenoids and vitamin A. Finally, we provide a brief discussion of the key uses of vitamin A
and retinoids in public health and medicine, referring to their benefits as well as some of
the adverse effects caused by ingesting excessive amounts of this highly potent group
of compounds.

NUTRITIONAL ASPECTS OF VITAMIN A AND CAROTENOIDS
HISTORICAL
Vitamin A was discovered in the early 1900s by McCollum and colleagues at the University of
Wisconsin and independently by Osborne and Mendel at Yale. Both groups were studying the
effects of diets made from purified protein and carbohydrate sources, such as casein and rice
flour, on the growth and survival of young rats. They observed that growth ceased and
the animals died unless the diet was supplemented with butter, fish oils, or a quantitatively

Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 3 5.5.2007 2:46pm Compositor Name: BMani

Vitamin A: Nutritional Aspects of Retinoids and Carotenoids

3

minor ether-soluble fraction extracted from these substances, from milk, or from meats. The
unknown substance was then called ‘‘fat-soluble A.’’ Not long thereafter, it was recognized
that the yellow carotenes present in plant extracts had similar nutritional properties, and it
was postulated that this carotenoid fraction could give rise through metabolism to the
bioactive form of fat-soluble A, now called vitamin A, in animal tissues. This was shown to
be correct after b-carotene and retinol were isolated and characterized, and it was shown that
dietary b-carotene gives rise to retinol in animal tissues. Within the first few decades
of vitamin A research, vitamin A deficiency was shown to cause several specific disease
conditions, including xerophthalmia; squamous metaplasia of epithelial and mucosal tissues;
increased susceptibility to infections; and abnormalities of reproduction. Each of these
seminal discoveries paved the way for many subsequent investigations that have greatly
expanded our knowledge about vitamin A. Although the discoveries made in the early
1900s may now seem long ago, it is interesting to note, as reviewed by Wolf [2], that
physicians in ancient Egypt, around 1500 BC, were already using the liver of ox, a very rich
source of vitamin A, to cure what is now referred to as night blindness.

DEFINITIONS

OF

VITAMIN A, RETINOIDS, AND CAROTENOIDS

Vitamin A is a generic term that refers to compounds with the biological activity of retinol.
These include the provitamin A carotenoids, principally b-carotene, a-carotene, and

b-cryptoxanthin, which are provided in the diet by green and yellow or orange vegetables
and some fruits and preformed vitamin A, namely retinyl esters and retinol itself, present in
foods of animal origin, mainly in organ meats such as liver, other meats, eggs, and dairy
products.
The term retinoid was coined to describe synthetically produced structural analogs of the
naturally occurring vitamin A family, but the term is now used for natural as well as synthetic
compounds [3]. Retinoids and carotenoids are defined based on molecular structure. According
to the Joint Commission on Biochemical Nomenclature of the International Union of Pure
and Applied Chemistry and International Union of Biochemistry and Molecular Biology
(IUPAC–IUB), retinoids are ‘‘a class of compounds consisting of four isoprenoid units joined
in a head-to-tail manner’’ [4]. All-trans-retinol is the parent molecule of this family.
The retinoid molecule can be divided into three parts: a trimethylated cyclohexene ring, a
conjugated tetraene side chain, and a polar carbon–oxygen functional group. Additional
examples of key retinoids and structural subgroups, a history of the naming of these
compounds, and current nomenclature of retinoids are available online [4].
The IUPAC–IUB defines carotenoids [5] as ‘‘a class of hydrocarbons (carotenes) and their
oxygenated derivatives (xanthophylls) consisting of eight isoprenoid units joined in such a
manner that the arrangement of isoprenoid units is reversed at the center of the molecule.’’ All
carotenoids may be formally derived from the acyclic C40H56 structure that has a long central
chain of conjugated double bonds, by (i) hydrogenation, (ii) dehydrogenation, (iii) cyclization,
or (iv) oxidation, or any combination of these processes.

PROPERTIES, NUTRITIONAL EQUIVALENCY, AND RECOMMENDED INTAKES
Properties of Nutritionally Important Retinoids
Nutritionally important retinoids and some of their metabolites are illustrated in Figure 1.1.
The conventional numbering of carbon atoms in the retinoid molecule is shown in the
structure of all-trans-retinol in Figure 1.1a. Due to the conjugated double-bond structure
of retinoids and carotenoids, these molecules possess very characteristic UV or visible light
absorption spectra that are useful in their identification and quantification [6,7].

Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 4 5.5.2007 2:46pm Compositor Name: BMani

4

Handbook of Vitamins, Fourth Edition

16

17

19
7

20

9

11

13

1

2 6
345

8

10

12

14

15

COOH

CH2OH

18

(a)

(e)

All-trans-retinol

CH2OH
(b)

All-trans-retinoic acid

9-cis-Retinoic acid

3,4-Didehydroretinol

(f)

COOH

CHO
O

OH

All-trans-retinal
O

(c)

OH
OH

O
COOH

11-cis-Retinal

(d)

(g)

Retinoyl-β-glucuronide

CHO

FIGURE 1.1 Nutritionally important retinoids and major metabolites. The conventional numbering
system for retinoids is shown for all-trans-retinol, the parent molecule of the retinoid family.

Furr and colleagues have summarized the light absorption properties of over 50 retinoids
[8] and nutritionally active carotenoids [9]. Some of the properties of several retinoids related
to dietary vitamin A are summarized in Table 1.1.
Retinoids tend to be most stable in the all-trans configuration. Retinol is most often present
in tissues in esterified form, where the fatty acyl group is usually palmitate with lesser amounts
of stearate and oleate esters. Esterification protects the hydroxyl group from oxidation and
significantly alters the molecule’s physical properties (Table 1.1). Retinyl esters in tissues
are usually admixed with triglycerides and other neutral lipids, including the antioxidant
a-tocopherol. Retinyl esters are the major form of vitamin A in the body as a whole and the
predominant form (often more than 95%) in chylomicrons, cellular lipid droplets, and milk
fat globules. Thus, they are also the major form in foods of animal origin. Retinol contained
in nutritional supplements and fortified foods is usually produced synthetically and is stabilized by formation of the acetate, propionate, or palmitate ester. Minor forms of vitamin A
may be present in the diet, such as vitamin A2 (3,4-didehydroretinol) (Figure 1.1b), which is
present in the oils of fresh-water fish and serves as a visual pigment in these species [10].
Several retinoids that are crucial for function are either absent or insignificant in the diet,
but are generated metabolically from dietary precursors. Due to the potential for the double
bonds of the molecules in the vitamin A family to exist in either the trans- or cis-isomeric
form, a large number of retinoid isomers are possible. The terminal functional group can be
in one of several oxidation states, varying from hydrocarbon, as in anhydroretinol, to
alcohol, aldehyde, and carboxylic acid. Many of these forms may be further modified
through the addition of substituents to the ring, side chain, or end group. These changes in
molecular structure significantly alter the physical properties of the molecules in the vitamin A
family and may markedly affect their biological activity. While dozens of natural retinoids


C20H30O
286.44
C20H28O
284.44

C36H60O2
528
C20H28O;
284.44
C20H28O;
284.44
C20H28O2;
300.4
C20H28O2;
300.4
C20H28O2;
300.4
C26H36O8
476.1
C20H26O3;
314.4
Ethanol, methanol, dimethyl
sulfoxide

360

360

Crystalline solid
Crystalline solid

354

345

383
368
380
365
350

Crystalline solid

Crystalline solid

Crystalline solid

Crystalline solid

Crystalline solid

Viscous oil

Hexane, ether, dimethylsulfoxide
Ethanol, chloroform, cyclohexane,
petroleum ether, oils
Ethanol, chloroform, cyclohexane,
petroleum ether, oils
Ethanol, methanol, isopropanol,
dimethyl sulfoxide
Ethanol, methanol, isopropanol,
dimethyl sulfoxide
Ethanol, methanol, isopropanol,
dimethyl sulfoxide
Aqueous methanol

350

Crystalline solid
325

324–325

Crystalline solid

Physical State

Wavelength of Maximum
Absorption, lmax

Absolute alcohol, methanol, chloroform,
petroleum ether, fats, and oils
Alcohols, ether

Solvents in Which Soluble

Note: For additional absorption spectrum data, see Furr et al. [8,9].

