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Physiological, and
Molecular Aspects
of Human Nutrition

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Physiological, and
Molecular Aspects
of Human Nutrition
Martha H. Stipanuk, PhD
Division of Nutritional Sciences
Colleges of Human Ecology and
Agriculture and Life Sciences
Cornell University
Ithaca, New York

Marie A. Caudill, PhD, RD
Associate Professor
Division of Nutritional Sciences
Colleges of Human Ecology and
Agriculture and Life Sciences
Cornell University
Ithaca, New York

3251 Riverport Lane
St. Louis, Missouri 63043

Copyright © 2013, 2006, 2000 by Saunders, an imprint of Elsevier Inc.

ISBN: 978-1-4377-0959-9

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than as may be noted herein).


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our understanding, changes in research methods, professional practices, or medical treatment may become
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Library of Congress Cataloging-in-Publication Data
Biochemical, physiological, and molecular aspects of human nutrition/[edited by] Martha H. Stipanuk,
Marie A. Caudill. – 3rd ed.
   p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4377-0959-9 (pbk.)
I. Stipanuk, Martha H. II. Caudill, Marie A.
[DNLM: 1. Nutritional Physiological Phenomena. 2. Metabolism--physiology. QU 145]
LC classification not assigned
Senior Editor: Yvonne Alexopoulos
Senior Developmental Editors: Lisa P. Newton and Karen C. Turner
Editorial Assistant: Kit Blanke
Publishing Services Manager: Jeff Patterson
Project Manager: Megan Isenberg
Designer: Jessica Williams
Front cover image copyright Dennis Kunkel Microscopy, Inc.

Printed in the United States of America
Last digit is the print number: 9

8 7


5 4


2 1

Chapter Contributors


Associate Professor
Department of Biochemistry and Molecular Biology
School of Medicine
Indiana University
Evansville, Indiana

Research Scientist
Cordeliers Research Center
Department of Physiology, Metabolism, Differentiation
INSERM/Université Pierre et Marie Curie/CNRS
Paris, France



Professor Emeritus
Department of Agricultural, Food and Nutritional Science
University of Alberta
Edmonton, Alberta, Canada

PhD Candidate
Department of Nutritional Sciences
University of Toronto
Toronto, Ontario, Canada



Assistant Professor
Department of Nutritional Sciences
Faculty of Medicine
University of Toronto
Toronto, Ontario, Canada

Division of Medical Oncology
Department of Internal Medicine
The Ohio State University
Columbus, Ohio



Associate Professor, Nutrition
School of Applied Health Sciences and Wellness
Edison Biotechnology Institute
Ohio University
Athens, Ohio

Professor Emeritus
Cornell University
Ithaca, New York
Center Director
Grand Forks Human Nutrition Research Center
Grand Forks, North Dakota


Division of Nutritional Sciences
Cornell University
Ithaca, New York

Division of Nutritional Sciences
Cornell University
Ithaca, New York

University Research Professor
Department of Biochemistry
Memorial University of Newfoundland
St. John’s, Newfoundland, Canada

Department of Biochemistry
Memorial University of Newfoundland
St John’s, Newfoundland, Canada


Professor Emeritus
IMCN, Bâtiment Lavoisier
Université Catholique de Louvain
Louvain-la-Neuve, Belgium

Associate Professor
Department of Human Nutrition, Foods and Exercise
College of Agriculture and Life Sciences
Virginia Polytechnic Institute and State University
Blacksburg, Virginia

Department of Nutritional Sciences
College of Agriculture and Natural Resources
University of Connecticut
Storrs, Connecticut



Chapter Contributors



Director and Endowed Chair
Distinguished Professor of Biochemistry and Biophysics
Linus Pauling Institute
Oregon State University
Corvallis, Oregon

Postdoctoral Fellow
Department of Animal & Poultry Science
University of Guelph
Guelph, Ontario, Canada


Senior Scientist
Edison Biotechnology Institute
Ohio University
Athens, Ohio

Department of Food Science and Human Nutrition
University of Florida
Gainesville, Florida

Associate Professor
Department of Foods and Nutrition
College of Family and Consumer Sciences
University of Georgia
Athens, Georgia

Associate Professor
Department of Human Nutrition, Foods and Exercise
College of Agriculture and Life Sciences
Virginia Polytechnic Institute and State University
Blacksburg, Virginia

Adjunct Professor
Department of Pathology and Laboratory Medicine
University of Cincinnati
Cincinnati, Ohio

Department of Food Science and Human Nutrition
College of Agricultural, Consumer and Environmental
Department of Pharmacology
College of Medicine
University of Illinois
Urbana, Illinois

Executive Director of the Research Institute
Carle Foundation Hospital
Adjunct Assistant Professor
Department of Food Science and Human Nutrition
University of Illinois
Urbana, Illinois

Research Scientist
Cordeliers Research Center
Department of Physiology, Metabolism, Differentiation
INSERM/Université Pierre et Marie Curie/CNRS
Paris, France



Research Associate
Department of Biochemistry
College of Medicine
University of Arkansas for Medical Sciences
Little Rock, Arkansas

Departments of Nutritional Sciences and Molecular and
Cell Biology
The University of Connecticut
Storrs, Connecticut

Professor of Surgery
Stony Brook University Medical Center
Stony Brook, New York

Research Associate
Linus Pauling Institute
Oregon State University
Corvallis, Oregon

Department of Medical Pathology and Laboratory Medicine
School of Medicine
University of California, Davis
Sacramento, California

Department of Biochemistry and Molecular Biology
Department of Pediatrics
College of Medicine
University of Arkansas for Medical Sciences
Little Rock, Arkansas

Distinguished Professor and Director
Riddet Institute
Massey University
Palmerston North, New Zealand

Chapter Contributors




Research Nutritionist
U.S. Department Agriculture, Agricultural Research Service
Grand Forks Human Nutrition Research Center
Grand Forks, North Dakota

Honorary Associate Professor
Departments of Physiology, Pharmacology, and Pharmacy
Li Ka Shing Faculty of Medicine
The University of Hong Kong
Hong Kong, China


Departments of Pharmacology and Nutrition
Case Western Reserve University
School of Medicine
Cleveland, Ohio

PhD Candidate
Department of Nutritional Sciences
University of Toronto
Toronto, Ontario, Canada

Associate Professor
Division of Nutritional Sciences
Cornell University
Ithaca, New York

Associate Professor of Medicine
Section of Endocrinology, Diabetes, and Nutrition
Boston University School of Medicine
Boston, Massachusetts

Department of Molecular Biology and Microbiology
College of Medicine
University of Central Florida
Orlando, Florida

Assistant Professor
Department of Food Science
Cornell University, New York State Agricultural
­Experiment Station
Geneva, New York

Department of Nutritional Science and Toxicology
University of California
Berkeley, California

Department of Nutritional Sciences
Rutgers University
New Brunswick, New Jersey


Department of Food Science and Nutrition
College of Food, Agricultural and Natural Resource
University of Minnesota
Minneapolis, Minnesota

Professor Emeritus
Department of Biochemistry
Carver College of Medicine
University of Iowa
Iowa City, Iowa

Nutrition Specialist
Division of Nutritional Sciences
Cornell University
Ithaca, New York

Department of Physiology & Functional Genomics
College of Medicine
University of Florida
Gainesville, Florida

Department of Nutritional Sciences
School of Environmental and Biological Sciences
Rutgers University
New Brunswick, New Jersey

Professor, Calloway Chair in Human Nutrition
Department of Nutritional Science and Toxicology
University of California
Berkeley, California

Department of Food Science and Human Nutrition
University of Illinois at Urbana-Champaign
Champaign, Illinois


Chapter Contributors



Associate Professor
Medical Dietetics Division and
Department of Family Medicine
School of Allied Medical Professions
College of Medicine
The Ohio State University
Columbus, Ohio

Research Scientist
Southern California Institute for Research and Education
Long Beach, California


Distinguished University Professor
University of Alberta
Adjunct Professor
University of Western Ontario

Department of Pathology and Laboratory Medicine
College of Medicine
University of Cincinnati
Cincinnati, Ohio
JÜRGEN VORMANN, Dr. rer. nat.

Director and Professor
Institute for Prevention and Nutrition
Ismaning/Munich, Germany

Professor Emeritus
Department of Internal Medicine
Section on Molecular Medicine
Wake Forest University School of Medicine
Winston-Salem, North Carolina

Regents’ Professor
Department of Oral Biology
College of Dental Medicine
Georgia Health Sciences University
Augusta, Georgia

PhD Candidate
Division of Nutritional Sciences
Cornell University
Ithaca, New York

Division of Nutritional Sciences
Cornell University
Ithaca, New York


Professor of Medicine and Nutrition, Tufts University
Scientist I and Director, Vitamins & Carcinogenesis
­Laboratory, Jean Mayer USDA Human Nutrition
­Research Center on Aging at Tufts University
Boston, Massachusetts

Research Scientist
Southern California Institute for Research and Education
Long Beach, California

Chief of Hepatology
VA Long Beach Healthcare System
Long Beach, California
Professor of Medicine
University of California, Irvine
Irvine, California

Division of Nutritional Sciences
Faculty of Health and Medical Sciences
University of Surrey
Guildford, United Kingdom

Nutritional Sciences Major
Division of Nutritional Sciences
Cornell University
Ithaca, New York

Professor and Director
Division of Nutritional Sciences
Cornell University
Ithaca, New York

Division of Nutritional Sciences and Department
of ­Psychology
Cornell University
Ithaca, New York



Associate Professor
Department of Human Nutrition
The Ohio State University
Columbus, Ohio

Postdoctoral Fellow
College of Medicine
University of Cincinnati
Cincinnati, Ohio



Professor, Friedman School of Nutrition Science and Policy,
Tufts University
Senior Scientist and Associate Director, Jean Mayer USDA
Human Nutrition Research Center on Aging at Tufts
Boston, Massachusetts

Associate Professor
Friedman School of Nutrition Science
Tufts University
Boston, Massachusetts


Department of Kinesiology and Nutrition
University of Illinois at Chicago
Chicago, Illinois

Assistant Professor
Department of Foods and Nutrition
Purdue University
West Lafayette, Indiana

Postdoctoral Fellow
Dana-Farber Cancer Institute
Harvard Medical School
Boston, Massachusetts


Division of Nutritional Sciences
Cornell University
Ithaca, New York

Department of Food Science and Human Nutrition
Iowa State University
Ames, Iowa

Department of Nutritional Sciences
School of Health Related Professions
University of Medicine and Dentistry of New Jersey
Newark, New Jersey


