Table Of ContentChemical
Carcinogens
and DNA
Volume II
Editor
Philip L. Grover
Chester Beatty Research Institute
Institute of Cancer Research
Royal Cancer Hospital
London, England
Boca Raton London New York
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PREFACE
Since so little is known in molecular terms about the organization of eukaryotic cells
and the homeostatic mechanisms that control them, it is not very surprising that the
changes that are involved in the acquisition of malignancy are not understood either.
It is, however, generally accepted that chemical carcinogens exert their effects through
initial reactions with specific targets within the cell. The nature of these targets also
remains unknown but, partly because of correlations between mutagenicity and carcin-
ogenicity and partly because of the simplistic appeal of the somatic mutation hypoth-
esis, reactions of chemical carcinogens with nucleic acids, particularly DNA, continue
to receive much attention.
These two volumes represent an attempt to make an up-to-date appraisal of chemical
carcinogens from the point of view of their effects on DNA and the subject matter is
arranged in a sequence. The opening contributions deal with extents to which carcino-
gens react with DNA and with the formation and detection of DNA-carcinogen ad-
ducts and these are followed by more specialized chapters dealing with the activation
of particular types of chemical carcinogens and their reactions with DNA. The later
contributions cover the conformational changes induced in nucleic acids by chemical
carcinogens and deal with the mechanisms by which these chemical reactions may be
translated, either directly or indirectly, into biological effects that include mutagenesis
and carcinogenesis.
P. L. Grover
March 1978
THE EDITOR
Philip L. Grover, D.Sc, is a Senior Scientist on the staff of the Chester Beatty
Research Institute, Institute of Cancer Research, London, England.
Dr. Grover graduated from the University of London in 1956 and subsequently
obained M.Sc. and Ph.D. degrees for research on detoxication reactions. He joined
the scientific staff of the Chester Beatty Research Institute in 1959 where he has
worked, largely in collaboration with Dr. Peter Sims, on the metabolic activation of
the carcinogenic polycyclic hydrocarbons. He was awarded a D.Sc. by the University
of London in 1977.
CONTRIBUTORS
W. M. Baird, Ph.D. E. Kriek, Ph.D.
Associate Professor Research Biochemist and Chief
The Wistar Institute Division of Chemical Carcinogenesis
Philadelphia, Pennsylvania The Netherlands Cancer Institute
Amsterdam, The Netherlands
C. C. Chang, Ph.D.
Assistant Professor
P. D. Lawley, D.Sc.
Department of Human Development
Senior Lecturer
College of Human Medicine
Pollards Wood Research Station
Michigan State University
Institute of Cancer Research
East Lansing, Michigan
Bucks, United Kingdom
C. C. J. Culvenor, Ph.D., D.Sc.
Chief Research Scientist V. M. Maher, Ph.D.
CSIRO Associate Professor
Division of Animal Health Department of Microbiology and
Animal Health Research Laboratory Public Health and Department of
Victoria, Australia Biochemistry
and
M. Duquesne, Ph.D. Co-Director
Professor Carcinogenesis Laboratory-Fee Hall
Department of Physics Michigan State University
University of Paris and Institut Curie East Lansing, Michigan
Paris, France
G. P. Margison, Ph.D.
R. C. Garner, Ph.D.
Scientific Officer
Senior Lecturer
Paterson Laboratories
Cancer Research Unit
Christie Hospital and Holt Radium
University of York
Institute
York, United Kingdom
Manchester, United Kingdom
M. H. L. Green, Ph.D.
Scientist H. W. J. Marquardt, M.D.
MRC Cell Mutation Unit Associate Member
University of Sussex Sloan-Kettering Institute for Cancer
Brighton, United Kingdom Research
New York, New York
D. Grunberger, Ph.D. and
Associate Professsor Associate Professor
College of Physicians and Surgeons Department of Pharmacology
Institute of Cancer Research Sloan-Kettering Division
Columbia University Graduate School of Medical Sciences
New York, New York Cornell University
New York, New York
M. V. Jago, Ph.D.
Principal Research Scientist C. N. Martin, Ph.D.