4-Oxo-all-trans-retinoic acid

Retinoyl-b-glucuronide

13-cis-Retinoic acid

9-cis-Retinoic acid

All-trans-retinoic acid

11-cis-Retinal

All-trans-retinal

All-trans-retinol
(vitamin A1)
3,4-Didehydroretinol
(vitamin A2)
Retinyl palmitate

Compound

Formula and
Molecular Mass

TABLE 1.1
Properties of Vitamin A Compounds and Their Metabolites

in ethanol
in hexane
in ethanol
in hexane
in ethanol

58,220 in ethanol

50,700 in methanol

39,750 in ethanol

36,900 in ethanol

42,880
48,000
24,935
26,360
45,300

49,260 in ethanol

52,770 in ethanol
51,770 in hexane
41,320 in ethanol

Molar Extinction
Coefficient, «, in
Indicated Solvent

Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 5 5.5.2007 2:46pm Compositor Name: BMani

Vitamin A: Nutritional Aspects of Retinoids and Carotenoids
5


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 6 5.5.2007 2:46pm Compositor Name: BMani

6

Handbook of Vitamins, Fourth Edition

Lycopene
(a)
BCO
15
15Ј

BCO-2
10Ј
9Ј

All-trans-β-carotene

(b)

α-Carotene

(c)

OH

(d)

HO

(e)

HO

Lutein

β-Cryptoxanthin

FIGURE 1.2 Nutritionally important carotenoids. (a) Lycopene, a nonprovitamin A carotene; (b) alltrans-bb0 -carotene; arrows indicate sites of cleavage by b-carotene monooxygenase, BCO, and BCO-2;
(c) all-trans (a,b0 ) carotene; (d) lutein, a nonprovitamin A xanthophyll; (e) b-cryptoxanthin.

have been isolated, the molecules illustrated in Figure 1.1 and Figure 1.2 are the principal
retinoids and carotenoids, respectively, of nutritional importance, and thus are the main focus
of this chapter. Nevertheless, it is important to recognize that numerous minor metabolites
can be formed at several branch points as retinol and the provitamin A carotenoids are
metabolized.
All-trans-retinal (Figure 1.1c) is the immediate product of the central cleavage of
b-carotene as well as an intermediate in the oxidative metabolism of retinol to all-transretinoic acid. The 11-cis isomer of retinal (Figure 1.1d) is formed in the retina and most of it is
covalently bound to one of the visual pigments, rhodopsin in rods or iodopsin in cones. The
aldehyde functional group of 11-cis-retinal combines with specific lysine residues in these
proteins as a Schiff’s base.
All-trans-retinoic acid (Figure 1.1e) is the most bioactive form of vitamin A. When fed to
vitamin A-deficient animals, retinoic acid restores growth and tissue differentiation and
prevents mortality, indicating that this form alone, or metabolites made from it, is able to
support nearly all of the functions attributed to vitamin A. A notable exception is vision,
which is not restored by retinoic acid because retinoic acid cannot be reduced to retinal
in vivo. Retinoic acid is also the most potent natural ligand of the retinoid receptors, RAR
and RXR (described later), as demonstrated in transactivation assays. Several cis isomers of
retinoic acid have been studied rather extensively, but they are still somewhat enigmatic as to
origin and function. 9-cis-Retinoic acid (Figure 1.1f ) is capable of binding to the nuclear
receptors and may be a principal ligand of the RXR. 13-cis-Retinoic acid is present in plasma,
often at a concentration similar to all-trans-retinoic acid, and its therapeutic effects are well
demonstrated (see the section Dermatology), but it is not known to be a high-affinity ligand

for the nuclear retinoid receptors. It is possible that 13-cis-retinoic acid acts as a relatively
stable precursor or prodrug that can be metabolized to all-trans-retinoic acid or perhaps


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 7 5.5.2007 2:46pm Compositor Name: BMani