Assistant Professor
Department of Food Science and Nutrition
University of Minnesota
St. Paul, Minnesota




e are pleased to present the third edition of Biochemical,
Physiological, and Molecular Aspects of Human Nutrition.
Our understanding of nutrition and its role in health and
disease has grown immensely over the past two decades, and
much of this progress has been made at the biochemical,
physiological, and molecular levels. Recognizing that it is difficult for students, instructors, clinicians, and practitioners
to obtain and sustain a deep understanding of the biology of
human nutrition, we have worked to develop a textbook that
provides a comprehensive, accessible, scientifically accurate,
and up-to-date overview of the current understanding of the
biological bases of human nutrition. Individuals specializing in nutrition and its effects on health will want to have
the third edition of Biochemical, Physiological, and Molecular
Aspects of Human Nutrition on their shelves as a convenient
The third edition of Biochemical, Physiological, and
Molecular Aspects of Human Nutrition reflects the contributions of over 60 researchers and academicians who represent a diverse range of expertise. These individuals have
written, revised, and reviewed chapters, helping us distill
complex scientific information into readable chapters and
helpful illustrations. Input from experts was deemed essential to ensure up-to-date and accurate information. As editors, we have done our best to ensure consistency of style
and approach so that the individual chapters and units work
together as a whole, especially for those who will use this text
to teach the biology of nutrition or to acquire a solid understanding of this topic for themselves.
Students in nutrition, metabolism, and other life sciences—
This book is intended largely for upper-level undergraduate
students and graduate students who have completed studies
in organic chemistry, biochemistry, molecular biology, and
physiology. Hence topics are covered at a more advanced
level than in introductory and intermediate textbooks that
assume less background in these supporting disciplines.
Nevertheless, an effort has been made to present material
in a manner that allows a reader who is unfamiliar with a
particular topic to obtain a clear, concise, and thorough
understanding of the essential concepts. Particular attention has been given to the design of figures and choice of
tabular material to ensure that illustrations and tables clarify,
extend, and enrich the text.
Instructors in nutrition, metabolism, and other life sciences—
Although the topics are logically arranged for reading
from first to last, each chapter is also written to be a selfcontained unit to facilitate use of a subset of chapters or a

different sequence of presentation of chapters according
to instructional needs. The depth and breadth of coverage
make this text somewhat unique among nutrition texts.
It is an especially good choice for courses on macronutrient
metabolism and for courses on micronutrient (vitamin and
mineral) metabolism. Teaching resources for instructors,
including an image collection (which includes all images
and selected tables from the text) and three supplementary
tables for chapter 24, are available on CD. To obtain a copy,
please contact your local Elsevier rep or call Faculty Support
at 1-800-222-9570.
Dietitians, clinicians, and other health professionals—
Given the broad availability of scientific and pseudoscientific information to the general public, it is important that
dietitians and other health practitioners have a solid understanding of the biology of human nutrition and health.
Biochemical, Physiological, and Molecular Aspects of Human
Nutrition provides insights into recommended nutritional
practices as well as the science behind the advice.
The text consists of six units that encompass a traditional
coverage of nutrients by classification (macronutrients, vitamins, and minerals) as well as the integrated metabolism
and use of these nutrients. In recognition of new paradigms
in thinking about nutrition, Unit I considers the historical foundations of nutrition, changes in how nutrients are
being defined and in how dietary recommendations are
being made, as well as the potentially beneficial nonnutrient
components of food. The macronutrients or energy-yielding
nutrients (carbohydrates, proteins, and lipids) are discussed
in Units II through V. Unit II provides an overview of the
structure and properties of the macronutrients. The digestion and absorption of the macronutrients are discussed in
Unit III, and the metabolism of the macronutrients is the
topic of Unit IV. The last two chapters in Unit IV provide
an integrated overview of the regulation of metabolism of
macronutrients. Finally, the relation of these macronutrients
to energy balance is discussed in Unit V. The vitamins are
discussed in Unit VI. The B vitamins have been grouped and
discussed in three chapters in a manner that facilitates an
understanding of their functions in macronutrient metabolism. The unique functions of vitamins C, K, E, A, and D are
described in individual chapters. The minerals and water are
the subjects of Unit VII; those with well-characterized nutritional or health-related roles are discussed in detail. Included
within each chapter are feature boxes with Nutrition
Insights, Clinical Correlations, Life Cycle Considerations,
and Historical Tidbits. Significant disease-related aspects of


nutrition are incorporated into the individual chapters and
also are highlighted in many of the feature boxes scattered
throughout the book.
The third edition includes many new figures drawn
specifically for this book. Illustrations have been carefully


prepared to enhance the text, providing further insights and
facilitating understanding. References to the research literature and recommended readings, as well as related websites,
are provided for each chapter as appropriate.



orking on the third edition of Biochemical, Physiological, and Molecular Aspects of Human Nutrition
has been a very positive experience for us. All of those who
helped us as we worked on this project contributed to our
enjoyment of this work, and we extend our deep gratitude
to each of you.
In particular, our deep appreciation goes to the chapter
contributors. The text is much enriched by the contributions
of so many talented researchers and teachers. Their commitment to making scientific advances available and accessible
to our audiences is clear from the willingness of these busy
individuals to accept the challenge and devote the time and
effort required to see their chapters through the entire process. Their willingness to respond to queries, to discuss and
resolve apparent differences of opinion among authors, and
to allow the editorial flexibility needed to turn individual
chapters into a coherent and integrated text was superb.
It has been a delight to work with the amazing staff at
Elsevier who handled the publication process. Senior Editor
Yvonne Alexopoulos and Developmental Editor Lisa ­Newton

kept the process running smoothly and efficiently and made
our job so much easier in many ways. The support and
efforts of Developmental Editor Karen Turner on the art
and of Project Manager Megan Isenberg on the production
process are also greatly appreciated. We would also like to
acknowledge Dennis Kunkel Microscopy, Inc. for supplying
the front cover image.
During the time we worked on this book, our colleagues
in the Division of Nutritional Sciences in the College of
Human Ecology and the College of Agriculture and Life Sciences at Cornell University supported our efforts in many
ways, especially by serving as sources of expertise and by
contributing several of the chapters. We also acknowledge
our own graduate students and research staff, who kept our
research programs moving forward with full force during
our work on this book, and our families and friends who
supported and encouraged us in this work. A special thank
you is extended to Kelsey Shields for her assistance with
chapter formatting.

Martha H. Stipanuk
Marie A. Caudill



Other Classes of Carbohydrate Units 56

Nutrients: Essential and Nonessential

Disaccharides and Oligosaccharides and Their
Properties 58

1.	Nutrients: History and Definitions
Martha H. Stipanuk, PhD

Polysaccharides of Nutritional Importance 61
Glycoconjugates of Physiological Interest 65

Discovery of the Nutrients 3

5.	Structure, Nomenclature, and Properties
of Proteins and Amino Acids
Martha H. Stipanuk, PhD

Setting Criteria for Essentiality 8
Concerns about Excessive Intakes 10
Nutrients That Do Not Meet the Strict Criteria
for Essentiality 10

The Proteinogenic Amino Acids 69

Health Effects of Nutrients and Nonnutrient
Components of Food 11

Synthesis of Peptides and Proteins 75

Use of Nutrients as Pharmacological Agents


2.	Food Components with Health Benefits
Elizabeth H. Jeffery, PhD; Kelly A. Tappenden,
PhD, RD; and Anna-Sigrid Keck, PhD, CIP
Functional Foods and Dietary Supplements 14
Carotenoids 16
Plant Sterols/Stanols 19
Polyphenolics 20


Stabilization of Protein Conformations 83
Stable Posttranslational Modifications of
Proteins 85
Regulation of the Amount of Protein and Its
Functional State 87

The Chemical Classes of Lipids—Their Structure
and Nomenclature 91

Phytoestrogens 22
Isothiocyanates 24

Fatty Acids and Food Fats 110

Organosulfurs 25

Physical and Structural Properties of Lipids 112

Polyols 26
Dietary Fiber 26

Digestion and Absorption of the

Prebiotics/Probiotics 27
Overall Recommendations 28

3.	Guidelines for Food and Nutrient Intake
Christina Stark, MS, RD, CDN
Dietary Reference Intakes 34
Food Guides

Protein Structure

6.	Structure, Nomenclature, and Properties
of Lipids
J. Thomas Brenna, PhD, and
Gavin L. Sacks, PhD

Polyunsaturated Fatty Acids 17

Dietary Advice: Goals and Guidelines

Modifications of Amino Acid Side Chains 74



Labeling of Foods and Supplements 42

Structure and Properties of the
4.	Structure, Nomenclature, and Properties of
Joanne L. Slavin, PhD, RD
Monosaccharides or Sugar Residues 50

7.	Overview of Digestion and Absorption
Alan B. R. Thomson, MD, PhD, and
Patrick Tso, PhD
General Structure and Function of the GI
Tract 122
The Upper GI System 125
The Small Intestine 128
The Large Intestine 139

8.	Digestion and Absorption of Carbohydrate
Armelle Leturque, PhD, and
Edith Brot-Laroche, PhD
Carbohydrate Components of the Human
Diet 142
Digestion of Starch 142


Digestion of Dietary Disaccharides 146

Physiological Characterization of Dietary
Fiber 197

Expression and Processing of the
Oligosaccharidases and Disaccharidases


Glycosidic Bonds Not Hydrolyzed by Human
Digestive Enzymes 149

Major Physiological Effects of Fiber and Structure–
Function Relationships 198
Effects of Fiber on Whole-Body Energy Status 201

Absorption of Monosaccharides by the
Enterocyte 149

Recommendations for Fiber Intake and
Typical Intakes 201

Factors Affecting Carbohydrate Assimilation 152

Dietary Fiber Intake and Disease 202

Deficiencies of Carbohydrate Assimilation 153

Dietary Fiber and Microbiota 203

9.	Digestion and Absorption of Protein
Paul J. Moughan, PhD, DSc, FRSC, FRSNZ, and
Bruce R. Stevens, PhD
Digestion of Protein in the Gastrointestinal
Tract 162

Metabolism of the Macronutrients
12.	Carbohydrate Metabolism: Synthesis and
Mary M. McGrane, PhD

The Gastric Phase: Denaturation and Initial
Hydrolysis of Proteins 162
Small Intestinal Luminal Phase: Activation and
Action of Pancreatic Proteolytic Enzymes 163

