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手植记:旅行找食材,原生本初心

手植记:旅行找食材,原生本初心

 

手植记:旅行找食材,原生本初心

2015年央视“3.15晚会”刚刚结束,今年的主题是“消费在阳光下”,小编特别留意了一下,今年的晚会在食品安全方面并没有过多阐述,其中一个亮点性的内容是在食品安全召回方面有了制度上的规范。当然我们不希望等到食品召回时才发现有安全问题,那早已晚了,于是如何吃得好,吃得安全就成了亟需解决的问题。

事情发生问题,我们的第一反应就是寻找原因,因为寻找根源才是问题解决之本,作为生活在钢筋混凝土包围的都市人群,每天高楼大厦、工业污染、尾气排放,处处都充满着危机感。在都市中生活的越久,人们越觉得植物自然生长带来的魅力,对原生食材的关注和诉求也越来越多。

谈“吃”色变是现代人对都市生活方式的真实写照,这个想吃,怕抹激素,那个也想尝尝,怕添加防腐剂,想起那捧起一捧溪水就能张口大喝的日子,一阵唏嘘,这也不过是十几年的时间,我们的世界已经被各种污染、添加剂所侵蚀,想寻点原生态的食材也成为一种奢侈。越难寻找就越有人参与到其中,体验与大自然亲密接触。从央视的《舌尖上的中国》到《走遍中国》,再到互联网年轻群体的小圈层活动,越来越多的团队参与到寻找原生食材的行列之中。

  “手植之旅”的诞生便成为一种必然。“手植之旅”是由原生农产品电商品牌手植记组织发起的在全国探寻原生食材的一个寻访活动,目前已开展两季(第一季,为生活探寻原生食材,主要是山东丘陵地区,第二季,专注于食物与生活的品质,主要是山西太行山脉地区。)手植记最早这个想法来自于某创意公司CEO的一个小私心,他觉得原生食材确实是难得的好东西,就想着找来给员工发福利,改善一下员工的生活品质,却意外发现人们对原生食材需求很大,便想着干脆把它做成一个品牌吧。没想到竟迅速赢得大众的认可,也积累了不少忠实的顾客。

一个招募生活理念相同的人参与其中,一起寻访手植系食材,共同追求积极的生活精神和生活品质的想法便逐渐成型。说起“手植之旅”的初衷,用他们自己的话就是:“不道听途说,寻找真正的原生食材,送给自己和家人,算是在奔向大叔/大妈的旅途中,做出的一点点改变”。

手植记的一系列活动也为那些平时没时间打理自己生活,加班熬夜且满脸痘痘还依然热爱生活,积极向上的都市人,在繁杂的生活中增添点阳光之色。

  手植记
  我们快乐&精神食粮
  为生活寻找原生态食材

CONTENTS
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
v

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

CONTRIBUTORS
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
vii

EDITOR’S PREFACE
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
ix

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
Merk.
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
void.

Genotoxicity of Chromate
James J. Covino and Kent D. Sugden
Contents
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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