Molecular and Biochemical Toxicology, 4th Edition

by Editor: Robert C. Smart; Editor: Ernest Hodgson (North Carolina State University)

• ISBN13: 9780470285244
• ISBN10: 0470285249
• Format: eBook
• Copyright: 2008-07-01
• Publisher: Wiley

Summary

An essential resource for graduate students, academic and industrial toxicologists, and environmental health scientists and professionalsOver the course of thirty years and three editions, Introduction to Biochemical Toxicology has been an important source for coverage of the ongoing quest to define the biochemical, cellular, and molecular events induced by toxicants at the cellular and organismic levels. Now, as the principles and methods of molecular and cellular biology as well as genomic sciences play an ever increasing role in mechanistic toxicology, significant changes have been made to the book, resulting in this important new edition-now titled Molecular and Biochemical Toxicology, Fourth Edition.Much more than an introductory text, this crucial new edition has been completely revised to provide timely and thorough coverage of the underlying biochemical, molecular, and cellular mechanisms through which toxicants produce their adverse effects. Toxicological issues are covered from the molecule to the cell to the organ level. Complex methods used in toxicology are also described in a straightforward, easy-to-understand style. Additional features of this new edition include: New chapters that explore the interface between toxicology and genomic sciences, including: bioinformatics, proteomics, metabolomics, and toxicogenomics Increased emphasis on structure, mechanism, and regulation of xenobiotic metabolizing enzymes, toxicogenetics, and xenobiotic transporters Additional new chapters on: molecular epidemiology and genetic susceptibility, DNA damage and mutagenesis, DNA repair, mechanisms of cell death, mitochondrial dysfunction, metals, reproductive toxicology, developmental toxicology, and reactive oxygen/metabolites and toxicityMolecular and Biochemical Toxicology, Fourth Edition guides graduate students, toxicologists, and environmental health professionals through the principles of molecular and biochemical toxicology and the complex mechanisms of toxicity. Whether it's used in the classroom or in industry, research, or academia, this book is essential for anyone interested in understanding the molecular mechanisms through which toxicants produce adverse effects.

Table of Contents

Preface

Contributors

Molecular and Biochemical Toxicology: Definition and Scope

Introduction

Toxicology

Biochemical Toxicology

Cellular Toxicology

Molecular Toxicology

Proteomics, Metabolomics

Conclusions

Suggested Reading

Overview of Molecular Techniques in Toxicology: Genes and Transgenes

Applicability of Molecular Techniques to Toxicology

Overview of the Genetic Code and Flow of Genetic Information

Molecular Cloning

Southern and Northern Blot Analyses

Polymerase Chain Reaction (PCR)

Some Methods to Evaluate Gene Expression and Regulation

Toxicogenomics (Marjorie FOleksiak)

Introduction

A Primer of Genomics

Tools and Approaches

Genomes

Functional Genomics

Proteomics (BAlex Merrick)

Introduction to Proteomics

Properties of Proteins

Fields of Proteomic Research

Mass Spectrometers and Protein Identification

Proteomic Platforms

Proteomes and Subproteomes: Expectations and Reality

Summary

Metabolomics

Introduction

Methods

Diagnostics and Functional Genomics

Metabolomics and Toxicology

Bioinformatics

Introduction

Obtaining the Genbank Record of a Known Gene

Sequence Comparison

Database Searching With BLAST

Extensions to Multiple Sequences

Genetic Mapping

Conclusion

Immunochemical Techniques in Toxicology

Introduction

Definitions

Immunogens and Antigens

Polyclonal Antibodies

Monoclonal Antibodies

Immunoassays

Conclusions

Cellular Techniques

Introduction

Cellular Studies in Intact Tissue

Studies with Dispersed, Isolated Cells

Monolayer Cell Culture

Observation of Cultured Cells

Indicators of Toxicity

Artifacts and Confounders

Replacement of Animal Testing with Cell Culture Models

Conclusions

Structure, Mechanism and Regulation of Cytochromes P450

Introduction

Complexity of the Cytochrome P450 Gene Superfamily

Cytochrome P450 Structure

Mechanisms of P450 Catalysis

Cytochrome P450 Regulation

Transgenic Animal Models

Reactive Oxygen Species

Posttranslation Modification of P450s

Summary

Phase I Metabolism of Toxicants and Metabolic Interactions

Introduction

Microsomal Monooxygenations: General Background

Nonmicrosomal Oxidations

Cooxidation by Prostaglandin Synthetase

Reduction Reactions

Hydrolysis

Epoxide Hydration

DDT Dehydrochlorinase

Interactions Involving Xenobiotic-Metabolizing Enzymes

Phase I-Pharmacogenetics

Introduction

Polymorphisms in CYP Isoforms

Polymorphisms in Alcohol Dehydrogenase

Polymorphisms in Aldehyde Dehydrogenase

Polymorphisms in Flavin-Containing Monooxygenases

Polymorphisms in Epoxide Hydrolase

Polymorphisms in Serum Cholinesterase

Polymorphisms in Paraoxonase (PON1)