Overview of Tissue-Specific Glucose
Metabolism 209

Small Intestinal Mucosal Phase: Brush Border and
Cytosolic Peptidases 166

Transport of Glucose across Cell Membranes 211

Absorption of Free Amino Acids and Small
Peptides 166

Metabolism of Monosaccharides Other Than
Glucose 217

Metabolism of Amino Acids in Intestinal Epithelial
Cells 173

Gluconeogenesis 220

Use of Free Amino Acids and Peptides for Oral
Rehydration Therapy 173
Physiologically Active Dietary Peptides 173
Determining Dietary Protein Digestibility


10.	Digestion and Absorption of Lipids
Patsy M. Brannon, PhD, RD; Patrick Tso, PhD;
and Ronald J. Jandacek, PhD
Luminal Digestion of Lipids 179
Uptake of Lipid Digestion Products by the
Enterocytes 182
Intracellular Metabolism of Absorbed Lipids 185
Factors Affecting Formation and Secretion of
Chylomicrons 189
Portal Transport of Long-Chain Fatty
Acids 189

Regulation of Glycolysis and
Gluconeogenesis 224
Glycogen Metabolism


Pyruvate Dehydrogenase Complex and Citric Acid
Cycle 242
Electron Transport and Oxidative
Phosphorylation 246
ATP Equivalents Produced from the Complete
Oxidation of Glucose 248
Other Pathways of Carbohydrate Metabolism


Dietary Reference Intakes and Typical Intakes
of Carbohydrates 252

13.	Protein Synthesis and Degradation
Tracy G. Anthony, PhD, and
Margaret McNurlan, PhD
Protein Turnover

Hormonal Regulation of Lipid
Absorption 189
Disorders of Intestinal Lipid Absorption

Glycolysis 213


Protein Synthesis 259

Molecular Mechanisms of Protein
Degradation 270

Intestinal Fatty Acids and Mucosal
Injury 190

Role of Hormones and Cytokines in Regulation of
Protein Turnover 277

Satiety Effects of Fat Feeding 190

Responses of Protein Turnover to Nutrient
Supply 279

11.	Dietary Fiber
Joanne L. Slavin, PhD, RD
Definition of Fiber


Chemical and Physical Characterization of Dietary
Fiber 195

Protein Turnover in Growth and Exercise 280
Protein Loss with Disuse, Injury, and Disease 281
Current Challenges in Protein Metabolism



14.	Amino Acid Metabolism
Margaret E. Brosnan, PhD, and
John T. Brosnan, DPhil, DSc

Formation of Ketone Bodies from Acetyl-CoA
in the Liver as a Fuel for Extrahepatic
Tissues 379

Overview of Amino Acid Metabolism 287
Amino Acid Pools and Transport 289

Synthesis of Dispensable Amino Acids 301
Interorgan Amino Acid Metabolism 301
Metabolism of the Dispensable Amino Acids 302
Catabolism of Indispensable Amino Acids 310
Neuroactive Amines, Hormones, and Pigments
Formed from Amino Acids by Specialized Cell
Types 323
Nitrogen Excretion

Phosphatidic Acid and Diacylglycerol as Precursors
of the Common Phospholipids 381
Remodeling of Phospholipids in Situ 386

Amino Acids as Signaling Agents 291
Two Themes in Amino Acid Metabolism


Generation of Signaling Molecules by Regulated
Phospholipases 386
Synthesis of Ether-Linked
Glycerolphospholipids 387

17.	Cholesterol and Lipoproteins: Synthesis,
Transport, and Metabolism
Hei Sook Sul, PhD, and Judith Storch, PhD
Overview of Cholesterol Metabolism


Synthesis of Cholesterol and Isoprenoids 394
Regulation of Cholesterol Synthesis 396

15.	Protein and Amino Acid Requirements
Crystal L. Levesque, PhD, and
Ronald O. Ball, PhD

Intracellular Trafficking of Cholesterol Synthesized
in Cell versus Cholesterol Taken from Plasma in
LDL 398

Classification of Dispensable and Indispensable
Amino Acids 331

Synthesis of Steroid Hormones from
Cholesterol 399

Requirement for Protein (Amino Acids) 332

Synthesis of Bile Acids and Oxysterols from
Cholesterol 400

Requirements for Individual Amino Acids 337
Factors That Affect Amino Acid Requirements 341
Food Proteins and Protein Quality 343
Typical Intakes of Protein and Amino Acids and
Significance of Protein to Energy Ratios 350
Effects of Inadequate Protein Intake and
Assessment of Protein Status 352

Cholesterol Transport During Enterohepatic
Recirculation 400
Lipoproteins and Their Metabolism 401
Postprandial Lipoprotein Metabolism 407
Atherosclerotic Cardiovascular Disease


How Much Protein is Too Much Protein? 352

Chronic Effects of Dietary Lipids on Plasma
Lipoproteins and Lipid Metabolism 412

The Need for Additional Research in Nutritional
Science 354

Recommendations and Typical Intakes for
Dietary Fat 413

16.	Metabolism of Fatty Acids, Acylglycerols,
and Sphingolipids
Hei Sook Sul, PhD
Biological Roles for Lipids 357
Overview of Fatty Acid and Triacylglycerol
Metabolism 358
Synthesis of Palmitate from Acetyl-CoA 358
Transfer of Acetyl-CoA from Inside the
Mitochondria to the Cytosol 358
Synthesis of Fatty Acids Other Than Palmitate 365
Synthesis of Triacylglycerol



Hydrolysis of Triacylglycerol in Lipoproteins, Uptake
of Fatty Acids, and Utilization of Fatty Acids for
Energy or Storage as Triacylglycerol 370
Mobilization of Stored Triacylglycerol 371
Oxidation of Fatty Acids 371
β-Oxidation of Fatty Acids with an Odd Number of
Carbons or with Methyl Side Chains to Generate
Propionyl-CoA 376

18.	Lipid Metabolism: Polyunsaturated Fatty
Sarah K. Orr, BSc; Chuck T. Chen, BSc;
Arthur A. Spector, MD; and
Richard P. Bazinet, PhD
Discovery of Essential Fatty Acids 416
Structure of Polyunsaturated Fatty Acids


Essential Fatty Acid Metabolism 418
Essential Fatty Acid Composition of Plasma and
Tissue Lipids 421
Functions of Polyunsaturated Fatty
Acids 423
Regulation of Gene Expression by Essential Fatty
Acids 428
Recommendations for Essential Fatty Acid
Intake 428
Essential Fatty Acid Deficiency 429
Peroxidation of Polyunsaturated Fatty
Acids 431



19.	Regulation of Fuel Utilization in Response
to Food Intake
Martha H. Stipanuk, PhD
Regulation of Macronutrient Metabolism at the
Whole-Body Level 435
Distributed Control 437
Regulation of Macronutrient Metabolism at the
Cellular Level 437
Integrative Pathways for Regulation of Macronutrient
Metabolism at the Cellular Level 441
The Metabolic Fates of Macronutrients 444
Stages of Glucose Homeostasis during Prolonged
Starvation 454

20.	Regulation of Fuel Utilization in Response
to Physical Activity
Martha H. Stipanuk, PhD
Muscle Structure


Muscle Fiber Types

Biological Control of Energy Intake and Energy
Expenditure 506
Afferent Signals 507
Central Nervous System Integration of Satiety and
Adiposity Signals 511
Efferent Signals 514
Importance of Diet and Exercise in Prevention of
Overweight and Obesity 515

23.	Disturbances of Energy Balance
Darlene E. Berryman, PhD, RD, and
Christopher A. Taylor, PhD, RD, LD
Adipose Tissue in Energy Balance 519




Starvation and Protein-Energy Malnutrition 530


Definitions of PEM 530

The Energy Cost of Movement 464
Skeletal Muscle Fuel Utilization During Rest


Fuel Utilization by Working Muscle 465
Fuels for Short Bursts of Super Intense Physical
Activity 471
Skeletal Muscle Adaptations in Response to
Training and the Consequences for Fuel
Utilization and Performance 473
Nutritional and Ergogenic Aids to Training
and/or Performance 473
Muscle Fuel Utilization and Health
Outcomes 475

The Vitamins
24.	Niacin, Riboflavin, and Thiamin
W. Todd Penberthy, PhD


Niacin History 540
Niacin Nomenclature, Structure, and
Biochemistry 541
Niacin Physiological Function 541

Skeletal Muscle Adaptations in Response to Disuse,
Aging, and Disease and the Consequences for
Fuel Utilization and Well-Being During Normal
Daily Life 476


Proteins That Require Niacin 542
Niacin Sources, Chemical Stability, and
Biochemical Assessment of Niacin Nutriture, Dietary
Requirements, and High-Dose Responses 547
Riboflavin 548


Riboflavin History 548

21.	Cellular and Whole-Animal Energetics
Darlene E. Berryman, PhD, RD, and
Matthew W. Hulver, PhD
Cellular Energetics 481

22.	Control of Energy Balance
Darlene E. Berryman, PhD, RD;
Brenda M. Davy, PhD, RD; and
Edward O. List, PhD

Riboflavin Physiological Function 549
Proteins That Require Riboflavin 551

Biochemical Assessment of Riboflavin Nutriture
and Dietary Requirements 553


Thiamin History 554

Energy Balance 501

Thiamin Nomenclature, Structure, and
Biochemistry 555


Relative Stability of Body Weight

Riboflavin Nomenclature, Structure, and
Biochemistry 548

Riboflavin Sources, Chemical Stability, and

Whole-Animal Energetics 490

Nutrient Balance

Behavioral Aspects of Control of Energy Intake and
Energy Expenditure 504


Thiamin Physiological Function 555

Proteins That Require Thiamin


Thiamin Sources, Chemical Stability, and
Biochemical Assessment of Thiamin Nutriture and
Dietary Requirements 560
Interdependence of B3, B2, and B1 561

25.	Folate, Choline, Vitamin B12, and
Vitamin B6
Marie A. Caudill, PhD, RD;
Joshua W. Miller, PhD;
Jesse F. Gregory III, PhD; and
Barry Shane, PhD

Intracellular Metabolism and Metabolic Functions
of Vitamin B12 591
Vitamin B12 Deficiency: Symptoms and Metabolic
Bases 593
Vitamin B12 Requirements


Vitamin B12 Dietary Intakes 596
Vitamin B12 Toxicity


Vitamin B6 597
Chemistry of Vitamin B6 597
Sources of Vitamin B6 597
Absorption of Vitamin B6 597
Bioavailability of Vitamin B6 597

