SELENIUM Its Molecular Biology and Role in Human

Health

The Cover shows the genetic code emphasizing how selenium has altered our understanding of the code by its insertion into protein as the amino acid, selenocysteine (Sec), that is dictated by UGA. The background shows the increased histopathology of lung tissue five days post influenza infection of a selenium-deficient mouse (see page 242).

SELENIUM Its Molecular Biology and Role in Human

Health

edited by

Dolph L. Hatfield National Cancer Institute, U.S.A.

SPRINGER SCIENCE+BUSINESS MEDIA, L L C

Library of Congress Cataloging-in-Publication

Selenium : its molecular biology and role in human health / edited by Dolph L . Hatfield, p. cm. Includes bibliographical references and index. ISBN 978-1-4613-5639-4 ISBN 978-1-4615-1609-5 (eBook) DOI 10.1007/978-1-4615-1609-5 1. Selenium—Health aspects. 2. Selenium—Physiological effect. 3. Selenium in

human nutrition. I. Hatfield, Dolph L.

QP535.S5 S445 2001 621' .01524-dc21 2001020364

Copyright ° 2001 by Springer Science+Business Media New York. Second Printing 2003. Originally published by Kluwer Academic Publishers in 2001

This printing is a digital duplication of the original edition.

Al l rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photo-copying, recording, or otherwise, without the prior written permission of the publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work.

Printed on acid-free paper

DEDICATION

to my wife, Mary Wilson Hatfield

to my grandchildren, Amber Nicole Hatfield, Logan Alexa

Hatfield and Tristan Lee Clubb.

TABLE OF CONTENTS

List of Contributors .................................................................... xi

Foreword .•....•....................................................................... xv Raymond F. Burk

Preface .......•.•.................••...•.....•................... I.' ••••••••••••••••••• xvii Dolph L. Hatfield

Acknowledgements ...•. II •••••••••••••••••••••••••••••••••••••••••••••••••••••••••• xix

Chapter 1 Introduction .•................................................. 1 ••••••••••••••••••••••••• 1 Dolph L. Hatfield

Part I. Biosynthesis of selenocysteine and its incorporation into protein

Chapter 2 Selenium metabolism in bacteria ................................................. 7 August BiXk

Chapter 3 Mammalian selenocysteine tRNA ......................•........................ 23 Bradley A. Carlson, F. Javier Martin-Romero, Easwari Kumaraswamy, Mohamed E. Moustafa, Huijun Zhi, Dolph L. Hatfield and Byeong Jae Lee

Chapter 4 Selenophosphate - selenium donor for protein and

tRNA •.••..•.•••.•.......••...•...............................•...............••........ 33 Gerard M Lacourciere

Chapter 5 SECIS elements ......•.•....•....•.........•.....•................••...•.•............ 45 Glover W. Martin, III and Marla J. Berry

viii Selenium: Its molecular biology and role in human health

Chapter 6 SECIS binding proteins ........................................................... 55 Paul R Copeland and Donna M Driscoll

Chapter 7 Towards a mechanism for selenocysteine incorporation in

eukal'Y'otes •••.•••.•••..••••••.••.••••••••••.•.•••••••..•.••.••.•••••.••••.•........... 69 John B. Mansell and Marla J. Berry

Chapter 8 Regulation ofselenoprotein expression ........................................ 81 Roger A. Sunde

Part II. Selenium-containing proteins

Chapter 9 Identity, evolution and function ofselenoproteins and

selenoprotein genes ................................................................. 99 Vadim N Gladyshev

Chapter 10 Bacterial selenoenzymes and mechanisms of action ••••••.•.•••..•...••...• 115 Thressa C. Stadtman

Chapter 11 Selenoprotein P ..................................................................... 123 Kristina E. Hill and Raymond F. Burk

Chapter 12 Selenoprotein W: A muscle protein in search ofa function ............................................................................ 137

L. Walt Ream, William R Vorachek and Phillip D. Whanger

Chapter 13 The 15 kDa selenoprotein (Sep15): functional studies

and a role in cancer etiology .................................................. 147 Vadim N Gladyshev, Alan M Diamond and Dolph L. Hatfield

Table of Contents IX

Chapter 14 Selenoproteins of the glutathione system .................................... 157 Leopold Flohe and Regina Brigelius-Flohe

