Toxicology of Metals: Biochemical Aspects

479 Pages·1995·8.79 MB·English

by  Robert A. Goyer M.D., M. George Cherian Ph.D. (eds.)

Handbook of
Experimental Pharmacology
Volume 115
Editorial Board
G.V.R. Born, London
P. Cuatrecasas, Ann Arbor, MI
D. Ganten, Berlin
H. Herken, Berlin
K.L. Melman, Stanford, CA
Toxicology of Metals
Biochemical Aspects
Contributors
N. Ballatori, M.G. Cherian, D.C. Dawson, M. Delnomdedieu
P. Druet, B.R Fisher, P. Goering, RA. Goyer, S. Himeno
N. Imura, E.H. leffrey, M.M. lones, l.H.R Kagi, S. Kawanishi
C.D. Klaassen, l. Koropatnick, l.S. Lazo, M.E.I. Leibbrandt
K. Miura, A. Naganuma, E.l. O'Flaherty, L. Pelletier
T.G. Rossman, S. Silver, M. Styblo, D.M. Templeton, D.l. Thomas
M.P. Waalkes, M. Walderhaug, l.S. Woods, l. Zeng
Editors
Robert A. Goyer and M. George Cheri an
Springer-Verlag
Berlin Heidelberg New York London Paris
Tokyo Hong Kong Barcelona Budapest
ROBERT A. GOYER, M.D.
Professor Emeritus
Department of Pathology
University of Western Ontario
Health Sciences Centre
London, Ontario, Canada N6A SCI
M. GEORGE CHERIAN, Ph.D.
Professor
Department of Pathology
University of Western Ontario
Health Sciences Centre
London, Ontario, Canada N6A SCI
With 37 Figures and 17 Tables
ISBN-13:978-3-642-79164-2 e-ISBN-13:978-3-642-79162-8
001: 10.1007/978-3-642-79162-8
Library of Congress Cataloging·in·Publication Data. Toxicology of metals: biochemical aspects/contributors
N. Ballatori ... [et al.]; editors, Robert A. Goyer and M. George Cherian. p. cm. - (Handbook of
experimental pharmacology; v. 115) Includes bibliographical references and index. ISBN-13:978-3-642-79
164-2 1. Metals - Toxicology. I. Ballatori, N. II. Goyer, Robert. III. Cherian, M.
George, 1941- . IV. Series. [DNLM: 1. Metals - toxicity. 2. Maximum Permissible Exposure Level.
WI HA51L v. 115 1995/QV 290 T755 1995] QP905.H3 vol. 115 [RA1231.M52] 615'. I s-dc20
[615.9'253] DNLMIDL-C for Library of Congress 94-26484
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List of Contributors
BALLATORI, N., Department of Environmental Medicine, University of
Rochester School of Medicine, Rochester, NY 14642, USA
CHERIAN, M.G., Department of Pathology, University of Western Ontario,
Health Sciences Centre, London, Ontario, Canada N6A 5C1
DAWSON, D.C., Department of Physiology, University of Michigan Medical
School, 6811 Med.Sci. 2, Ann Arbor, MI 48109-0622, USA
DELNOMDEDIEU, M., Center for Environmental Medicine and Lung Biology,
. University of North Carolina at Chapel Hill, Chapel Hill, NC 27514,
USA
DRUET, P., Institut National de la Sante et de la Recherche Medicale
(INSERM U28), Hopital Broussais, 96 rue Didot, F-75674 Paris, Cedex
14, France
FISHER, B.R., Health Sciences Branch, Division of Life Sciences, Office of
Science and Technology, Center for Devices and Radiological Health,
Food and Drug Administration, 12709 Twinbrook Parkway, Rockville,
MD 20857, USA
GOERING, P.L., Health Sciences Branch, Division of Life Sciences, Office of
Science and Technology, Center for Devices and Radiological Health,
Food and Drug Administration (HFZ-112), 12709 Twinbrook Parkway,
Rockville, MD 20857, USA
GOYER, R.A., Department of Pathology, University of Western Ontario,
Health Sciences Centre, London, Ontario, Canada N6A 5C1
HIMENO, S., Department of Public Health and Molecular Toxicology,
School of Pharmaceutical Sciences, Kitasato University, Minato-ku,
Tokyo 108, Japan
IMURA, N., Department of Public Health and Molecular Toxicology, School
of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo 108,
Japan
JEFFREY, E.H., Institute for Environmental Studies, University of Illinois at
Urbana-Champaign, 1101 W. Peabody Drive, Urbana, IL 61801, USA
VI List of Contributors
JONES, M.M., Department of Chemistry and Center in Toxicology,
Vanderbilt University, P.O. Box 1583, Station B, Nashville, TN 37235,
USA
KAGI, J .H.R., Biochemistry Institute of the University of Zurich, Winter-
thurerstraBe 190, CH-8057 Zurich, Switzerland
KAWANISHl, S., Department of Public Health, Faculty of Medicine, Kyoto
University, Kyoto 606, Japan