Folate 565
Chemistry of Folate
Sources of Folate

Metabolism, Turnover, and Transport
of Vitamin B6 598



Metabolic Functions of Vitamin B6 598

Folate Absorption 566
Folate Bioavailability
Transport of Folate

Vitamin B6 Deficiency: Symptoms and Metabolic
Bases 600


Tissue Accumulation of Folate


Folate Turnover 567
Metabolic Functions of Folate


Folate Deficiency: Symptoms, Metabolic Bases, and
Disease 571
Folate Status Assessment 574
Folate Dietary Recommendations 575
Folate Toxicity 576

Vitamin B6 and Disease Risk 601
Detection of Vitamin B6 Deficiency 601
Vitamin B6 Requirements


Vitamin B6 Intake 602
Vitamin B6 Toxicity 603

26.	Biotin and Pantothenic Acid
Donald M. Mock, MD, PhD, and Nell I.
Matthews, BA
Biotin 610

Choline 577

Biotin Synthesis 610

Choline Chemistry 577
Food Sources of Choline 577

Holocarboxylases and Holocarboxylase
Synthetase 610

Choline Absorption

Biotin-Containing Carboxylases 611


Choline Bioavailablity


Biotin and Gene Regulation 614

Transport of Choline 579

Biotin Digestion and Absorption 615

Metabolism of Choline

Biotin Uptake and Transport in Tissues 616


Physiological Functions of Choline 583

Biotin Degradation 617

Choline Deficiency

Biotin Deficiency 617


Choline and Disease 585

Inborn Errors of Biotin Metabolism 618

Choline Homeostasis 586

Dietary Sources and Recommended
Intakes 619

Status Assessment of Choline 587
Dietary Recommendations, Factors Affecting
Dietary Requirements, and Dietary Choline
Intake 587
Choline Toxicity



Vitamin B12 588
Chemistry of Vitamin B12 588

Toxicity 619
Pantothenic Acid 620
Pantothenic Acid Synthesis 620
Dietary Sources and Intake 620
Digestion, Absorption, and Transport 620

Sources of Vitamin B12 589

Metabolism of Pantothenic Acid to CoA and
ACP 620

Absorption and Bioavailability of Vitamin B12 590

Functions of CoA and ACP 621

Plasma Transport, Tissue Uptake, and Turnover of
Vitamin B12 590

CoA and Carnitine 621



30.	Vitamin A
Noa Noy, PhD

Dietary Requirement 622
Pantothenic Acid Deficiency 622
Purported Therapeutic Uses of Pantothenic
Acid 623

Chemistry and Physical Properties of Vitamin A
and Carotenoids 683


Physiological Functions of Vitamin A 684


27.	Vitamin C
Alexander Michels, PhD, and Balz Frei, PhD
Vitamin C Nomenclature, Structure, and Chemical
Properties 626
Food Sources of Vitamin C 628

Enzymatic Functions of Vitamin C 634
Nonenzymatic Functions of Vitamin C 639
Vitamin C and Human Health


Dietary Reference Intakes for Vitamin C 647

28.	Vitamin K
Reidar Wallin, PhD

Nutritional Considerations of Vitamin A 696

Dietary and Endogenous Sources of
Vitamin D 703
Biological Actions of Vitamin D 706
Evaluation of Vitamin D Status 708
Dietary Sources of Vitamin D 709
Solar Contribution to Vitamin D Status 709
Vitamin D Toxicity 710
Dietary Reference Intakes for Vitamin D 710

Nomenclature of Vitamin K Active
Compounds 655
Mechanism of Action of Vitamin K

Vitamin D and Health Outcomes 711

Antagonism of Vitamin K Action by Clinically
Used Inhibitors 659
Warfarin Resistance and the Vitamin K–Dependent
γ-Carboxylation System 660
Sources of Vitamin K

Retinol-Binding Proteins 692

31.	Vitamin D
Steven K. Clinton, MD, PhD

Ascorbate 626
Vitamin C Transport

Absorption, Transport, Storage, and Metabolism of
Vitamin A and Carotenoids 688

Controversy Over Recommendations for
Vitamin D Intake and Status Testing 714

The Minerals and Water


Vitamin K1 Conversion to MK-4 in Extrahepatic
Tissues 663

32.	Calcium and Phosphorus
Sue A. Shapses, PhD

Bioavailability 663

Chemical Properties of Calcium 721

Absorption, Transport, and Metabolism
of Vitamin K 664

Chemical Properties of Phosphate 722

Physiological Roles of Vitamin K–Dependent
Proteins 664
Vitamin K Deficiency 665
Assessment of Vitamin K Status


Recommendations for Vitamin K
Intake 666

29.	Vitamin E
Robert S. Parker, PhD
Nomenclature and Structure of
Vitamin E 670
Absorption, Transport, and Metabolism
of Vitamin E 670
Biological Functions of Vitamin E 675
Deficiency, Health Effects, and Biopotency of
Vitamin E 677
Food Sources and Intake of Vitamin E 679
Recommended Intake of Vitamin E and Assessment
of Vitamin E Status 680

Physiological and Metabolic Functions of Calcium
and Phosphate 722
Hormonal Regulation of Calcium and Phosphate
Metabolism 726
Calcium and Phosphate Homeostasis 731
Dietary Sources, Bioavailability, and
Recommended Intakes for Calcium and
Phosphorus 736
Calcium and Phosphate Deficiency, Excess, and
Assessment of Status 740
Clinical Disorders Involving Altered Calcium and
Phosphate Levels 742

33.	Magnesium
Jürgen Vormann, Dr. rer. nat.
Chemistry of Magnesium 747
Absorption, Bioavailability, and Excretion of
Magnesium 747
Body Magnesium Content 749
Physiological Roles of Magnesium 750



Food Sources, Recommended Intakes, and Dietary
Intakes of Magnesium 751

Selected Functions of Zinc, Copper, and
Manganese 838

Magnesium Depletion 753

Assessment of Zinc, Copper, and Manganese Status
and Deficiency Symptoms 841

Diagnosis of Magnesium Deficiency 755

Dietary Reference Intakes and Food Sources of
Zinc, Copper, and Manganese 842

Magnesium Toxicity 755
Magnesium and Disease Risks 755

Toxicity of Zinc, Copper, and Manganese 845

Conclusion 756

34.	Sodium, Chloride, and Potassium
Hwai-Ping Sheng, PhD
Functions and Distribution of Sodium, Chloride,
and Potassium 759
Sodium, Chloride, and Potassium Balance


Regulation of Sodium, Chloride, and Potassium
Balance 766
Interactions Among Systems in Volume
Regulation 771
Sodium and Chloride Imbalance and Its
Consequences 772
Potassium Imbalance and Its Consequences 773
Nutritional Considerations 774

35.	Body Fluids and Water Balance
Hwai-Ping Sheng, PhD
Physiological Functions of Water 781
Body Water Compartments 781
Water Balance 786
Renal Excretion of Water


Regulation of Water Balance


Water Imbalance and Its Consequences 797

36.	Iron
Robert R. Crichton, PhD, FRSC
Biological Functions of Iron 801

38.	Iodine
Elizabeth N. Pearce, MD, MSc, and Hedley C.
Freake, PhD
Production and Metabolism of Thyroid
Hormones 849
Mechanism of Action of Thyroid Hormones 854
Physiological Functions of Thyroid
Hormones 858
Iodine Deficiency 861
Dietary Recommendations, Dietary Intake, and
Toxicity 864

39.	Selenium
Gerald F. Combs, Jr., PhD
Chemistry of Selenium 867
Utilization of Dietary Selenium 870
The Selenoproteins 874
Tissue Distribution of Selenium 878
Nutritional Essentiality of Selenium 878
Selenium Toxicity 880
Selenium Anticarcinogenesis 881
Human Selenium Requirements 881
Selenium Intakes 884

40.	Fluoride
Gary M. Whitford, PhD, DMD

Proteins of Iron Transport, Storage, and
Recycling 803

Dental Fluorosis and Dental Caries 888

Body Iron Compartments and Daily Iron
Exchange 807

Fluoride Physiology 892

Internal Iron Exchange and Cellular Iron
Metabolism 807

Chronic Fluoride Toxicity 896

External Iron Exchange, Iron Absorption, and
Systemic Iron Homeostasis 814
Dietary Reference Intakes for Iron 818
Iron Deficiency
Iron Excess



37.	Zinc, Copper, and Manganese
Arthur Grider, PhD
Zinc, Copper, and Manganese in Enzyme
Systems 828
Absorption, Transport, Storage, and Excretion of
Zinc, Copper, and Manganese 829

Fluoride Intake 890
Acute Fluoride Toxicity 895

41.	Molybdenum and Beneficial Bioactive
Trace Elements
Forrest H. Nielsen, PhD
Definition of Ultratrace Elements 899
Molybdenum 899


Chromium 904
Silicon 906
Bioactive Ultratrace Elements: Nickel, Vanadium,
and Arsenic 906

