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Contributors vii
Editor’s Preface ix
1. Genotoxicity of Chromate 1
James J. Covino and Kent D. Sugden
1. Introduction 1
2. Chromate Uptake, Metabolism and Speciation 2
3. Mechanisms of Chromate Genotoxicity 5
Acknowledgments 18
References 18
2. Drug-Induced Hepatotoxicity: Learning from Recent Cases of
Drug Attrition 25
Axel Pa¨hler and Christoph Funk
1. Introduction 25
2. Postulated Mechanisms of Hepatotoxicity 29
3. Proactive Approaches to Drug Safety 47
4. Summary and Conclusions 49
References 52
3. Glucuronidation-Dependent Toxicity and Bioactivation 57
Benedetta C. Sallustio
1. Introduction 57
2. Pharmacologically Active Glucuronide Conjugates 59
3. Chemically Reactive Glucuronide Conjugates 60
4. Glucuronidation-Dependent Protein Damage 64
5. Glucuronidation-Dependent DNA Damage 68
6. Glucuronidation-Dependent Translocation of Toxins and Carcinogens 70
7. Summary 77
References 77
4. Allergic Contact Dermatitis — A Common Skin Disease Caused by
Allergic Reactions to Chemicals in Our Environment 87
Ann-Therese Karlberg, Jens Baron and Hans Merk
1. Introduction 88
2. Hand Eczema 89
3. Mechanisms of Contact Allergy 90
4. Hapten–Protein Interactions 95

5. Activation of Prohaptens 101
6. Chemical Aspects on the Most Common Allergens in the Standard Series 108
7. Predictive Testing 109
8. Outlook 112
Acknowledgement 112
References 113
5. Inorganic Molecular Toxicology and Chelation Therapy of Heavy
Metals and Metalloids 123
Graham N. George, Ingrid J. Pickering, Christian J. Doonan, Malgorzata Korbas,
Satya P. Singh and Ruth E. Hoffmeyer
1. Introduction 124
2. In Situ Probes of Molecular Form 124
3. Chemical Form and Function in Toxicology 128
4. Molecular Mimicry — A Case of Mistaken Identity 131
5. Synergism and Antagonism 136
6. Chelation Therapy — Towards a Rational Design of Custom Chelators 140
7. Conclusions and Future Directions 147
Acknowledgments 148
References 148
6. Pyrimidine Damage and Repair 153
Agus Darwanto, Lynda Ngo and Lawrence C. Sowers
1. Biologically Important Pyrimidines 154
2. Physical Properties of the Pyrimidines 155
3. Hydrolytic Damage 157
4. Oxidation Damage of Pyrimidines 160
5. Alkylation Damage of Pyrimidines 166
6. Repair of Damaged Pyrimidines in DNA 170
7. Conclusions 173
References 173
7. Formation, Persistence and Significance of DNA Adduct Formation in
Relation to Some Pollutants from a Broad Perspective 183
Annie Pfohl-Leszkowicz
1. Introduction 184
2. Steps of the Carcinogenic Process 184
3. Biotransformation and Genetic Alteration (DNA Adduct Formation) 193
4. Time-Course Formation and Persistence of DNA Adduct — Is DNA Adduct
Predictive of Cancer? 218
5. Conclusion 225
Acknowledgements 227
References 227
Subject Index 241

Jens Baron 87
James J. Covino 1
Agus Darwanto 153
Christian J. Doonan 123
Christoph Funk 25
Graham N. George 123
Ruth E. Hoffmeyer 123
Ann-Therese Karlberg 87
Malgorzata Korbas 123
Hans Merk 87
Lynda Ngo 153
Axel Pa¨hler 25
Annie Pfohl-Leszkowicz 183
Ingrid J. Pickering 123
Benedetta C. Sallustio 57
Satya P. Singh 123
Lawrence C. Sowers 153
Kent D. Sugden 1