KLAASSEN, C.D., Department of Pharmacology, Toxicology, and Thera-
peutics, University of Kansas Medical Center, 39th and Rainbow, Kansas
City, KS 66103, USA
KOROPATNICK, J., Department of Oncology, London Regional Cancer
Centre, University of Western Ontario, 790 Commissioners Road E.,
London, Ontario, Canada N64 4L6
LAzo, J.S., Department of Pharmacology, University of Pittsburgh, Ex-
perimental Therapeutics Program, Pittsburgh Cancer Institute, E-1340
Biomedical Science Tower, Pittsburgh, PA 15261, USA
LEIBBRANDT, M.E.I., Parke-Davis Pharmaceutical Research, General
Toxicology, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
MIURA, K., Department of Environmental Sciences, Wako University,
Machida-shi, Tokyo, 104-01, Japan
NAGANUMA, A., Department of Public Health and Molecular Toxicology,
School of Pharmaceutical Sciences, Kitasato University, Minato-ku,
Tokyo 108, Japan
O'FLAHERTY, E.J., Department of Environmental Health, University of
Cincinnati College of Medicine, 3223 Eden Ave., Cincinnati, OH 45267-
0056, USA
PELLETIER, L., Institut National de la Sante et de la Recherche Medicale
(INSERM U28), Hopital Broussais, 96 rue Didot, F-75674 Paris, Cedex
14, France
ROSSMAN, T.G., Nelson Institute of Environmental Medicine and Kaplan
Cancer Center, New York University Medical Center, 550 First Avenue,
New Yark, NY 10016, USA
SILVER, S., Department of Microbiology and Immunology, University of
Illinois College of Medicine, M/C 790, Room 703, 835 South Wolcott
Ave., Chicago, IL 60612-7344, USA
STYBLO, M., Curriculum in Toxicology, University of North Carolina at
Chapel Hill, Chapel Hill, NC 27514, USA
List of Contributors VII
TEMPLETON, D.M., Department of Clinical Biochemistry, University of
Toronto, Banting Institute, 100 College Street, Toronto, Ontario,
Canada M5G 1L5, and Division of Biochemistry, The Research Insti-
tute, Hospital for Sick Children, 555 University Ave., Toronto, Ontario,
Canada M5G 1X8
THOMAS, D.J., Health Effects Research Laboratory, MD-74, U.S. Environ-
mental Protection Agency, Research Triangle Park, NC 27711, USA
WA ALKES, M.P., Inorganic Carcinogenesis Section, Laboratory of Com-
parative Carcinogenesis, National Cancer Institute, Frededck, MD
21702, USA
WALDERHAUG, M., Division of Microbiological Studies, Microbial Ecology
Branch, Food and Drug Administration, CFSAN HFS-517, 200 C.
Street, SW, Washington, DC 20204, USA
WOODS, J.S., Battelle Seattle Research Center, 400 N.E. 41st Street, Seattle,
WA 98105,USA
ZENG, J., Biochemistry Institute of the University of Zurich, Winter-
thurerstraBe 190, CH-8057 Zurich, Switzerland. Present address:
Laboratory of Biochemistry, Bldg. 37, Rm. 4A13, National Cancer
Institute, National Institutes of Health, Bethesda, MD 20892, USA
Preface
The toxicology of metals has been concerned in the past with effects
that produced clinical signs and symptoms. However, this view of metal
toxicology has expanded in recent years due principally to two advances.
There has been a considerable increase in our knowledge of the biochemical
effects of metals. In addition, biomarkers of toxicity can now be recognized
that identify toxicity at levels of exposure that do not produce overt clinical
effects. Thus, the toxicology of metals is now focused on nonclinical events
that reflect adverse health effects. This new awareness has produced
the challenge of determining the lowest adverse level of exposure. With
increasing analytical sensitivity and methodologies to detect small changes at
the molecular level, the lowest level of exposure of some toxic metals,
like lead, is very small. Indeed, for metals in which there is no biologic
requirement, it may be questioned whether there is a level of exposure that
does not produce some degree of toxicity. For essential metals, the question
is being asked as to the levels at which exposure exceeds biologic require-
ments and excess exposure becomes toxic. The appropriateness of health
decisions and the formation of public policy are dependent on the availability
of current scientific information that addresses these questions.