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Nutrients: Essential and Nonessential


utrition may be defined simply as the utilization of foods by living organisms
for normal growth, reproduction, and maintenance of health. Nutrients can be
divided into two broad groups: (1) organic and (2) inorganic.
Inorganic nutrients include minerals and water. Those nutrients that can be used
in inorganic form do not need to come from living sources such as plants or animals.
Minerals are present in the earth’s crust and are taken up from soil or water by plants
and microorganisms, thereby making their way into the food chain. In some cases, the
mineral elements are incorporated into organic compounds; for example, selenium and
phosphate are present in food proteins. The amount of some minerals in foods can
vary substantially depending on the concentration of that mineral in the soil or water
in which the food was grown. Humans require more than a dozen different minerals
in their diets. These include calcium and phosphorus that we need to make bones and
teeth, iodine that we need to make thyroid hormone, and iron that we need as part
of certain proteins including the hemoglobin in red blood cells. Much of our mineral
intake comes from the foods we eat, but we also obtain minerals from water sources,
salts, and food additives.
Nutrients in the organic or carbon-containing group make up the bulk of our diets and
provide us with energy as well as many essential organic compounds. Organic nutrients
include proteins, carbohydrates (sugars and starches), fats, and vitamins. These organic
compounds are synthesized by living cells from simpler compounds. Green plants and
photoplankton (such as algae and a special group of photosynthetic bacteria) form the base
of the organic nutrient chain. These chlorophyll-containing forms of life use energy from
sunlight to combine carbon dioxide from the atmosphere and water to make carbohydrates
by a process we call photosynthesis. Therefore plants and photoplankton are able to make
organic compounds (such as sugars and carbohydrates) from inorganic compounds (CO2
and H2O) in the environment. Animals and most microorganisms, however, cannot carry
out photosynthesis and must have preformed organic material in their diets. These species
obtain organic nutrients by eating other organisms. Bacteria generally have simple nutrient
needs. Most bacteria need a simple organic carbon source, usually decaying plant or animal
life. Conversely, animals and humans have complex nutritional needs and require a number of different organic compounds in their diets. We obtain organic nutrients—­protein,
carbohydrates, fats including some essential fatty acids, and 13 essential vitamins—by
­consuming a variety of plant and animal foods.
This first unit contains three chapters. Chapter 1 explores the scientific efforts that
resulted in the identification and definition of essential nutrients. Much of this work took
place during the first half of the twentieth century, with the goals of preventing nutrient
deficiency disease and determining the actual amount of each nutrient that is required to
prevent deficiency symptoms. Much more attention was given during the latter decades
of the twentieth century to the role of nutrition in the maintenance or enhancement of
health and in the reduction of risk of certain chronic diseases, such as heart disease and
cancer. This latter focus is continuing in the twenty-first century as much remains to be


understood about the relationships of nutrition, diet, and health, and about beneficial or
harmful “nonnutrient” components of foods. In Chapter 2, various groups of compounds
that are actively being studied for their health effects and the current state of knowledge
of how these compounds impact health are presented. How we put the knowledge of the
science of nutrition into practice is of only academic interest unless it is applied to improvement of the health and well-being of individuals and populations. Chapter 3 presents various means by which the understanding of biological needs and functions of nutrients is
translated into information that allows consumers to make healthy dietary choices.




Nutrients: History and Definitions
Martha H. Stipanuk, PhD


utrients are defined as chemical substances found in
foods that are necessary for human life and growth,
maintenance, and repair of body tissues. It is now commonly accepted that proteins, fats, carbohydrates, vitamins,
minerals, and water are the major nutritional constituents
of foods.
Before the chemical nature of food was understood, food
was believed to be made up of nutriment, medicines, and
poisons. In ancient Greece (~500-300 bc), differences in the
physical properties of foods and in their content of medicinal and toxic substances were recognized. The role of diet
in the causation and treatment of disease was recognized,
as evidenced by the use of liver to treat night blindness.
However, the physicians of this era had no understanding
of the chemical nature of foods and believed that foods
contained only a single nutritional principle that was called
aliment. In some ways this ancient understanding is still
appropriate in that foods do contain nutrients, substances
beneficial to health, and substances that have adverse
effects on health, although we now know that each of the
three principles in fact includes many different chemical

The belief that foods contained a single nutritional principle persisted for more than two millennia up until the
nineteenth century and impeded progress in understanding nutrition. Some recorded observations made during the
seventeenth and eighteenth centuries hinted at scientific
progress to come. For example, during the 1670s Thomas
Sydenham, a British physician, observed that a tonic of iron
filings in wine produced a clinical response in patients with
chlorosis, a condition now recognized as hypochromic or
iron-deficiency anemia (McCollum, 1957). In 1747 James
Lind of Scotland, while serving as a naval surgeon, conducted a clinical trial of various proposed treatments of
sailors who were ill with scurvy. He observed that consumption of citrus fruits (oranges and lemons), but not other
typical foods and medicines, cured the disease (Carpenter,
1986). Nevertheless, chlorosis and scurvy were not viewed
as nutritional diseases, and the concept that a disease might

be caused by a deficit of a substance that was nutritionally
essential did not exist. Before 1900, toxins, heredity, and
infections, but not yet nutrition, were recognized as causes
of disease.

By the early 1800s the elements carbon, nitrogen, hydrogen,
and oxygen were recognized as the primary components of
food, and the need for the carbon-containing components
of food as a substrate for combustion (heat production)
was recognized (Carpenter, 2003a). Protein was identified
as a specific essential dietary component by the observations of François Magendie in Paris in 1816. Magendie
showed that dogs fed only carbohydrate or fat lost considerable body protein and weight within a few weeks, whereas
dogs fed foods that contained nitrogen (protein) remained
healthy. In 1827 William Prout, a physician and scientist
in ­London, proposed that the nutrition of higher animals
could be explained by their need for proteins, carbohydrates, and fats, and this explanation was widely accepted.
During the next two decades, the need of animals for several
mineral elements was demonstrated, and at least six mineral elements (Ca, P, Na, K, Cl, and Fe) had been established as essential for higher animals by 1850 (Harper, 1999;
­Carpenter et al., 1997).
The nineteenth century German chemist Justus von
Liebig postulated that energy-yielding substances (carbohydrates and fats) and proteins, together with a few minerals,
represented the essentials of a nutritionally adequate diet,
and he proposed that the nutritive value of foods and feeds
could be predicted from knowledge of their gross chemical
composition. Liebig prepared tables of food values based
on this concept—work that was facilitated by the work of
­Wilhelm Henneberg, who devised the Weende system,
known as proximate analysis, for analyzing foods and feeds
for protein, fat, fiber, nitrogen-free extract (carbohydrate),
and ash (McCollum, 1957). Throughout the remainder of
the nineteenth century, nutritional thinking continued to
be dominated by the belief that sources of energy, protein,
and a few minerals were the sole principles of a nutritionally
adequate diet.
Despite the dominance of Liebig’s views during the
mid to late nineteenth century, it should be noted that the


    UNIT I Nutrients: Essential and Nonessential

The Connection between Combustion and Respiration
The Experiments of Antoine Lavoisier



Nearly 300 years before Lavoisier, during the sixteenth
century, the artist and scientist Leonardo da Vinci noted
the part played by air in combustion. The ancients realized
that air was necessary for burning but did not understand
the nature of the combustion process. Leonardo arranged
deliberate experiments on enclosed combustion and
arrived at the correct answer to a problem that continued
to worry experimenters for years afterward. In manuscripts
deposited as the Codex Leicester, Leonardo noted that
“air is consumed by the introduction of the fire.” He also
noted, in the Codice Atlantico, that “where flame cannot
live, no animal that draws breath can live,” clearly correlating the phenomenon of combustion with the one of
animal respiration. Like Leonardo, Robert Fludd and John
Mayow came to their own correct interpretations of the
phenomenon of combustion in the seventeenth century.
However, despite the work of these early insightful scientists, the phlogiston theory dominated the view of combustion from the late seventeenth century through much
of the eighteenth century. The phlogiston theory posited
the existence of the substance called phlogiston in combustible materials; the process of combustion was thought
to involve the release of phlogiston into the air. Because
substances in a sealed container were observed to burn
for only a limited period of time, air was thought to have a
limited capacity to accept phlogiston.
This phlogiston theory of combustion was widely
accepted until it was refuted by Antoine Lavoisier’s experiments showing that respiration was essentially a slow
combustion of organic material using inhaled oxygen and

The world’s first ice-calorimeter, used in the winter of 1782-83
by Antoine Lavoisier and Pierre-Simon Laplace. The guinea pig
was placed in a mesh chamber (M) surrounded by two shells
(A and B) filled with ice. Heat produced by the animal melted the
ice and the water that flowed out of the calorimeter was collected
and weighed.

producing carbon dioxide and water (Wilkinson, 2004).
Lavoisier and mathematician Pierre-Simon Laplace performed experiments in 1780 with guinea pigs in which
they quantified the oxygen consumed and carbon dioxide
produced by metabolism. They also developed an ice-calorimeter apparatus to measure the amount of heat given
off during combustion or respiration (see drawing). They
measured the quantity of carbon dioxide and heat produced by a live guinea pig that was confined in this apparatus and then determined the amount of heat produced
when sufficient carbon was burned in the ice-calorimeter
to produce the same amount of carbon dioxide as had
been exhaled by the guinea pig. They found the same
ratio of heat to carbon dioxide for both processes, leading to the conclusion that animals produced energy by
a type of combustion reaction. Lavoisier further showed
that combustion involved the reaction of the combustible substance with oxygen and that heat or light were
released as weightless by-products. Lavoisier and his colleagues viewed respiration as a very slow combustion phenomenon that is conducted inside the lungs. About 50
years later in 1837, German physiologist Heinrich Gustav
Magnus performed his famous experiments showing that

CHAPTER 1 Nutrients: History and Definitions   


The Connection between Combustion and Respiration
The Experiments of Antoine Lavoisier
both carbon dioxide and oxygen existed in both arterial
and venous blood, with oxygen higher and carbon dioxide
lower in arterial blood compared to venous blood. Magnus correctly concluded that combustion (oxygen uptake;
carbon dioxide, water, and heat production) must occur
throughout the body (not just in the lungs), and other scientists subsequently showed that oxidation occurs in the
tissues, not in the blood plasma.
With Armand Sequin, Lavoisier pushed his studies further to investigate the influence of work, food, and environmental temperature on metabolism. By measuring the
amount of carbon dioxide exhaled, they showed that respiration (oxygen consumption or carbon dioxide production) increased by about 10% in a cold environment, by
50% due solely to food intake, and by 200% with exercise.
They also showed a direct correlation between the heart

validity of his assumptions was challenged during the nineteenth century (McCollum, 1957). In 1843 Jonathan Pereira
in England stated that diets containing a wide variety of
foods were essential for human well-being, whereas diets
containing only a few foods were associated with the acquisition of diseases such as scurvy. Jean Baptist Dumas, based
on his observation that an artificial milk formula that contained all of the known dietary constituents failed to prevent
deterioration of health of children during the siege of Paris
(1870-1871), also questioned the validity of Liebig’s assumptions. In addition, Nikolai Lunin (~1881), who worked in
­Gustav von Bunge’s laboratory in Dorpat, Estonia, conducting studies with mice in an effort to identify inadequacies in
the mineral component of purified diets, demonstrated that
mice fed a diet composed of purified proteins, fats, carbohydrates, and a mineral mixture survived less than 5 weeks,
whereas mice that received milk or egg yolk in addition to
the purified components remained healthy throughout the
experiment. Lunin concluded that milk must contain small
quantities of other unknown substances essential to life, but
von Bunge apparently did not encourage him or subsequent
students in his laboratory who made similar observations
to investigate what the active factor in milk might be. The
Liebig–von Bunge view that nutritional requirements consisted only of protein, energy-yielding substances, and a few
minerals still had such hold on scientific thought that, rather
than consider that these observations might point to the
presence of other essential nutrients in foods, the inadequacies of the purified diets were attributed to mineral imbalances, failure to supply minerals as organic complexes, or
lack of palatability (Wolf and Carpenter, 1997).
Also of significance were the studies of beriberi that were
conducted during the nineteenth century. Kanehiro Takaki
was concerned during the 1880s with the devastating effects
of beriberi on sailors in the Japanese navy. Because of the
superior health of British sailors, he compared the food

rate (pulse) and the amount of work performed (sum of
weights lifted to a predetermined height) and between
the heart rate and the quantity of oxygen consumed.
These studies, along with some knowledge of the chemical
composition of plant and animal foods, allowed Lavoisier
to make the fundamental conclusion that the oxidation of
carbon compounds was the source of energy for activity
and other bodily functions of animals.
Although Lavoisier’s experiments were cut short by the
French Revolution and his execution by the French revolutionists during the Reign of Terror (because of Lavoisier’s
service as a tax collector), Lavoisier’s seminal contributions
to modern chemistry, metabolism, nutrition, and exercise
physiology were enormous. He is often called the “Father
of Modern Chemistry.”