Chapter 15 Selenoproteins of the thioredoxin system .••.•.....•..••..••..•••••..•.•••.•• 179 Arne Holmgren

Chapter 16 Selenium, deiodinases and endocrine function •••••..•••.•....•.•••••.•••• 189 Donald L. St. Germain

Part III. Selenium and human health

Chapter 17 Selenium as a cancer preventive agent ....................................... 205 Gerald F. Combs, Jr. and Junxuan Lii

Chapter 18. Selenium deficiency and human disease ..................................... 219 Ruth J. Coppinger and Alan M Diamond

Chapter 19 Selenium as an antiviral agent ••••••••••••••••••••.•••••.•••••••••••.•••••••••• 135 Melinda A. Beck

Chapter 20 Role of selenium in HIV I AIDS ••••••••••••••••••••••••••••••••••••.••...••••••. 247 Marianna K. Baum, Adriana Campa, Maria Jose Miguez-Burbano, Ximena Burbano and Gail Shor-Posner

Chapter 21 Effects ofselenium on immunity and aging •......••••.•......••.••..•..•••• 257 Roderick C. McKenzie, Teresa S. Rafferty, Geoffrey J. Beckett and John R. Arthur

x Selenium: Its molecular biology and role in human health

Chapter 22 Selenium and male reproduction .............................................. 273 Leopold Flohtf, Regina Brigelius-Flohtf, Matilde Maiorino, Antonella Roveri, Josef Wissing and Fulvio Ursini

Chapter 23 Role of low molecular weight, selenium-containing compounds in human health .................................... 283

Henry J. Thompson

Chapter 24 Evolution of human dietary standards for selenium ............................................................................ 299

Orville A. Levander

Chapter 25 Selenium in biology and human health: controversies and perspectives .................................................................. 313

Vadim N. Gladyshev

Index ................................................................................. 319

CONTRIBUTORS

John R. Arthur Division of Cell Integrity Rowett Research Institute,

Bucksbum Aberdeen, Scotland AB21 9SB,

UK

Mariana K. Baum Division of Metabolism and

Disease Prevention Department of Psychiatry and

Behavioral Sciences University of Miami School of

Medicine Miami, FL 33136, USA

Melinda A. Beck Department of Pediatrics and

Nutrition University of North Carolina at

Chapel Hill Chapel Hill, NC 27599, USA

Geoffrey J. Beckett Department of Clinical

Biochemistry University of Edinburgh Edinburgh, Scotland, EH3 9YW,

UK

Marla J. Berry Thyroid Division Brigham and Women's Hospital

and the Department of Biological Chemistry and Molecular Pharmacology

Harvard Medical School Boston, MA 02115, USA

August Bock Lehrstuhl fUr Mikrobiologie der

Universitat Miichen D-80638 Munich, Germany

Regina Brigelius-Flohe Department of Vitamins and

Atherosclerosis German Institute for Research of

Nutrition (DIfE) Arthur-Scheunert-Allee 114-116 D-14558 Potsdam, Germany

Ximena Burbano Division of Metabolism and

Disease Prevention Department of Psychiatry and

Behavioral Sciences University of Miami School of

Medicine Miami, FL 33136, USA

Raymond F. Burk Department of Medicine Vanderbilt University School of

Medicine Nashville, TN 37232, USA

Adriana Campa Division of Metabolism and

Disease Prevention Department of Psychiatry and

Behavioral Sciences University of Miami School of

Medicine Miami, FL 33136, USA

xii Selenium: Its molecular biology and role in human health

Bradley A. Carlson Section on the Molecular Biology

of Selenium Basic Research Laboratory National Cancer Institute National Institutes of Health Bethesda, MD 20892 USA

Gerald F. Combs, Jr. Division of Nutritional Sciences Cornell University Ithaca, NY 14853, USA

Paul R. Copeland Department of Cell Biology Lerner Research Institute Cleveland Clinic Foundation Cleveland, OH 44195, USA

Ruth J. Coppinger Department of Human Nutrition University of Illinois at Chicago Chicago, IL 60612, USA

Alan M. Diamond Department of Human Nutrition University of Illinois at Chicago Chicago, IL 60612, USA

Donna M. Driscoll Department of Cell Biology Lerner Research Institute Cleveland Clinic Foundation Cleveland, OH 44195, USA

