Table Of ContentCellular and Molecular
Toxicology and In Vitro
Toxicology
Editor
Daniel Acosta, Jr., Ph.D.
Department of Pharmacology and Toxicology
College of Pharmacy
The University of Texas at Austin
Austin, Texas
First published 1990 by CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite
300 Boca Raton, FL 33487-2742
Reissued 2018 by CRC Press
© 1990 by Taylor & Francis
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
This book contains information obtained from authentic and highly regarded sources.
Reasonable efforts have been made to publish reliable data and information, but the author and
publisher cannot assume responsibility for the validity of all materials or the consequences of
their use. The authors and publishers have attempted to trace the copyright holders of all
material reproduced in this publication and apologize to copyright holders if permission to
publish in this form has not been obtained. If any copyright material has not been
acknowledged please write and let us know so we may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted,
reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means,
now known or hereafter invented, including photocopying, microfilming, and recording, or in
any information storage or retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.
copyright. com (http:/ /www.copyright.com/) or contact the Copyright Clearance Center, Inc.
(CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit
organiza-tion that provides licenses and registration for a variety of users. For organizations
that have been granted a photocopy license by the CCC, a separate system of payment has been
arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks,
and are used only for identification and explanation without intent to infringe.
A Library of Congress record exists under LC control number: 90001589
Publisher's Note
The publisher has gone to great lengths to ensure the quality of this reprint but points out that
some imperfections in the original copies may be apparent.
Disclaimer
The publisher has made every effort to trace copyright holders and welcomes correspondence
from those they have been unable to contact.
ISBN 13:978-1-138-50607-7 (hbk)
ISBN 13: 978-1-315-15036-9 (ebk)
Visit the Taylor & Francis Web site at http:/ /www.taylorandfrancis.com and the CRC Press
Web site at http://www.crcpress.com
PREFACE
This new volume on Cellular and Molecular Toxicology and In VitroToxicol-
ogy reflects the importance of understanding the toxicity of xenobiotics at levels
beyond the whole animal. An objective of this book is to provide a better
understanding of the mechanisms by which xenobiotics are toxic to mammalian
tissues and cells. The mechanism(s) by which toxic compounds injure or disrupt
normal functioning of the whole organism is more clearly delineated by
correlating changes at the whole animal level with discrete changes at the cellular
and subcellular levels. The other aspect of the volume, as reflected in the title,
concerns the use of in vitro systems as experimental tools to provide valuable
insight into the biochemical mechanisms that underlie the toxicity of a xenobi-
otic. Thus, the purpose of the book is to focus on the cellular and molecular
effects of toxicants on living systems and to highlight the use of in vitro
experimental systems to assess toxic manifestations of xenobiotics.
This book concentrates on the cellular and molecular toxicity of selected well-
known drugs or chemicals on the cardiovascular system. The chapters will
highlight the most recent findings on the cellular and molecular mechanisms of
toxicity of several important cardiotoxic agents: doxorubicin, ethanol, cocaine,
and the catecholamines. In addition, an overview of vascular toxins and their
biochemical effects and a summary on in vitro cardiovascular techniques for
assessing toxicity of xenobiotics will be presented. We look forward to com
ments on this first volume, as well as to suggestions on topics for future volumes.
Daniel Acosta, Jr.
EDITOR
Daniel Acosta, Jr. was bom in El Paso, Texas, on March 25,1945. He attended
the University of Texas at El Paso for his pre-pharmacy training from 1963 to
1965. He then transfered to the University of Texas at Austin College of
Pharmacy in 1965 and received a B.S. in Pharmacy in 1968. He graduated first
in his class with Highest Honors. In 1970, he was awarded a National Science
Foundation Traineeship for his graduate work at the University of Kansas School
of Pharmacy in the Department of Pharmacology and Toxicology. He received
a Ph.D. in Pharmacology and Toxicology in 1974 under the supervision of Dr.
Duane G. Wenzel.
In the fall of 1974 Dr. Acosta joined the faculty of the University of Texas
College of Pharmacy as an assistant professor of pharmacology and toxicology.
Before he was promoted to associate professor in 1979, he received a Ford
Foundation Postdoctoral Fellowship from the National Chicano Council on
Higher Education for the year 1978-1979. After his promotion to associate
professor, he continued to develop his teaching and research program. His
current research interests include cellular toxicology, cellular models of target
organ toxicity, and cellular models of drug metabolism and toxicity. This
research has been supported by grants from the National Heart, Lung, and Blood
Institute, National Institute of Environmental Health Sciences, Environmental
Protection Agency, American Heart Association, Pharmaceutical Manufactur
ers Association, Johns Hopkins Center for Alternatives to Animal Testing,
Johnson & Johnson, and several pharmaceutical companies. Dr. Acosta has
directed the research of 20 graduate and postdoctoral students. He has over 80
publications in such journals as Toxicology and Applied Pharmacology, Bio
chemical Pharmacology, In Vitro, and Toxicology.