supplies of the two navies and was struck by the higher protein content of the British rations. He, therefore, included
evaporated milk and meat in the diet and substituted barley
for part of the polished rice in the Japanese rations. These
changes eradicated beriberi. He attributed this to the additional protein. In retrospect, we know that this was incorrect (i.e., beriberi is caused by thiamin deficiency), but his
conclusion does imply that he correctly considered beriberi
to be a disease caused by a nutritional inadequacy (Takaki,
1906). Christiaan Eijkman, an army physician in the Dutch
East Indies, began his investigations of beriberi in the 1890s
(Jansen, 1956). He had observed a high incidence of beriberi in the prisons in Java in which polished rice was a
staple. He assumed it was caused by chronic consumption
of a diet consisting largely of polished rice. He noted during his experimental studies that chickens fed on a military
hospital diet composed mainly of polished rice developed a
neurological disease resembling beriberi, whereas birds fed
rice with the pericarp intact remained healthy. He concluded
that ingestion of the high starch diet resulted in formation in
the intestine of a substance that acted as a nerve poison and
that rice hulls contained an antidote. Eijkman’s conclusion
illustrates the fact that a connection between nutrient deficiency and disease was still a foreign concept at the end of the
nineteenth century.

Resistance to the notion of nutritional deficiency diseases
continued into the early twentieth century. With the accumulating number of diet-associated diseases, however, the
concept that a disease might be caused by a deficit of an essential nutrient slowly gained acceptance (Carpenter, 2003b).
In 1901 Gerrit Grijns, who took over Eijkman’s research
in the Dutch East Indies in 1896, showed through feeding trials that Eijkman’s active substance was present in other foods


    UNIT I Nutrients: Essential and Nonessential

(Jansen, 1956; Carpenter, 1995). After demonstrating that
beriberi could be prevented by including rice polishings, beans,
or water extracts of these foods in the diet, he proposed that
beriberi was a dietary deficiency disease caused by the absence
of an essential nutrient present in rice hulls. Grijns thus interpreted Eijkman’s results correctly and provided for the first
time a clear concept of a dietary deficiency disease. The broad
implications of Grijns’ interpretation of his investigation of
beriberi were not appreciated for some years, however.
In 1907 Alex Holst and Theodore Fröhlich in Norway
reported that guinea pigs fed dry diets with no fresh vegetables developed a disease resembling scurvy; supplying
them with fresh vegetables cured the disease—giving rise to
a second example of a dietary deficiency disease (Carpenter,
1986). Interestingly, Holst and Fröhlich had been looking for
a mammal to test a diet that had earlier produced beriberi
in pigeons; they were surprised that scurvy resulted instead
because, up until that time, scurvy had not been considered
to occur in any species other than humans. This was a fortuitous occurrence because the guinea pig allowed assessment
of the antiscorbutic value of different foodstuffs, leading to
the isolation and identification of vitamin C.
In 1914 Joseph Goldberger was appointed by the Surgeon
General of the United States to study the disease pellagra,
which was prevalent in the southern United States. At the
time, pellagra was thought to be an infectious disease, but
Goldberger correctly theorized that the disease was caused
by malnutrition (Carpenter, 2003c). He observed that those
who treated the sick never developed the disease and noticed
that people with restricted diets (mainly corn bread, molasses, and a little pork fat) were more likely to develop pella­
gra. Goldberger, however, had difficulty convincing others of
this theory. Eventually, Goldberger’s group found that dogs
developed a condition called “blacktongue” when fed mixtures with mostly cornmeal and no meat or milk ­powder,
allowing dogs to be used to “assay”’ fractions from various
foods for anti-blacktongue potency. The dogs responded
rapidly to yeast, and yeast was also found to cure pellagra
in humans. After Goldberger’s death, Conrad Elvehjem at
the University of Wisconsin went on to show in 1937 that
nicotinic acid, which had been discovered to be a bacterial
growth factor, was extremely potent in curing blacktongue
and also prevented and healed pellagra.
The iodination of salt in the 1920s, the fortification of
milk with vitamin D in the 1930s (even before vitamin D had
been purified and synthesized), and the addition of niacin,
thiamin, and iron to cereal flours and products in the 1930s
were successful efforts to reduce the incidence of goiter, rickets, and pellagra (Bishai and Nalubola, 2002), respectively.
The concept of nutritional deficiency disease was firmly

The first evidence of essentiality of a specific small organic
molecule was the discovery by Edith Willcock and Fredrick
G. Hopkins (1906) that a supplement of the amino acid

tryptophan, which had been discovered in 1900, prolonged
survival of mice fed a zein-based diet. Zein is the major storage protein in corn endosperm and it contains only a small
proportion of tryptophan. It was also recognized at this time
that enzyme hydrolysates of protein supported adequate
growth rates, whereas acid hydrolysates of protein failed to
support growth (Carpenter, 2003b). This difference was also
attributed to a deficiency of tryptophan due to the destruction of tryptophan by acid digestion (Henriques and Hansen, 1905). But the growth rate of rats fed on semipurified
diets was not satisfactory, so further work on amino acid
requirements was delayed until this problem was solved.

The validity of Liebig’s hypothesis—that the nutritive value
of foods and feeds could be predicted from measurements
of their gross composition—was directly tested at the University of Wisconsin from 1907 to 1911 in what has become
known as the Wisconsin single-grain experiment (Carpenter
et al., 1997; Hart et al., 1911). This study was suggested to E.
B. Hart by his predecessor at the University of ­Wisconsin,
Stephen M. Babcock, who had observed that milk production by cows consuming rations composed of different
feedstuffs differed considerably, even when the rations were
formulated to have the same gross composition and energy
content. Hart and colleagues compared the performance of
four groups of heifers fed rations composed entirely of corn
(cornmeal, corn gluten, and corn stover), wheat (ground
wheat, wheat gluten, and wheat straw), or oats (oat meal
and oat straw), all formulated to be closely similar in gross
composition and energy content; or a mixed ration consisting of equal parts of the three plants. Six-month-old heifers
were fed the assigned rations to maturity and through two
reproductive periods. Differences between performance of
the corn and wheat groups were marked, with other groups
being intermediate. Calves born to cows consuming the corn
ration were strong and vigorous and all lived, but cows consuming the wheat ration all delivered 3 to 4 weeks prematurely and none of the calves lived beyond 12 days. Cows
fed the corn ration produced almost double the amount of
milk produced by those fed the wheat ration. Thus Hart and
colleagues demonstrated that the nutritive value of a ration
could not be predicted solely from measurements of its content of protein, energy, and a few minerals. In hindsight, the
signs of inadequacy in the wheat and oat groups resembled
those of vitamin A deficiency, which was probably prevented
by the carotene in the ration that contained corn.

Although investigators were beginning to conduct nutritional studies with rodents fed purified diets in the early
1900s, it was difficult to maintain growth in rats using diets
composed of starch, lard, isolated protein, and mineral
mixes, even with casein as the protein source. This problem was overcome by addition of a protein-free extract of

CHAPTER 1 Nutrients: History and Definitions   

milk to these diets (­Willcock and Hopkins, 1906; Block and
Mitchell, 1946). In 1912 Hopkins suggested that an organic
complex that animals cannot synthesize was absent from
the purified diets. Also in 1912, Casimir Funk, a young Polish chemist who had been trying to purify the antiberiberi
principle from rice polishings, expressed the opinion that
beriberi, as well as scurvy and pellagra, were dietary deficiency diseases (­Rosenfeld, 1997). Funk believed these diseases were caused by a dietary lack of “special substances
which are in the nature of organic bases, which we will call
vitamines” (from the Latin vita, meaning “life,” and amine,
because he thought all of these compounds contained an
amine functional group). Soon after these ideas were proposed, the concept that foods contained small quantities of
organic substances that were essential nutrients was generally accepted. The name vitamine soon became synonymous
with Hopkins’ “accessory factor.” By the time it was shown
that not all vitamines were amines, the word was already
ubiquitous. In 1920 Jack Cecil Drummond proposed
that the final “e” be dropped to deemphasize the “amine”
Between 1909 and 1913 Elmer V. McCollum and Margaret Davis noted that growth of rats was satisfactory if
the fat was supplied as butterfat, but not if butterfat was
replaced by lard or olive oil. Meanwhile, Thomas Osborne
and Lafayette Mendel in Connecticut observed that if they
further purified the protein-free milk included in their
diets by a process that included removal of ether-soluble
compounds, growth failure of rats again occurred; if they
substituted butterfat for the lard in this diet, growth was
restored (Osborne and Mendel, 1911, 1914). Both groups
concluded that butterfat contained an unidentified substance essential for growth. McCollum and Davis proceeded
to extract an active substance from butterfat and transferred
it to olive oil, which then promoted growth. They called this
substance fat-soluble A. When they further tested this substance in a polished rice diet of the type used by ­Eijkman
and Grijns in their studies of beriberi, they found that even
though the diet contained the fat-soluble A, it still failed to
support growth. An aqueous extract of either wheat germ
or boiled eggs provided the missing factor needed to cure
beriberi; this factor was designated water-soluble B. The
then-unknown substance preventing scurvy was named
water-soluble C. Following Drummond’s recommendations
in 1920, these substances were subsequently referred to as
vitamins A, B, and C.
The work of McCollum and colleagues in Wisconsin and
of Osborne and Mendel in Connecticut in developing rodent
models and the use of long-term growth of rats as a measure
of nutritional adequacy opened up a new approach to the
search for essential amino acids as well as vitamins. Using
semipurified diets supplemented with a protein-free milk
extract, Osborne and Mendel (~1915) demonstrated that
proteins from different sources differed in nutritive value;
and they discovered that lysine, sulfur-containing amino
acids, and histidine were required by rats for growth (Block
and Mitchell, 1946).