The information in this volume is intended to be a resource for this
purpose as well as a reference for students of toxicology and other health
professionals. Specific topics of current relevance are addressed in chapters
on aluminum, cadmium, chromium, lead, and mercury. A number of
chapters are concerned with metal-protein interactions, including effects on
heat shock proteins and on metallothionein, a protein important in the
metabolism of both essential and toxic metals. Zinc-containing finger
proteins are related to gene expression, as are chapters on the mutagenicity
of metals, plasmid-mediated metal resistance, drug resistance, and the
effects of oxygen radicals in the production of DNA damage. Some
metals may become involved in basic physiologic processes within cells
including transport at the level of the cell membrane and porphyrin meta-
bolism. These are effects that may produce new biochemical markers
that provide early evidence of toxicity. And, finally, the toxicity of low-
level exposures is stimulating increased efforts to develop chelators or
therapeutic agents that may be used for intervention and prevention of
toxicity.
x Preface
The field of biochemical toxicology is rapidly expanding in terms of the
sophistication of the science base and a corresponding public interest. The
editors are hopeful that this volume will contribute to these interests.
London, Ontario, Canada M. GEORGE CHERIAN
August 1994 ROBERT A. GOYER
Contents
CHAPTER 1
Transplacental Transfer of Lead and Cadmium
R.A. GOYER. With 2 Figures ................................... 1
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
I. Comparison of Human
and Rodent Fetal-Maternal Blood Barriers. . . . . . . . . . . . . . 2
II. Methods for Sampling the Human Placenta. . . . . . . . . . . . . . 3
B. Placental Transfer of Lead. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
I. Mechanism of Placental Transfer of Lead ............... 3
II. Maternal Blood Lead Levels During Pregnancy . . . . . . . . . . 5
III. Effect of Maternal Lead on Birth Outcomes ... . . . . . . . . . . 6
IV. Effect of Lead on Neurobehavioral
and Cognitive Development In Utero. . . . . . . . . . . . . . . . . . . 6
V. Mechanisms for the Neurotoxicity of Lead. . . . . . . . . . . . . . . 7
C. Placental Transfer of Cadmium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
I. Cadmium Levels in Human Placenta.. . . ... . . ... . . .. . .. . 9
II. Cadmium Effects on Placenta and Fetus. . . . . . . . . . . . . . . . . 10
III. Interactions in Placenta Between Cadmium, Zinc
and Copper, and Metallothionein ...................... 11
D. Summary................................................. 13
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
CHAPTER 2
Porphyrin Metabolism as Indicator of Metal Exposure and Toxicity
J.S. WOODS. With 8 Figures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
B. Heme Biosynthesis and Porphyrin Metabolism ................ 19
C. Mechanistic Basis of Metal-Induced Porphyria (Porphyrinuria) .. 23
I. Metal Effects on Specific Steps
of the Heme Biosynthetic Pathway . . . . . . . . . . . . . . . . . . . . . 23
II. Metal-Induced Oxidation of Reduced Porphyrins. . . . . . . . . 25
XII Contents
D. Metal- and Metalloid-Induced Porphyrinopathies
and Porphyrinurias ........................................ 27
I. Lead............................................... 27
1. Erythrocyte ALA Dehydratase. . . . . . . . . . . . . . . . . . . . . . 28
2. Erythrocyte Zinc-Protoporphyrin. . . . . . . . . . . . . . . . . . . . 30
3. Urinary Coproporphyrin. . . . . . . . . . . . . . . . . . . . . . . . . . . 33
II. Mercury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
1. Mercury-Directed Alteration
of Renal Coproporphyrinogen Metabolism. . . . . . . . . . . . 36
2. Mercury-Facilitated Porphyrinogen Oxidation. . . . . . . . . 38
III. Arsenic............................................. 39
IV. Other Metals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
1. Cadmium ........................................ 41
2. Platinum......................................... 41
3. Aluminum....................................... 42
4. Metal Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
E. Perspectives on the Use of Porphyrins as Biomarkers
of Metal Exposure in Human Studies. . . . . . . . . . . . . . . . . . . . . . . . . 43
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
CHAPTER 3
Membrane Transporters as Sites of Action and Routes of Entry
for Toxic Metals
D.C. DAWSON and N. BALLATORI. With 4 Figures... . . . .. . ... . .... . 53
A. Introduction: Metals and Membranes ........................ 53
B. Chemical Properties of Metals in Solutions. . . . . . . . . . . . . . . . . . . . 54
C. Model Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
D. Mercury Inhibition of NaCI Cotransport:
An Example Problem with a Model System ................... 62
E. Metal Entry into Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
F. Permeation in a Lipid-Soluble Form. . . . . . . . . . . . . . . . . . . . . . . . . . 63
G. Permeation as a Cation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
H. Permeation as an Anion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
I. Transport of Organic Complexes ............................ 69
J. Physiological Significance of Metal Permeation Pathways. . . . . . . . 71
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72