Leopold Flohe Department of Biochemistry Technical University of

Braunschweig Mascheroder Weg 1 D-38124 Braunschweig, Germany

Vadim N. Gladyshev Department of Biochemistry University of Nebraska Lincoln, NE 68588, USA

Dolph L. Hatfield Section on the Molecular Biology

of Selenium Basic Research Laboratory National Cancer Institute National Institutes of Health Bethesda, MD 20892, USA

Kristina E. Hill Department of Medicine Vanderbilt University School of

Medicine Nashville, TN 37232, USA

Arne Holmgren Medical Nobel Institute for

Biochemistry Department of Medical

Biochemistry and Biophysics Karolinska Institute SE-171 77 Stockhom, Sweden

Easwari Kumaraswamy Section on the Molecular Biology

of Selenium Basic Research Laboratory National Cancer Institute National Institutes of Health Bethesda, MD 20892, USA

Gerard M. Lacourciere Laboratory of Biochemistry National Heart, Lung, and Blood

Institute National Institutes of Health Bethesda, MD 20892, USA

Contributors

Byeong Jae Lee Laboratory of Molecular Genetics Institute for Molecular Biology

and Genetics Seoul National University Seoul 151-742, Korea

Orville A. Levander Beltsville Human Nutrition

Research Center U.S. Department of Agriculture Agricultural Research Service Beltsville, MD 20705, USA

Junxuan Lii AMC Cancer Center 1600 Pierce Street Denver, CO 80214, USA

Matilde Maiorino Dipartimento di Chimica

Biologica Universita di Padova Viale G. Colombo 3 1-35121, Padova, Italy

John B. Mansell Thyroid Division Brigham and Women's Hospital

and the Department of Biological Chemistry and Molecular Pharmacology

Harvard Medical School Boston, MA 02115, USA

Glover W. Martin, HI HarvardlMIT Division of Health

Sciences and Technology, and the Department of Microbiology and Molecular Genetics

Harvard Medical School Cambridge, MA, 02139, USA

XIll

F. Javier Martin-Romero Section on the Molecular Biology

of Selenium Basic Research Laboratory National Cancer Institute National Institutes of Health Bethesda, MD 20892 USA

Roderick C. McKenzie Department of Medical and

Radiological Sciences University of Edinburgh Edinburgh, Scotland, EH3 9YW,

UK

Maria Jose Miguez-Burbano Division of Metabolism and

Disease Prevention Department of Psychiatry and

Behavioral Sciences University of Miami School of

Medicine Miami, FL 33136, USA

Mohamed E. Moustafa Section on the Molecular Biology

of Selenium Basic Research Laboratory National Cancer Institute National Institutes of Health Bethesda, MD 20892, USA

Teresa S. Rafferty Department of Medical and

Radiological Sciences University of Edinburgh Edinburgh, Scotland, EH3 9YW,

UK

xiv Selenium: Its molecular biology and role in human health

L. Walt Ream Departments of Microbiology and

Environmental and Molecular Toxicology

Oregon State University Corvallis, OR 97331, USA

Antonella Roveri Dipartimento di Chimica

Biologica Universita di Padova Viale G. Colombo 3 1-35121, Padova, Italy

Gail Shor-Posner Division of Metabolism and

Disease Prevention Department of Psychiatry and

Behavioral Sciences University of Miami School of

Medicine Miami, FL 33136, USA

Donald L. St. Germain Departments of Medicine and of

Physiology Dartmouth Medical School Lebanon, NH 03756, USA

Thressa C. Stadtman National Heart, Lung, and Blood

Institute National Institutes of Health Bethesda, MD 20892, USA

Roger A. Sunde F21C Nutrition Cluster Leader Professor of Nutritional Sciences

and of Biochemistry University of Missouri Columbia, MO 65211, USA

Henry J. Thompson Center for Nutrition in the

Prevention of Disease AMC Cancer Research Center Denver, CO 80214, USA

Fulvio Ursini Dipartimento di Chimica

Biologica Universita di Padova Viale G. Colombo 3 1-35121, Padova, Italy

William R. Vorachek Departments of Microbiology and

Environmental and Molecular Toxicology

Oregon State University Corvallis, OR 97331, USA

Philip D. Whanger Departments of Microbiology and

Environmental and Molecular Toxicology

Oregon State University Corvallis, OR 97331, USA

Josef Wissing Department of Biochemistry Technical University of

Braunschweig Mascheroder Weg 1 D-38124 Braunschweig, Germany

Huijun Zhi Section on the Molecular Biology

of Selenium Basic Research Laboratory National Cancer Institute National Institutes of Health Bethesda, MD 20892, USA

FOREWORD

From molecular biology to human health, selenium research is booming. It has become clear that most physiologic effects of selenium are exerted by selenoproteins. Therefore, most of the basic research on the element examines selenoprotein expression and regulation. Synthesis of a selenoprotein requires a complex process with several elements that are unique. The details of this process are emerging from the work of a number of groups.