In 1983 he was appointed to full professor and was the initial holder of the Eli
Lilly and C.R. Sublett Centennial Fellowship and Alcon Professorship in Phar
macy. He is presently the initial holder of the Johnson & Johnson Centennial
Professorship in Pharmacy. At the national level, he is a member of the Tissue
Culture Association, Society of Toxicology, American Society for Pharmacol
ogy and Experimental Therapeutics, American Heart Association, Basic Sci
ences Council, Phi Kappa Phi, Rho Chi, and Phi Delta Chi. In addition to
membership in these organizations, he has served as a consultant to the Minority
Biomedical Support Program of the National Institutes of Health; member of the
NIDA’s Drug Abuse Biomedical Research Review Committee (Pharmacology
II Subcommittee); member of the Board of Directors of the American Heart
Association, Texas Affiliate; member of the Central Research Review Commit
tee of the American Heart Association, Texas Affiliate; member of the National
Research Council’s Panel on Biomedical Sciences for the National Science
Foundation Graduate Fellowship Program; member of the editorial boards of In
Vitro, Fundamental and Applied Toxicology, In Vitro Toxicology, and Toxicol
ogy In Vitro; Formal Liaison between the Society of Toxicology and the Tissue
Culture Association; member of the Program Committee of the Society of
Toxicology; chairman, Membership Committee of the Society of Toxicology;
and President, Gulf Coast Regional Chapter of the Society of Toxicology. Most
recently he was selected as the 1986 recipient of the Burroughs Wellcome
Toxicology Scholar Program, a five-year program to develop a toxicology
program at the University of Texas.
CONTRIBUTORS
Paul J. Boor, M.D. Philip Posner, Ph.D.
Department of Pathology Department of Physiology
University of Texas Medical Branch University of Florida College
Galveston, Texas of Medicine
Gainesville, Florida
Phillip S. Mushlin, M.D., Ph.D.
Department of Anesthesia
Kenneth Ramos, Ph.D.
Brigham and Women’s Hospital
Department of Physiology and
Harvard Medical School
Pharmacology
Boston, Massachusetts
College of Veterinary
Richard D. Olson, Ph.D. Medicine
Department of Medicine Texas A & M University
University of Washington School of College Station, Texas
Medicine
Seattle, Washington, and
Gordon L. Todd, M.S., Ph.D.
Clinical Pharmacology Unit
Department of Anatomy
VA Medical Center
University of Nebraska Medical
Boise, Idaho
Center
Philip I. Polimeni, Ph.D. Omaha, Nebraska
Department of Pharmacology and
Therapeutics Allison A. Welder, Ph.D.
University of Manitoba Faculty of Department of Pharmacodynamics
Medicine, and and Toxicology
Departments of Medicine and College of Pharmacy
Surgery The University of Oklahoma
St. Boniface General Hospital Health Sciences Center
Winnipeg, Manitoba, Canada Oklahoma City, Oklahoma
TABLE OF CONTENTS
Chapter 1
The Vascular Toxicity of Xenobiotics.................................................................1
Paul J. Boor
Chapter 2
The Molecular and Cellular Toxicology of Ethanol on the Heart.................19
Philip I. Polimeni and Philip Posner
Chapter 3
Mechanisms of Anthracycline Cardiotoxicity:
Are Metabolites Involved?...................................................................................51
Richard D. Olson and Phillip S. Mushlin
Chapter 4
Cardiotoxicity of Catecholamines ......................................................................83
Gordon L. Todd
Chapter 5
The Toxic Effects of Cocaine on the Heart.....................................................121
Allison Anne Welder
Chapter 6
Cellular and Molecular Basis of Xenobiotic-Induced Cardiovascular
Toxicity: Application of Cell Culture Systems................................................139
Kenneth Ramos
Index.....................................................................................................................157
C\
Taylor & Francis
~-
Taylor & Francis Group
http:/ /taylora ndfra ncis.com
1
Chapter 1
THE VASCULAR TOXICITY OF XENOBIOTICS
Paul J. Boor
TABLE OF CONTENTS
I. Introduction...................................................................................................2
II. Atherosclerosis..............................................................................................2
III. Medial Toxins...............................................................................................3
A. (3-Aminopropionitrile.........................................................................3
B. Allylamine..........................................................................................6
IV. Endothelial/Capillary Toxins....................................................................12
A. Snake Venoms..................................................................................12
B. Cyclophosphamide...........................................................................12
C. 1,3-Butadiene.....................................................................................13
V. Conclusions: Experimental Systems in Vascular Toxicity....................13
Acknowledgments ...............................................................................................14
References 14