Polymorphisms: Mechanistic Classification

Polymorphisms and Drug Metabolism

Methods Used For the Study of Polymorphisms

Epidemiology

Phase II-Conjugation of Toxicants

Introduction

Conjugation Reactions

Glycosides

Sulfation

Methylation

Acylation

Glutathione S-Transferases

Cysteine S-Conjugate ß-Lyase

Lipophilic Conjugation

Phase II Activation

Phase III Elimination

Conclusions

Regulation and Polymorphisms in Phase II Genes

Introduction

Roles of Phase II Genes and Polymorphisms

The Antioxidant Responsive Element and Phase II Gene Regulation

Summary

Developmental Effects on Xenobiotic Metabolism

Introduction

Xenobiotic Metabolism During Development

Effects of Pregnancy on Maternal Xenobiotic Metabolism

Developmental Effects on Xenobiotic Metabolism in Non-Mammalian Species

Cycles in Development

Cellular Transport and Elimination

Transport as a Determinant of Xenobiotic Action

Factors Affecting Membrane/Tissue Permeability

Xenobiotic Transporters

Altered Xenobiotic Transport

Mechanisms of Cell Death

Introduction

How Cells/Tissues React to "Stress"

Cell Injury and Cell Death

Morphology of Cell Injury and Cell Death

Apoptosis

Mitochondrial Dysfunction

Introduction

Mitochondrial Function

Mitochondrial Apoptosis/Necrosis

Toxicant-Induced Mitochondrial Apoptosis/Necrosis

Glutathione-Dependent Mechanisms in Chemically Induced Cell Injury and Cellular Protection Mechanisms

Introduction

Glutathione-Dependent Conjugation of Chemicals

GSH Dependent Bioactivation of Chemicals

Oxidative Stress

Glutathione Dependent Cellular Defense Systems

Glutathione/Glutathionylation Dependent Signaling Systems and Antioxidant Defense

Conclusions

Toxicant-Receptor Interactions: Fundamental Principles

Definition of a "Receptor"

Receptor Superfamilies

The Study of Receptor-Toxicant Interactions

Relationship of Receptor Occupancy to Functional Effects

Reactive Oxygen/ Reactive Metabolites and Toxicity

Introduction

Enzymes Involved in Bioactivation

Stability of Reactive Metabolites

Factors Affecting Activation and Toxicity

Reactive Oxygen Species and Toxicity

Metals (David BBuchwalter)

Introduction

Understanding Metal Ion Reactions in Biological Systems

Modes of Metal Toxicity

Metals and Oxidative Stress

Metallothioneins

Examples of Toxic Metals

Metals and Cancer

DNA Damage and Mutagenesis

Introduction

Endogenous DNA Damage

Environmental DNA Damage

Concepts of Mutagenesis

Mechanisms of DNA Damage-Induced Mutagenesis

DNA Repair

Introduction

Direct Reversal of Base Damage

Base Excision Repair

Nucleotide Excision Repair

Mismatch Repair

Recombinational Repair

DNA Repair and Chromatin Structure

DNA Damage and Cell Cycle Checkpoints

Summary

Carcinogenesis

Introduction and Historical Perspective

Human Cancer

Categorization of Agents Associated with Carcinogenesis

Somatic Mutation Theory

Epigenetic Mechanism of Tumorigenesis

Multistage Tumorigenesis

Tumor Viruses

Cellular Oncogenes

Tumor Suppressor Genes

Mutator Phenotype/DNA Stability Genes

Interactions of Oncogenes and Tumor Suppressor Genes

Genetically Modified Mouse Models

Conclusions

Genetic Toxicology

Introduction and Historical Perspective

Genetic Toxicology and Risk Assessment

Genotoxicity Assays

Use of Mechanistic Data in Cancer and Genetic Risk Assessments

New Research Directions

Conclusions

Molecular Epidemiology and Genetic Susceptibility

Introduction

Basic Concepts in Epidemiology

Biomarkers Used in Molecular Epidemiology

Biomarkers of Genetic Susceptibility

Summary and Concluding Remarks

Respiratory Toxicology

Introduction

Anatomy and Function of the Respiratory Tract

Toxicant-Induced Lung Injury, Remodeling and Repair

Occupational and Environmental Lung Diseases

Hepatotoxicity

Introduction

Liver Organization and Cellular Components

Types of Chemically Induced Lesions

Mechanisms of Chemically Induced Hepatotoxicity

Interactions

Detection and Prediction of Hepatotoxicity

Compounds Causing Liver Injury

Conclusion

Biochemical Mechanisms of Renal Toxicity

Introduction

Fundamental Aspects of Renal Physiology

Factors Contributing to Nephrotoxicity

Assessment of Nephrotoxicity

Site-Specific Nephrotoxicity

Summary

Biochemical Toxicology of the Peripheral Nervous System

Introduction

Specialized Aspects of Neuronal Metabolism

Specialized Aspects of Schwann Cell Transport

Toxic Neuropathies

Conclusion

Biochemical Toxicology of the Central Nervous System

Introduction

CNS Sites of Toxic Action

Factors Affecting Neurotoxicant Susceptibility

Mechanisms of Neurotoxicity and Neuroprotection

The Dynamic Nervous System: Adaptibility, Plasticity and Repair

Immunotoxicology

Introduction

Organization of the Immune System

Immunotoxicology

Mechanisms of Immune Suppression

Mechanisms Associated with Hypersensitivity

Mechanisms Associated with Autoimmune Disease

Reproductive Toxicology

Introduction

General Principles of Reproductive Toxicology

Sexual Differentiation

Neuroendocrine Regulation of Reproduction

Male Reproductive System

Female Reproductive System

General Categories of Reproductive Toxicants

Summary

Developmental Toxicology

Introduction

Overview of Development

WilsonÆs Principles of Teratology

Selected Examples of Developmental Toxicants

Summary

Dermatotoxicology

Introduction

Functions of Skin

Epidermis

Anatomical Factors to Consider in Model Selection

Percutaneous Absorption and Penetration

Dermatotoxicity

Dermal Toxicity of Nanoparticles

Conclusion

Index

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