The emergence of the use of the animal growth model and
semipurified diets was extremely important to the identification of essential nutrients. By 1915 six minerals (Ca, P, Na,
K, Cl, and Fe), four amino acids (tryptophan, lysine, sulfurcontaining amino acids, and histidine), and three vitamins
(A, B, and C) had been identified as essential nutrients. By
1918 the concept of the presence of “accessory factors or
vitamins” or “minor constituents of foods” that are ­essential
for health was established. Also, the importance of consuming a wide variety of foods to ensure that diets provided adequate quantities of these substances was being emphasized
in health programs for the public in the United States and
Great Britain and by the League of Nations; this was followed
by a decline in the incidence of dietary deficiency diseases
during the next three decades. Acceptance of the new paradigm was followed by a period of unparalleled discovery in
nutritional science from about 1915 to the 1950s (­Carpenter,
In 1919 Sir Edward Mellanby incorrectly identified
rickets as a vitamin A deficiency based on the ability of
cod liver oil to cure rickets in dogs. In 1922 McCollum
destroyed the vitamin A in cod liver oil but found that it
still cured rickets, indicating that fat-soluble A was really
two substances. The factor capable of curing xerophthalmia was then named vitamin A, and the substance that
prevented rickets was named vitamin D. Also in 1922 Herbert McLean Evans and ­Katharine Scott Bishop discovered
vitamin E as a factor essential for rat pregnancy; this new
vitamin was called “food factor X” until 1925. In 1929
Henrik Dam found that a factor present in green leaves and
in liver, vitamin K, was necessary for blood ­clotting. Vitamin B was found to have components in addition to the
heat-labile thiamin (vitamin B1). In 1933 Richard Kuhn,
Paul György, and Theodor Wagner-Jauregg found that
thiamin-free extracts of yeast, liver, or rice bran prevented
the growth failure of rats fed a thiamin-supplemented diet,
and this vitamin B2 was found to be a fluorescent substance
subsequently called riboflavin. The remaining components
of the vitamin B complex were discovered between 1920
and 1941.
The essentiality of the long-chain polyunsaturated fatty
acids (linoleic and α-linolenic acids) was shown by George
and Mildred Burr in 1929 (Burr and Burr, 1929, 1930;
­Holman, 1988) at the University of Minnesota Medical
School. To show the essentiality of fatty acids, they prepared
diets that were completely fat-free by using sucrose instead
of cornstarch (which contained 0.7% lipid ­unextractable
with ether); they supplied vitamins A and D by adding the
nonsaponifiable fraction of cod liver oil to the diet.
The animal growth model also facilitated the further
­identification of the essential components provided by
dietary protein. William C. Rose and colleagues at the University of Illinois purified 13 of the known amino acids and
synthesized 6 others. They then tested the ability of a mixture
of these 19 amino acids to substitute for dietary protein. Rats


    UNIT I Nutrients: Essential and Nonessential

lost weight when fed diets containing these 19 amino acids,
suggesting a missing essential component of protein (Rose,
1931). They then went on to identify the yet undiscovered
amino acid, threonine, and to show that a mixture of all 20
amino acids could substitute for dietary protein (McCoy
et al., 1935). With the identification of all of the amino acid
components of protein, Rose and colleagues later identified
which of these amino acids were indispensable in the diet of
With the discovery of the presence of minute organic factors (vitamins) essential to the diet came also the recognition
and research into minute amounts of certain minerals that
are essential in the diet (Mertz, 1981). Discovery of the role
of trace minerals in the diet was facilitated by the development of analytical procedures using emission spectroscopy
in 1929. The importance of iodine, copper, manganese, and
magnesium in animal nutrition had been established by
1940 (Carpenter, 2003d). The essentiality of zinc was firmly
established during the 1950s and 1960s, and the roles of
selenium and molybdenum as essential elements were first
recognized and explored during the same decades. Recognition of the essentiality of some of the ultratrace elements has
been facilitated by the discovery of unique roles of these elements in normal metabolism (e.g., selenium for formation
of selenocysteine moieties of proteins, iodine for formation
of thyroid hormones, and molybdenum for enzyme cofactor formation). Clear essentiality of some other elements
present in minute amounts in the diet (e.g., chromium and
boron) have been much more difficult to demonstrate and

will likely remain so unless they also are shown to be critical components of normal physiological compounds in the
Thus, by 1960, most of the essential nutrients had been identified and characterized and their functions explored. These
essential nutrients included essential polyunsaturated fatty
acids, 9 amino acids, 12 vitamins, and 11 minerals (Box 1-1).
In the late 1950s, after rats had been maintained successfully
through four generations fed diets composed of constituents with known chemical structures (Schultze, 1957), it was
generally accepted that all (or, at least, most) of the essential
nutrients for rats had been discovered. Later, when human
subjects were maintained for long periods on intravenous
fluids containing only highly purified constituents, it was
accepted that the conclusion also applied to humans. Nevertheless, an avid search for additional essential nutrients continued for some years. Over the course of studies to identify
nutrients, specific criteria were established for declaring a
food constituent to be an essential nutrient. Alfred E. Harper
(1999) summarized the following criteria of essentiality that
had evolved by about 1950:
•	The substance is required in the diet for growth, health,
and survival.
•	The absence of the substance from the diet or inadequate
intake results in characteristic signs of a deficiency disease
and, ultimately, death.

BOX 1-1	  List of Essential Nutrients for Humans
Other amino acids to supply sufficient amino
Linoleic (n-6)
α-Linolenic (n-3)
Ascorbic acid
Vitamin A
Vitamin D
Vitamin E

Vitamin K
Vitamin B6
Pantothenic acid
Vitamin B12
Chromium (probably)
Boron (probably)

CHAPTER 1 Nutrients: History and Definitions   

•	Growth failure and characteristic signs of deficiency are
prevented only by the nutrient or a specific precursor of
it, not by other substances.
•	Below some critical level of intake of the nutrient, growth
response and severity of signs of deficiency are proportional to the amount consumed.
•	The substance is not synthesized in the body and is ­therefore
required for some critical function throughout life.
Harper also emphasized that nutritional essentiality is
characteristic of the species, not the nutrient. For example,
ascorbic acid is required by humans and guinea pigs but not
by most other species that can synthesize the nutrient from
During the 1960s and 1970s, the concept of essentiality
was modified for the mineral elements that could not be
fed at dietary concentrations sufficiently low to interfere
with growth, development, maturation, or reproduction—
some of the ultratrace elements. The most commonly used

criterion was that a dietary deficiency must consistently
and adversely change a biological function from optimal,
and this change must be preventable or reversible by physiological amounts of the element (Nielsen, 2000). However,
this latter basis for establishing essentiality of minerals ultimately was not very satisfactory for the ultratrace elements,
because it was impossible to determine whether some of the
changes were really the result of low intakes causing suboptimal functions or whether the mineral supplements had
pharmacological actions in the body. Today, most scientists
do not consider an element essential unless it has a defined
biochemical function. Nevertheless, there is no universally
accepted list of ultratrace elements that are considered
Forest Nielsen suggests that a nutritionally beneficial
element be defined as “one with health restorative effects
in response to an apparent deficient intake of that element, at intakes that are found with normal diets; these

The History of American Food Composition Tables

The U.S. Department of Agriculture (USDA) has been
compiling food composition data for well over a century.
The food composition data it maintains is widely used by
nutritionists, researchers, and individuals. Tabulation of
food composition data began with the work of Wilbur
Olin Atwater scarcely 50 years after the classical studies
of Justus von Liebig in Germany. Atwater received his PhD
from Yale in 1869 and then studied in Germany, where
he became familiar with the works of Carl von Voit, Max
Rubner, and Nathan Zuntz.


In 1896 Atwater and A. P. Bryant published the proximate composition of 2,600 American foodstuffs in a bulletin
called The Chemical Composition of American Food Materials.
Within 4 years, an additional 4,000 new foods had been
analyzed and a revised edition of the bulletin was published;
about a quarter of these new analyses were performed by
Atwater and his associates in the chemical laboratory at
Wesleyan College (Middletown, CT). A 1906 reprinting of
the bulletin stood until 1940 when the USDA Circular No.
549, Proximate Composition of American Food Materials, was
published. In addition to determining the proximate composition of foodstuffs (protein, fat, carbohydrate, and ash),
Atwater and his associates devised a method for calculating
the physiological energy value of foodstuffs. By correcting
the heat of combustion of food components (i.e., the heat
released by the complete combustion of the food in a calorimeter) by factors for incomplete digestion and incomplete
oxidation of the food in the body, they calculated the physiological fuel values of protein, fat, and carbohydrate isolated from various foods. They then applied these factors to
the proximate composition of individual foods to calculate
their available energy, or caloric, values. The caloric values
in current food composition tables and on food product
labels are still calculated this way today.
The first extensive revision of Atwater’s work was
in 1950 with the publication of the USDA Agriculture
Handbook No. 8, Composition of Foods—Raw, Processed,
Prepared, which contained values for 11 nutrients. Agriculture Handbook No. 8 was subsequently revised in
1963 and then expanded into a series of publications
from 1976 to 1992. The USDA Nutrient Database for Standard Reference is the current form of the food composition tables. It has been maintained electronically since
1980, with frequent updates, and can be downloaded
from the USDA’s Nutrient Data Laboratory Home Page:


    UNIT I Nutrients: Essential and Nonessential

health restorative effects can be amplified or inhibited by
nutritional, physiologic, hormonal, or metabolic stressors”
(Nielsen, 2000, p. 116). Nielsen (2000) gives the following
examples of nutritionally beneficial elements:
•	Boron, the effects of which can be amplified by a marginal
vitamin D deficiency,
•	Vanadium, the effects of which can be amplified by deficient or luxuriant dietary iodine, and
•	Nickel, the beneficial effects of which are inhibited by
vitamin B12, pyridoxine, or folic acid deficiency.
Nielsen (2000, pp. 116-117) suggested use of the following four categories of evidence to support the contention
that a trace element is nutritionally essential:
1.	A dietary deprivation in some animal models consistently
results in a changed biological function, body structure,
or tissue composition that is preventable or reversible by
an intake of an apparent physiological amount of the element in question.
2.	The element fills the need at physiological concentrations for a known in vivo biochemical action to proceed
in vitro.
3.	The element is a component of known biologically
important molecules in some life form.
4.	The element has an essential function in lower forms of
Using Nielsen’s criteria, there is strong circumstantial
evidence for the essentiality of arsenic, boron, chromium,
nickel, silicon, and vanadium, and limited circumstantial
evidence for essentiality of aluminum, bromine, cadmium,
fluorine, germanium, lead, lithium, rubidium, and tin. The
strongest evidence for essentiality exists for boron and chromium, and these two elements likely belong in the category
of established essential nutrients for higher animals including humans.
With the successive discoveries of essential nutrients between
1915 and 1950 and the virtual disappearance of dietary deficiency diseases in developed countries, emphasis in nutrition changed to ensuring that diets would provide adequate
quantities of all essential nutrients to prevent impairment of
growth and development. In 1940 the Food and Nutrition
Board of the National Research Council was organized in
the United States with the function of advising on problems
of nutrition in connection with national defense. This committee recognized the need for standards or allowances for
intake of nutrients needed for maintenance of good health.
The Food and Nutrition Board formulated the first set of
Recommended Dietary Allowances (RDAs) for Americans
in 1941. This committee has subsequently published nine
revisions of the RDAs up through the 10th edition in 1989
and now has established the more extensive Dietary Reference Intakes.
During the first half of the twentieth century, relatively
little attention was given to total food intake and its effects

on health. An exception during this time was the work of
Clive McCay at Cornell in the 1930s (McCay et al., 1939).
McCay argued that short-term trials with an emphasis on
rapid growth did not provide an adequate test of the most
desirable nutritional state throughout life. His studies
showed that rats fed restricted amounts of a nutritionally
adequate diet grew slower and survived longer than those
allowed to eat freely. Concern about total food intake and
health, however, increased during the second half of the
twentieth century, as evidenced by the introduction of
dietary guidelines for Americans in 1977 and by the growing
concerns about obesity, metabolic syndrome, and chronic
disease. Various editions of dietary guidelines for Americans
have addressed concerns about excessive intakes of fat, saturated fat, cholesterol, salt and sodium, sugar, alcohol, and
total energy.
As knowledge of nutritional needs grew, it became clear
that there were conditions under which individuals
required the presence of dispensable (nonessential) nutrients in the diet. During the 1970s, young children and certain groups of patients were found not to synthesize some
of the nutritionally dispensable amino acids in amounts
sufficient to meet their needs. These normally “nonessential” amino acids, therefore, had to be provided in the diet.
These discoveries expanded the concept of “nutritional

Daniel Rudman and associates proposed the term conditionally essential for nutrients not ordinarily required in the diet
but which must be supplied exogenously to specific populations that do not synthesize them in adequate amounts. The
term was initially applied to dispensable nutrients needed by
seriously ill patients maintained on total parenteral nutrition, but the term has been expanded to apply to similar
needs that result from developmental immaturity, pathological states, or genetic defects. Rudman and A. G. Feller
(1986) proposed the following three criteria that must be
met to establish unequivocally that a nutrient is conditionally essential:
1.	Decline in the plasma level of the nutrient into the subnormal range
2.	Appearance of chemical, structural, or functional abnormalities
3.	Correction of both of these by a dietary supplement of
the nutrient
Harper (1999) stressed that conditional essentiality represents a qualitative change in requirements, that is, the
need for a nutrient that is ordinarily dispensable. He further
stressed that this term should not be used for alterations in
the need for an essential nutrient, for health benefits from
consumption of nonnutrients, or for health benefits from

CHAPTER 1 Nutrients: History and Definitions   

consumption of dispensable nutrients or essential nutrients
in excess of amounts needed for normal physiological function. Examples of conditionally essential nutrients include
the requirement of premature infants for cysteine and tyrosine, which cannot yet be synthesized in adequate amounts
from their precursor amino acids; a possible requirement
of long-chain n-3 fatty acids in preterm infants, because
preterm infants are not able to synthesize these from
α-linolenic acid at a rate that meets the infant’s need; a
requirement of some patients with cirrhosis of the liver for
cysteine, tyrosine, and taurine, owing to decreased hepatic
capacity for synthesis of these amino acids from their precursors; and requirements for carnitine or tetrahydrobiopterin by individuals with genetic defects preventing their
synthesis. Although choline can be synthesized in the body,
a dietary source is required to prevent choline inadequacy
in men, postmenopausal women, and populations with an
increased demand (i.e., pregnant and lactating women and
individuals with certain genetic variants affecting choline

Requirements for essential nutrients may be influenced
by the presence in the diet of substances that are precursors or metabolic products of the nutrient or substances
that interfere with the absorption or use of the nutrient
imbalances and disproportions of other related nutrients;
malabsorptive conditions; some genetic defects; and use of
drugs that impair use of nutrients. These conditions do not
alter basic requirements but rather increase or decrease the
amounts that must be consumed to meet requirements. For
example, tryptophan serves as a precursor in niacin synthesis; vitamin A is derived from β-carotene; phytic acid
impairs absorption of zinc and other cations; thiomolybdate forms complexes with copper and prevents its absorption; anticonvulsant medications interfere with folate use;
atrophic gastritis decreases absorption of vitamin B12; and
genetic defects in the enzyme responsible for reuse of biotin increase the dietary need for this vitamin. Many more
examples will be discussed throughout the other chapters
of this book.
In recent years diet–disease relationships have become
major areas of investigation in nutrition, and a new paradigm is emerging. Previously, the concept of deficiency
was the primary factor in determining nutritional requirements, but new research suggests that total health effects of
a nutrient should also be considered (Mertz, 1993). Individual food constituents that may confer health benefits
different from those of physiologically required quantities of essential nutrients, whether they are nonnutrients,
dispensable nutrients, or essential nutrients in quantities


exceeding those obtainable from diet, are appropriately
included in guidelines for health. This new paradigm
includes the determination of upper safe levels of intake
for nutrients as well as nonnutrients that may have harmful
effects on health.
This leads us to a new class of substances to consider in
terms of nutrition: nonnutritional components of foods
that are beneficial to health. The contribution of both fluoride and fiber to health has resulted in their inclusion in
the list of nutrients for which the Institute of Medicine has
now established Dietary Reference Intakes. Fluoride is prophylactic in low doses, protecting teeth against the action
of bacteria, but whether fluoride is essential for tooth and
bone development is controversial. Fiber, in moderate
amounts, is recognized to be beneficial for gastrointestinal function, and some forms of fiber may be fermented
into products that can be absorbed and oxidized to yield
energy. But there is no basis for classifying fiber as an essential nutrient. Numerous food constituents, including certain fatty acids, fiber, carotenoids, and various nonnutrient
substances in plants, have been associated with lower incidences of chronic or degenerative diseases such as heart disease and cancer.
Health benefits of essential nutrients have also been
given greater weight in making nutritional recommendations. Higher intakes of some essential nutrients
(especially vitamins E and C, which may function as
antioxidants) have also been shown to be associated with
lower risk of chronic disease or with enhanced immune
system function. Recommendations for folic acid intake
for women of childbearing age have taken into account
the ability of folic acid to reduce the incidence of neural
tube defects.
Obviously, any health benefits of nonnutritive food constituents or higher intakes of essential nutrients may depend
upon genetic differences among individuals, differences in
lifestyle, and diet–genetic interactions that influence expression of genetic traits. With increasing knowledge of differences in genetic makeup of persons and population groups,
more attention will likely be given to making nutritional recommendations relative to genetically determined metabolic
Some nutrients or food components, in large doses, may
function as drugs. The use of nutrients as pharmacological agents should not be considered under the category of
nutrients. Nicotinic acid in large doses (up to 9 g daily) is
used to lower serum cholesterol. Tryptophan has been used
to induce sleep. The continuous intravenous infusion of
magnesium is used in the treatment of preeclampsia and
myocardial infarction. Many herbal and natural remedies
are based on the use of food components as pharmacological agents.


    UNIT I Nutrients: Essential and Nonessential

Concepts of nutrition have clearly changed over the course
of history. In the search for essential and beneficial dietary
components, it has been necessary to establish definitions
and criteria, and these will likely continue to be modified
as our understanding and aims related to nutrition and
health undergo change.
1.	Would use of growth of young mammals or prevention
of deficiency diseases as the criterion for establishing
requirements or recommended intake levels of essential nutrients necessarily provide a measure of optimal
intake? What other types of criteria related to normal
physiological processes might be used?
2.	What would be the implications of defining all food components that have beneficial effects on health or disease
prevention as essential nutrients? What effect would this
have on the list of nutrients shown in Box 1-1? Which
nutrients for which we currently have ­recommended

intakes fall into the category of beneficial but not essential food components?
3.	What is the definition of a conditionally essential nutrient? How would the process of establishing requirements for conditionally essential nutrients differ from
the approaches used thus far in establishing nutrient
requirements of healthy populations?
4.	We are in the early stages of understanding how
genetic diversity affects nutritional requirements of
the population. For example, it is known that individuals who are homozygous for specific mutations in
the gene encoding methyltetrahydrofolate reductase
have higher requirements for dietary folate. How do
you think the issue of individual variability should be
addressed in setting recommended dietary intakes for
the population in the future?

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CHAPTER 1 Nutrients: History and Definitions   
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127, 1255–1259.


Food Components with Health Benefits

Elizabeth H. Jeffery, PhD; Kelly A. Tappenden, RD, PhD; and Anna-Sigrid Keck, PhD, CIP


α-linolenic acid
conjugated linoleic acid
cardiovascular disease
docosahexaenoic acid
eicosapentaenoic acid


ne of the most rapidly moving, exciting areas in nutrition research today is the study of foods and food
components that decrease risk for chronic diseases, including cardiovascular disease (CVD), chronic inflammatory
diseases, and cancer. Food components for which there is
emerging or strong scientific evidence suggesting health benefits beyond basic nutrition are discussed in this chapter. In
general, these food components are not essential for growth
and development as are the essential nutrients, but it should
be noted that some essential nutrients can also have beneficial effects on chronic diseases, albeit often at exposure levels
greater than what is provided in normal diets. Discovery of
bioactive food components that provide health benefits may