The significance of selenium to human health is a hot topic. There is little or no selenium deficiency in the USA, but large numbers of people elsewhere in the world are selenium deficient. Animal studies have shown that selenium deficiency in the host can modify the course of viral infections and cause mutations in the virus. Whether this occurs in human beings will be important to determine. Such selenium deficiency induced mutations could possibly be responsible for emergence of new viral strains.

Evidence has been presented from studies in animals that selenium has anticancer effects when given in pharmacologic amounts. An intervention study in human beings has supported this idea. A number of intervention studies are currently being pursued in this important, but difficult area.

The selenium field has not always been so active. Selenium came to the notice of biologists in the 1930s when it was discovered to be the dietary substance responsible for hair and hoof loss in animals grazing certain areas of the American Great Plains. This recognition of its toxicity led the USDA to map the selenium content of forage in the USA. The map that was produced demonstrated that the selenium content of plants varied tremendously according to where they were grown. Most areas of the country produced plants that contained a moderate (non-toxic) concentration of selenium. However, a few locales were distinctly different. Some produced plants that had very high selenium contents (toxic) and some produced plants that had very low selenium contents. Thus, the effort to locate high-selenium areas in order to prevent selenium toxicity in animals led also to the identification of low-selenium areas.

After selenium had been shown to be an essential nutrient in the mid-1950s, some veterinary disease endemic to areas that had been identified as low in selenium on the USDA selenium map were investigated. White muscle disease in sheep responded to selenium and thus was classed as a selenium deficiency disease. Several other pathological conditions that were vitamin E responsive, including mulberry heart disease of pigs, also responded to selenium. The association of the two nutrients in these conditions linked vitamin E with selenium and suggested that selenium

XVI Selenium: Its molecular biology and role in human health

might function as an oxidant defense because vitamin E was known to be an antioxidant.

In the early 1970s, Chinese workers investigating the cause of a childhood cardiomyopathy called Keshan disease took note of the veterinary literature of selenium deficiency diseases. Keshan disease only occurred in certain areas of China and the investigators noted that animals in those areas had clinical illnesses that were similar to those caused by selenium deficiency. They determined that hair selenium was low in the children with Keshan disease. Then they carried out a placebo-controlled study of selenium administration to children at risk for Keshan disease. Children that received selenium were protected from Keshan disease. Thus, a manifestation of selenium deficiency in human beings is a susceptibility to cardiomyopathy in children. A second (and unknown) factor is needed to cause the disease as not all selenium deficient children develop it. It is not known whether selenium deficiency has other adverse effects on human health but this is an important topic for further research. Efforts in the 1930s and 1940s to understand selenium biochemistry and

metabolism focused on mechanisms of its toxicity and excretion. However, the realization in the 1950s that selenium was an essential nutrient led to investigations of its role in normal biochemistry. Selenium deficiency was induced in experimental animals by feeding them a low selenium diet. Then biochemical systems were studied in selenium deficient animals and in controls. Using this approach, a group at the University of Wisconsin identified glutathione peroxidase as the first animal selenoenzyme in 1973. This solidified the nutritional essentiality of selenium and supported the idea that it provided defense against oxidative injury.

After almost a decade as the only know animal selenoprotein, glutathione peroxidase was joined by selenoprotein P in 1982 and by other selenoproteins soon thereafter. Presently, approximately 15 animal selenoproteins are known and that number is rising as new ones are discovered.

Studies in bacteria yielded more selenoproteins and led to the pioneering work by the Munich group in the late 1980s that elucidated the mechanism of selenoprotein synthesis in bacteria. Their work served as the starting point of the work on selenoprotein synthesis in animals.

This book is an up-to-date collection of research summaries and reviews written by active selenium researchers. Its coverage is broad with detailed basic science reviews as well as health related chapters. This book will provide an in depth summary of the field of selenium as well as a guide for future research.