This second volume of Advances in Molecular Toxicology, like its predecessor, does
not dwell on a particular focus. Instead, the editor has invited high quality
contributions from among the field’s top practitioners to highlight the diversity of
interests, areas and approaches encountered in this discipline. It is hoped that in
perusing the enclosed chapters, the reader will readily appreciate the highly
interdisciplinary nature of the research in these areas. While this may seem daunting
to the new practitioner or beginning student, it should surely be exciting to
recognize that recent advances in these and related areas draw on the skill sets of the
many disciplines for which molecular toxicology is an interface.
Owing to a historical lack of prudent waste management practices, chromate is
unfortunately extensively dispersed in the human environment due to the use of
chromium in manufacturing. There is an ongoing workplace exposure as well.
Chromate has long been known as a genotoxin. Despite this, the molecular basis of
its genotoxicity remains a matter of contention. This is partly due to multiple redox
states and also the somewhat perplexing spectrum of chemistries in which some of
these states can participates. James Covino and Kent Sugden elaborate the situation
admirably in Chapter 1.
Toxicity in the liver, hepatotoxicity, is a major barrier in the development of
new drugs and a leading cause of post-marketing withdrawal of pharmaceuticals.
Rosiglitazone, an anti-diabetic, and nefazodone, an anti-depressant, are examples of
entities withdrawn from market due to hepatotoxicity for which structural
analogues with better safety profiles have remained on market. Examination of the
detailed metabolism of withdrawn and still-marketed analogues is the subject of
Axel Pa¨hler and Christoph Funk’s review in Chapter 2. This comparative approach
can reveal the sources of particularly toxic functionalities and also allow the
development of some predictive power for avoiding/reducing hepatotoxicity and
aiding in development of safe new therapeutics.
Bennedetta Sallustio elaborates the ‘dark side’ of glucuronide conjugates in
Chapter 3. Historically such conjugates of xenobiotics and their metabolites were
considered safely destined for export. But more recent work has detailed greater
complexity. The glucuronide functionality targets certain tissues due to specific
transporter systems and can chemically activate certain functional groups or cause
damage by means of the potential inherent in the glucuronide functionality. The
chemistry and biochemistry of a number of recent examples is detailed within.
Allergic contact dermatitis affects a significant portion of the population and
derives from contact with agents as simple as metal ions to molecules such as
fragrance constituents. The molecular basis for this reaction is only recently
becoming clear. Initiation events involve interaction with or ‘‘haptenization’’ of
proteins, in the latter case often subsequent to metabolic activation. And the
ultimate manifestation is immune-mediated. The complex interplay of the

chemistries of sensitization and biology of elicitation, as well as the predictive
potential, based on the spectrum of agents known to elicit contact dermatitis, is the
subject of Chapter 4 authored by Ann-Therese Karlberg, Jens Baron and Hans
The stimulating complexity of the toxicology of metals and metalloids is the
subject of Chapter 5 authored by Graham George, Ingrid Pickering, Christian
Doonan, Malgorzata Korbas, Satya Singh and Ruth Hoffmeyer. Arsenic and
mercury are the prototypical elements that illustrate the considerations. A key aspect
in toxicity of metals is molecular form as this dictates chemistry, uptake and
distribution. A highlight of this chapter is the application of powerful tools for
elucidating structure including variations of X-ray absorption spectroscopy and
computational methods. Ultimately these approaches and their conclusions bear on
therapeutic approaches to heavy metal toxicities.
Agus Darwanto, Lynda Ngo and Lawrence Sowers thoroughly review the
literature on pyrimidine DNA base damage and repair in Chapter 6. This review
takes a sweeping approach from the chemical elements to larger biological
implications. Particularly intriguing is the novel hypothesis, pioneered by the
principal investigator, that some types of damage, endogenously originated
halogenation from immune response, may result in epigenetic changes devolving
as altered gene expression with toxic consequences. This is potentially a long sought
link between activated immune response and toxic consequences, clearly an area
that will attract significant future attention.
The final chapter in this volume, Chapter 7, summarizes key aspects of DNA
damage by exogenously encountered toxins. It emphasizes often under-appreciated
aspects that contribute to ultimate biological consequences such as adduct
persistence in the context of available repair mechanisms. The review also
highlights the important contribution of polymorphism in xenobiotic metabolism
and DNA damage repair to the ultimate impact of xenobiotic assault. These factors
are important contributors to inter-individual variability in response. Annie Pfohl-
Leszkowicz has eloquently summarized these key contributors that mediate DNA
damage and its consequences.
This volume is dedicated to Chris Michejda and Bob Moschel, both of whose
careers were sadly cut short by untimely demise. Both men’s early professional
careers were rooted in fundamental aspects of the chemistry of toxins. From these
strong roots both evolved understandings and approaches that allowed them to craft
important contributions to human health. Both were leaders in their fields and all
who encountered them were struck by their selfless generosity. The editor
gratefully recalls that each welcomed him to the discipline and gave him tangible
encouragement. For he and many others, there is a palpable and inextinguishable

Genotoxicity of Chromate
James J. Covino and Kent D. Sugden
1. Introduction 1
2. Chromate Uptake, Metabolism and Speciation 2
2.1. Radical formation from chromate reduction 3
2.2. High-valent chromium intermediate formation from chromate reduction 4
3. Mechanisms of Chromate Genotoxicity 5
3.1. DNA oxidation pathway 6
3.2. DNA-binding pathways 14
Acknowledgments 18
References 18
1. Introduction
The hexavalent oxidation state of chromium, chromate or Cr(VI), has been
established as a human respiratory carcinogen based on more than a century’s worth
of epidemiological and medical evidence. Several million people worldwide are
occupationally exposed to chromate and many more are at risk of environmental
exposure arising from chromate contaminated landfills and aquifers. Over the years,
research has illustrated chromate’s myriad mutagenic, genotoxic, and carcinogenic
effects in a wide range of in vitro, cellular, and whole animal model systems.
However, the exact nature of the lesion(s) responsible for chromium’s toxic and
mutagenic effects has yet to be elucidated. The lack of clear mechanistic
information regarding chromate genotoxicity is, at least partly, due to the number
of different oxidation states of this metal that may play a role in its carcinogenicity,
and the multiple oxidation and binding pathways that have been proposed to
account for the wide assortment of DNA lesions observed in cellular systems.





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