Vitamin A: Nutritional Aspects of Retinoids and Carotenoids

7

another bioactive metabolite. Di-cis isomers of retinoic acid also have been detected in
plasma, further illustrating the complex mix of retinoids in biological systems.
Retinoids that are more polar than retinol or retinoic acid are formed through oxidative
metabolism of the ionone ring and side chain. These include 4-hydroxy, 4-oxo, 18-hydroxy,
and 5,6-epoxy derivatives of retinoic acid, and similar modifications of other retinoids.
Conjugation of the lipophilic retinoids with very polar molecules such as glucuronic acid
renders them water-soluble. As an example, retinoyl-b-glucuronide (Figure 1.1g) is present as
a significant metabolite in the plasma and bile. Although some of these polar retinoids are
active in some assays, most of the more polar and water-soluble retinoids appear to result
from phase I and phase II metabolic or detoxification reactions. They may, however, be
deconjugated to some extent and recycled as the free compound.
Many retinoids have been chemically synthesized. A large number of structural
analogs have been synthesized and tested for their potential as drugs that may be able to
induce cell differentiation. In the field of dermatology, 13-cis-retinoic acid (isotretinoin) and
the 1,2,4-trimethyl-3-methoxyphenyl analog of retinoic acid (acetretin) are prominent
differentiation-promoting and keratinolytic compounds. Other retinoids have been developed
as agents able to selectively bind to and activate only a subset of retinoid receptors. Some
synthetic retinoids show none of the biological activities of vitamin A, but still are related in
terms of structure. Retinoids that show selectivity in binding to the RXR receptors rather
than RAR, sometimes referred to as rexinoids, also have been synthesized [11,12].

As analytical methods have improved, additional retinoids have been discovered. Retinol
metabolites have been identified in which the terminal group is dehydrated (anhydroretinol);
the 13,14 position is saturated or hydroxylated; or the double bonds of the retinoid side chain
are flipped back into a form known as a retro retinoid [4]. These retinoids tend to be
quantitatively minor or limited in their distribution, and their significance is still uncertain.
Properties of Nutritionally Important Carotenoids
Carotenoids are synthesized by photosynthetic plants and some algae and bacteria, but not by
animal tissues. The initial stage of biosynthesis results in the formation of the basic polyisoprenoid structure of the hydrocarbon lycopene (Figure 1.2a), a 40-carbon linear structure
with an extended system of 13 conjugated double bonds. Further biosynthetic reactions result
in the cyclization of the ends of this linear molecule to form either a- or b-ionone rings. The
carotene group of carotenoids comprises hydrocarbon carotenoids in which the ionone rings
bear no other substituents. The addition of oxygen to the carotene structure results in the
formation of the xanthophyll group of carotenoids. The double bonds in most carotenoids are
present in the more stable all-trans configuration, although cis isomers can exist. Carotenoids
are widespread in nature and are responsible for the yellow, orange, red, and purple colors of
many fruits, flowers, birds, insects, and marine animals. In photosynthetic plants, carotenoids
improve the efficiency of photosynthesis, while they are important to insects, birds, animals,
and humans for their colorful and attractive sensory properties.
Although some 600 carotenoids have been isolated from natural sources, only about
one-tenth of them are present in human diets [13], and only about 20 have been detected
in blood and tissues. b-carotene (Figure 1.2b), a-carotene (Figure 1.2c), lycopene, lutein
(Figure 1.2d), and b-cryptoxanthin (Figure 1.2e) are the five most prominent carotenoids
in the human body. However, only b-carotene, a-carotene, and b-cryptoxanthin possess
significant vitamin A activity. To be active as vitamin A, a carotenoid must have an
unsubstituted b-ionone ring and an unsaturated hydrocarbon chain. The bioactivity of
all-trans-b-carotene, with two symmetrical halves, is about twice that of an equal amount
of a-carotene and b-cryptoxanthin, in which only one unsubstituted b-ionone ring is present.
Even though lycopene, lutein, and zeaxanthin can be relatively abundant in the diet and

Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 8 5.5.2007 2:46pm Compositor Name: BMani