Raymond F. Burk

PREFACE

Research over the last 30 years involving selenium biology has yielded new and surprising insights into biochemical, molecular and genetic aspects of this fascinating element. During this same time period, data have also been obtained from both human and animal nutritional studies suggesting a vital role for selenium in disease incidence and severity. These two disciplines of study are beginning to merge and the interrelationships between the different observations are becoming apparent as is discussed in this book.

An active area of selenium research has been the functional characterization of selenoproteins. While several chapters in this book deal with this significant topic, there is, in fact, considerable debate in the selenium field whether selenoproteins or low molecular weight selenium compounds are responsible for the many reported beneficial effects of dietary selenium. Both viewpoints are expressed herein, so that the reader will have an opportunity to see how different leaders in the field view the topic of selenium and human health, and, at the same time, obtain a more comprehensive appreciation of the present status of the thinking on these subjects.

Diet plays an extremely important role in health and disease. For example, an increasing number of health professionals contend that environmental factors such as infection, unbalanced diets, smoking, excessive alcohol consumption and insufficient exercise contribute more to chronic disease in man than genetic disposition. These maladies include cancer, cardiovascular disease, diabetes and liver dysfunction. The origins of these diseases may be attributed, at least in part, to disruption of redox homeostasis, leading to the presence of excess reactive oxygen species and oxidative damage of essential cellular components, including nucleic acids and proteins. As dietary selenium is viewed as a potent regulator of cellular redox homeostatis, selenium may be an important dietary contributor to reducing the incidence of many debilitating disorders. Although the specific biological mechanisms of selenium that are responsible for promoting better health, and the extent to which this element is involved in promoting better health, remain to be established, the available data suggest that the benefits of dietary selenium are highly significant. Caution must be exercised, however, in touting the advantages of this element as too much selenium in the diet can have toxic consequences and the range between too little and too much selenium is not much more than an order of magnitude. The guidelines for the recommended daily allowance in humans have recently been revised and are discussed in this book.

Combs and Combs wrote in 1986 that "One of the most important discoveries in nutrition in the last 30 years has been the recognition of the

XVlll Selenium: Its molecular biology and role in human health

essentiality of the element selenium ..... " (GF Combs, SB Combs 1986 The Role of Selenium in Nutrition Academic Press, Inc New York). This statement was motivated by evidence that adequate dietary selenium has important health benefits that were primarily observed in laboratory animals and livestock. These findings followed the initial observations in the mid 1950s that selenium had a role in bacterial metabolism and in preventing liver necrosis in rats. Combs and Combs also noted in 1986 that the livestock industry had prevented losses estimated in the 100s of millions of dollars by supplementing the diet of livestock with selenium or with selenium and vitamin E. Today, these savings are in the billions of dollars.

In the last 15 years, many of the molecular mysteries surrounding selenium have been solved. We now know that selenium is incorporated into protein as selenocysteine, the 21 sl naturally occurring amino acid in protein. Unlike any of the other 20 amino acids that are present in protein, the biosynthesis of selenocysteine occurs on its transfer RNA. The donation of selenocysteine to the growing selenopeptide in protein synthesis requires a novel mRNA binding protein and a selenocysteine-tRNA specific elongation factor in archaea and eukaryotes, while a single protein carries out both these functions in eubacteria. Selenoproteins have clearly evolved to take advantage of the fact that the pKa of selenocysteine is lower than the physiological pH and, therefore, this amino acid residue is ideally suited to participate in redox reactions. This and other chemical properties of selenium result in the unique redox characteristics of selenocysteine and its use in antioxidant enzymes.

As discussed in the chapters in this book, a large body of evidence indicates that selenium is a cancer chemopreventive agent. Further evidence points to a role of this element in reducing viral expression, in preventing heart disease, and other cardiovascular and muscle disorders, and in delaying the progression of AIDS in HIV infected patients. Selenium may also have a role in mammalian development, in male fertility, in immune function and in slowing the aging process. If dietary selenium does indeed influence these diseases and cellular processes, then the significance of including adequate amounts of this element in the diet may be regarded as one of the more important discoveries in nutrition in the last century.

Dolph L. Hatfield

ACKNOWLEDGMENTS

The support and generous help of Va dim N. Gladyshev and

Bradley A. Carlson throughout the preparation of this book

are gratefully acknowledged.