CSIRO Research Fellow
Division of Animal Health Cancer Research Unit
Animal Health Research Laboratory University of York
Victoria, Australia York, United Kingdom
J. J. McCormick, Ph.D. J. E. Trosko, Ph.D.
Associate Professor Professor
Department of Microbiology and Department of Human Development
Public Health and Department of College of Human Medicine
Biochemistry Michigan State University
and East Lansing, Michigan
Co-Director
Carcinogenesis Laboratory-Fee Hall
Michigan State University
P. Vigny, Ph.D.
East Lansing, Michigan
Associate Professor
Department of Physics
P. J. O'Connor, Ph.D.
University of Paris and Institut Curie
Senior Research Officer
Paris, France
Paterson Laboratories
Christie Hospital and Holt Radium
Institute
I. B. Weinstein, M.D.
Manchester, United Kingdom
Professor
College of Physicians and Surgeons
D. H. Phillips, Ph.D.
Division of Environmental Sciences and
Post-doctoral Fellow
Institute of Cancer Research
McArdle Laboratory For Cancer
Columbia University
Research
New York, New York
University of Wisconsin
Madison, Wisconsin
P. Sims, Ph.D., D.Sc. J. G. Westra, Ph.D.
Reader in Biochemistry Research Chemist
Institute of Cancer Research Division of Chemical Carcinogenesis
Chester Beatty Research Institute The Netherlands Cancer Institute
London, United Kingdom Amsterdam, The Netherlands
TABLE OF CONTENTS
VOLUME I
Chapter 1
Approaches to Chemical Dosimetry in Mutagenesis and Carcinogenesis: The Relevance
of Reactions of Chemical Mutagens and Carcinogens with DNA 1
P. D. Lawley
Chapter 2
In Vitro Modification of Nucleic Acids by Indirect-Acting Chemical Carcinogens .. .37
P. L. Grover
Chapter 3
The Use of Radioactive Carcinogens to Detect DNA Modifications 59
W. M. Baird
Chapter 4
Fluorimetric Detection of DNA-Carcinogen Complexes 85
P. Vigny and M. Duquesne
Chapter 5
Nucleic Acid Modification by N-Nitroso Compounds Ill
G. P. Margison and P. J. O'Connor
Chapter 6
Carcinogenic Plant Products and DNA 161
C. C. J. Culvenor and M. V. Jago
Chapter 7
Fungal Toxins, Aflatoxins, and Nucleic Acids 187
R. C. Garner and C. N. Martin
Index 227
VOLUME II
Chapter 1
Metabolic Activation of Aromatic Amines and Amides and Interactions with Nucleic
Acids 1
E. Kriek and J. G. Westra
Chapter 2
Polycycfíc Aromatic Hydrocarbon Metabolites: Their Reactions with Nucleic
Acids 29
D. H. Phillips and P. Sims
Chapter 3
Conformational Changes in Nucleic Acids Modified by Chemical Carcinogens 59
D. Grunberger and I. B. Weinstein
Chapter 4
Mutagenic Consequences of Chemical Reaction with DNA 95
M. H. L. Green
Chapter 5
DNA Repair and Carcinogenesis 133
V. M. Maher and J. J. McCormick
Chapter 6
DNA — The Critical Cellular Target in Chemical Carcinogenesis? 159
H. W. J. Marquardt
Chapter 7
Chemical Carcinogenesis as a Consequence of Alterations in the Structure and-
Function of DNA 181
J. E. Trosko and C. C. Chang
Index 201
1
Chapter 1
METABOLIC ACTIVATION OF AROMATIC AMINES AND AMIDES
AND INTERACTIONS WITH NUCLEIC ACIDS
E. Kriek and J. G. Westra
TABLE OF CONTENTS
I. Introduction 2
II. Metabolic Activation Reactions of Aromatic Amines and Amides 3
A. N-oxidation to Hydroxamic Acids 3
B. Esterification Reactions of Arylhydroxamic Acids 4
1. O-Glucuronides 4
2. O-Acetates 5
3. O-Sulfates 6
C. Pathways of Formation of Arylhydroxylamines 7
1. Enzymic Deacetylation of Arylhydroxamic Acids 7
2. N-oxidation of Arylamines 7
3. Reduction of Nitro Compounds 8
D. Esterification Reactions of Arylhydroxylamines 9
1. O-Acetates 9
2. JV-Glucuronides 10
E. Peroxidase or Free Radical Activation 10
III. Interaction with Nucleic Acids 11
A. Sites of Covalent Reaction 12
1. 2-Acetylaminofluorene 12
2. 4-Acetylaminobiphenyl 14
3. 4-Acetylamino-4'-fluorobiphenyl 14
4. 2-Acetylaminophenanthrene 15
5. N-Methyl-4-aminoazobenzene 15
6. Other Aromatic Amines and Amides 17
B. Mechanistic Aspects of the Formation of Covalent Bonds 18
C. Distribution of Covalently Bound Aromatic Amine Residues in DNA . 19
D. Other Modes of Interaction 21
Acknowledgments 22
References 23