8

Handbook of Vitamins, Fourth Edition

humans can absorb them across the intestine into plasma, they lack vitamin A activity
because of the absence of a closed unsubstituted ring. In plants, provitamin A carotenoids are
embedded in complex cellular structures such as the cellulose-containing matrix of chloroplasts
or pigment-containing chromoplasts. Their association with these matrices of plants is a
significant factor affecting the efficiency of their digestion, release, and bioavailability [14,15].
Nutritional Equivalency
Units of Activity
Different forms of vitamin A differ in their biological activity per unit of mass. For this reason,
the bioactivity of vitamin A in the diet is expressed in equivalents (with respect to all-transretinol) rather than in mass units. Several different units have been adopted over time and most
of them are still used in some capacity. In 1967, the World Health Organization (WHO)=FAO
recommended replacing the international unit (IU), a bioactivity unit, with the retinol equivalent (RE); 1 RE was defined as 1 mg of all-trans-retinol or 6 mg of b-carotene in foods [16]. In
2001, the U.S. Institute of Medicine recommended replacing the RE with the retinol activity
equivalent (RAE) and redefining the average equivalency values for carotenoids in foods in
comparison with retinol [15]. These sequential changes in units were in large part a response to
better knowledge of the efficiency of utilization of carotenoids [15,16]; 1 mg RAE is defined as
1 mg of all-trans-retinol, and therefore is the same as 1 mg RE. Both are equal to 3.3 IU of
retinol. The equivalency of provitamin A carotenoids and retinol in the RAE system is
illustrated in Figure 1.3. These currently adopted conversion factors are necessarily approximations. Because the RAE terminology is not yet fully used, the vitamin A values in some
food tables, food labels, and supplements are still expressed in RE or IU.
Another term, daily value (% DV), is used in food labeling. It is not a true unit of activity,
but provides an indication of the percentage of the recommended dietary allowance (RDA)*
present in one serving of a given food.
Form consumed

Equivalency
after bioconversion

Dietary or supplemental
vitamin A (1 µg)

Retinol (1 µg)

Supplemental β-carotene
(pure, in oily solution) (2 µg)

Retinol (1 µg)

Dietary β-carotene
(in food matrix) (12 µg)

Retinol (1 µg)

Dietary α-carotene or
β-cryptoxanthin
(in food matrix) (24 µg)

Retinol (1 µg)

FIGURE 1.3 Approximate nutritional equivalency of dietary provitamin A carotenoids and retinol, as
revised in 2001. The values shown are used to convert the contents of carotenoids in supplements and
foods to equivalent amounts of dietary retinol. (From Institute of Medicine, Dietary Reference Intakes
for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum,
Nickel, Silicon, Vanadium, and Zinc, National Academy Press, Washington, 2002, pp. 8–9.)

* Based on the percentage of the RDA of a nutrient, for a person consuming a 2000 kcal diet.


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 9 5.5.2007 2:46pm Compositor Name: BMani

9

Vitamin A: Nutritional Aspects of Retinoids and Carotenoids

TABLE 1.2
Recommended Dietary Allowances (RDA) and Upper Level (UL)
Values for Vitamin A by Life Stage Group
Life Stage Group

RDA (mg=day)a

UL (mg=day)b

Infants
0–12 months

400c

600

Children
1–3 years
4–8 years

300

400

600
900

Adolescent and adult males
9–13 years
14–18 years
19 to !70 years

600
900
900

1700
2800
3000

Adolescent and adult females
9–13 years
14–18 years
19 to !70 years

600
700
700

1700
2800
3000

Pregnancy
<18 years
19–50 years

750
770

2800
3000

Lactation
<18 years
19–50 years

1200
1300

2800
3000

Source: From Institute of Medicine in Dietary Reference Intakes for Vitamin A, Vitamin
K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel,
Silicon, Vanadium, and Zinc, National Academy Press, Washington, 2002, pp. 8–9.
a
b
c

As retinol activity equivalents (RAEs).
As mg preformed vitamin A (retinol).

Adequate intake (RAEs).

Recommended Intakes
The conceptual framework and values for dietary reference intakes (DRI) are discussed by
Murphy and Barr in Chapter 18. DRI values for vitamin A, established in 2001 [15], are
summarized in Table 1.2. A tolerable upper intake level (UL, see Chapter 18) for vitamin A
was defined at this time [15]; similarly, a safe upper level for vitamin A and b-carotene has
been defined in the United Kingdom [17]. It is important to note that the UL applies only to
chronic intakes of preformed vitamin A (not carotenoids, which do not cause adverse effects).
For several life stage groups, the UL values are less than three times higher than the RDA.
Dietary Sources
Detailed tables of the vitamin A contents of foods can be found in several reference sources
and online resources. A database for carotenoids in foods is available online [18]. It should be
noted that nutrient databases provide only approximate values. The contents of vitamin A
and carotenoids in foods can vary substantially with crop variety or cultivar, the environment
in which it is grown, and with processing and storage conditions [19,20].
Foods in the U.S. diet with the highest concentrations of preformed vitamin A are liver
(4–20 mg retinol=100 g) and fortified foods such as powdered breakfast drinks (3–6 mg=100 g),
ready-to-eat cereals (0.7–1.5 mg=100 g), and margarines (~0.8 mg=100 g) [18]. The highest


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 10

10

5.5.2007 2:46pm Compositor Name: BMani

Handbook of Vitamins, Fourth Edition

levels of provitamin A carotenoids are found in carrots, sweet potatoes, pumpkin, kale,

spinach, collards, and squash (roughly 5–10 mg RAE=100 g) [18].
Data from NHANES 2001–2002 for food consumption in the United States showed that
the major contributors to the intake of preformed vitamin A are milk, margarine, eggs, beef
liver, and ready-to-eat cereals, whereas the major sources of provitamin A carotenoids are
carrots, cantaloupes, sweet potatoes, and spinach [21]. These data, compiled for both genders
and all age groups, showed that the mean intake of vitamin A is ~600 mg RAE=day from food
and that 70% –75% of this is as preformed vitamin A (retinol). The provitamin A carotenoids
b-carotene, a-carotene, and b-cryptoxanthin were ingested in amounts of ~1750, 350, and
150 mg=day, respectively. By comparison, the intakes of the nonprovitamin A carotene lycopene
and the xanthophylls (zeaxanthin and lutein) were ~6000 and 1300 mg=day, respectively. The
Institute of Medicine’s Micronutrients Report [15] includes sample menus to illustrate that an
adequate intake of vitamin A can be obtained even if a vegetarian diet containing only
provitamin A carotenoids is consumed.

TRANSPORT AND METABOLISM
Taken as a whole, the processes of vitamin A metabolism can be viewed as supporting two
main biological functions: providing appropriate retinoids to tissues throughout the body for
the local production of retinoic acid, which is required to maintain normal gene expression
and tissue differentiation, and providing retinol to the retina for adequate production of
11-cis-retinal. Major interconversions and metabolic reactions are diagrammed in Figure 1.4.

TRANSPORT

AND

BINDING PROTEINS

Carotenoids and retinyl esters are transported by lipoproteins and stored within the fat fraction
of tissues, whereas retinol, retinal, and retinoic acid are mostly found in plasma and cells in
association with specific retinoid-binding proteins. The associations of carotenoids and

retinoids with proteins greatly influence their distribution, metabolism, and physiological
functions. Amphiphilic retinoids—principally retinol, retinal, and retinoic acid—bind to
retinoid-binding proteins, which confer aqueous solubility on these otherwise insoluble
molecules. The concentration of free retinoid is very low. Binding proteins thus reduce the
potential for retinoids to cause membrane damage [22]. Different retinoid-binding proteins
function in plasma, interstitial fluid, and the cytosolic compartment of cells as chaperones that
direct the bound retinoids to enzymes that then carry out their metabolism. Table 1.3 summarizes
Dietary precursors

Carotenoids
Storage
Retinyl
esters

Retinol
Mobilization

Oxidative
metabolism
RA
Polar metabolites
Bioactivation

Cleavage
Retinal

11-cis-Retinoids,ocular
processes
Conjugation,
oxidation, and

excretion

Further oxidation and
conjugation reactions

FIGURE 1.4 Principal metabolic reactions of vitamin A. RA, retinoic acid.


136 kDa

55 kDa

Fatty acid-binding protein=cellular
retinoid-binding protein

CRAL=TRIO

Partial homology to enoyl-CoA
isomerase=hydratases

Transthyretin

Albumin

Cellular retinoic acid-binding
proteins, CRABP-I, CRABP-II

Cellular retinal-binding protein,
CRALBP

Interstitial retinoid-binding
protein, IRBP

Transthyretin, TTR

Albumin

67 kDa

~36 kDa

~14.8 kDa

~14.6 kDa

Fatty acid-binding protein=cellular
retinoid-binding protein

Cellular retinol-binding proteins,
CRBP-I, CRBP-II, CRBP-III,
CRBP-IV

21 kDa

Size

Lipocalin

Gene Family=Type

Retinol-binding protein, RBP

Protein

TABLE 1.3
Major Extracellular and Intracellular Retinoid-Binding Proteins

Retinoic acid; other acidic
retinoids; fatty acids

Thyroxin homotetramer

All-trans and 11-cis-retinal; other
lipophilic substances

All-trans-retinol and 11-cis-retinol;
11-cis-retinal

CRBP-I: retinol
CRBP-II: retinol and retinal
CRBP-III: trans- and cis-retinol
CRBP-IV: retinol
CRABP-I: retinoic acid
CRABP-II: retinoic acid

Retinol

Ligand (All-trans Isomer
Unless Indicated)

Binding of retinoic acid and
chaperone function to
enzymes of metabolism;
possible coreceptor function
for CRABP-II
Binding of retinol, retinal;
chaperone function to
enzymes of retinoid cycle
that regenerate visual pigments
in the retina
Improving the efficiency of
translocation of retinoids
between the RPE and
photoreceptor cells
Cotransport protein for holo-RBP;
prevents rapid loss by renal
filtration
General carrier for acidic lipids

Transport of retinol between
liver and extrahepatic tissues
Binding of retinol and
chaperone function to enzymes
of metabolism

Function

Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 11
5.5.2007 2:46pm Compositor Name: BMani

Vitamin A: Nutritional Aspects of Retinoids and Carotenoids
11


Robert B. Rucker/Handbook of Vitamins, Fourth Edition 4022_C001 Final Proof page 12

12

5.5.2007 2:46pm Compositor Name: BMani

Handbook of Vitamins, Fourth Edition

some of the characteristics of the retinoid-binding proteins involved in these absorptive,
transport, and metabolic processes.
Retinol-Binding Protein
Plasma retinol is transported by a retinol-binding protein (RBP) [23]. One molecule of retinol
is bound noncovalently within the beta-barrel pocket of the RBP protein. Although most
RBP is produced in liver parenchymal cells, the kidney, adipose tissue, lacrimal gland, and
some other extrahepatic organs also contain RBP mRNA, generally at levels less than 10% of
that in hepatocytes, and may synthesize RBP [24]. The maintenance of a normal rate of
RBP synthesis depends on an adequate intake of protein, calories, and some micronutrients
(Table 1.4); conversely, a deficiency of any of these can reduce the plasma concentrations of
retinol–RBP. RBP is synthesized in the endoplasmic reticulum of hepatocytes, transported
through the Golgi apparatus where apo-RBP combines with a molecule of retinol to form
holo-RBP [25], and then released into plasma. Nearly all circulating holo-RBP is bound
noncovalently to another hepatically synthesized protein, transthyretin (TTR), which also
binds thyroxine [26,27]. RBP protects retinol from oxidation, while TTR stabilizes the retinol–
RBP interaction [28]. Although retinol is the natural ligand of RBP, other retinoids such as
4-hydroxyphenylretinamide (4HPR) can compete for binding to RBP in vitro [29], destabilize
the RBP–TTR complex [30], and result in reduced levels of plasma retinol [31].

TABLE 1.4
Causes of a Low Level of Plasma Retinol
Etiology
Nutritional
Inadequate vitamin A in liver
Inadequate protein or energy
Inadequate micronutrients (zinc, iron)
Disease-related
Infection or inflammation
Liver diseases
Renal diseases
Treatment-related
Retinoid treatment (4HPR, RA)
Genetic
Hereditary disorders

Toxicologic
Alcohol-related
Environmental toxin-related

Mechanisms

Reduced secretion of holo-RBP
Reduced RBP synthesis, release
Reduced production and section of RBP, and
TTR (retinol not limiting)
Reduced synthesis of hepatic proteins,
including RBP, TTR
Reduced reabsorption

Displacement of retinol from RBP;
possibly altered synthesis is RBP
Rare natural mutations that affect the
production or the stability of RBP
and TTR proteins
Impaired vitamin A storage; generally
poor nutritional or health status
Altered retinol kinetics (e.g., dioxin or
TCDD exposure)

Note: 4HPR, 4-hydroxphenylretinamide; RA, retinoic acid; RBP, retinol-binding protein; TCDD,
2,3,7,8-tetrachlorodibenzo-p-dioxin; TTR, transthyretin.