Abstract
N. Plant’s Molecular Toxicology is a succinctly prepared primer to the expansive science of molecular biology. This text is intended primarily for undergraduate and graduate students in toxicology. The book will also be a valuable resource for experienced scientists from other disciplines who want to obtain a basic understanding of the principles of molecular toxicology including an introduction to some of the latest techniques used to assess toxicity.
This book is short and carefully organized in a reader-friendly manner. The author has synthesized a large amount of information into 150 pages. In the front of the book a very helpful listing of abbreviations used throughout the text is provided. The book is arranged into eight chapters. All chapters begin with either a question and then answer, or a brief introduction to the subject. Each chapter culminates with a summary of the material, and closes with a short preface to the next chapter. Figures and tables are used effectively throughout the text to help illustrate salient points. The author affords the reader a fundamental understanding of each chapter before moving to the subsequent chapters.
In Chapter One the book begins with an explanation of the general concepts of toxicology; especially the processes of absorption, distribution, metabolism, and excretion (ADME). The author discusses the importance of understanding how the body handles toxic insults. The inclusion of a concise prologue to the ensuing chapters is given preparing the reader for the concepts and technologies of the science of molecular toxicology.
In Chapter Two the initial steps concerning the enzymes involved in phase I metabolism of chemicals and drugs are presented. The role of ADME in detoxifying chemicals is examined. And, conversely, how metabolism can increase the toxicity of certain chemicals is considered. The reader is introduced to cytochrome P450–mediated phase I metabolism including an excellent description and clarification of the derivation of the hierarchical nomenclature system and structures used to identify the cytochrome P450 enzymes. This chapter also provides a reference to the cytochrome P450 (CTP) website whereby the latest information on identification and classification of CYPs is maintained.
Chapter Two also familiarizes the reader with the following topics: (1) cytochrome P450 catalytic cycle; (2) cytochrome P450 pharmacogenetics; (3)CYP1 and CYP2 families–mediated toxicity; and (4) CYP3A subfamily–mediated toxicity. Additionally, flavin monooxygenase–mediated phase I metabolism, including the nomenclature used to describe the flavin monooxygenase enzymes, flavin monooxygenase catalytic cycle, and flavin monooxygenase pharmacogenetics and mediated toxicity are described. Other enzymes that play roles in detoxification and toxification reactions are briefly discussed such as cytochrome P450 reductase, cytochrome b5, and prostaglandin H synthase.
In Chapter Three the differentiation between phase I and phase II reactions is elucidated. The author develops further the role of another group of enzymes that accomplish phase II metabolism, enhance the rate of excretion, and play a part in the detoxification of chemicals or drugs that were either not detoxified in phase I metabolism or made more toxic. Phase II reactions such as (1) glucuronide conjugation, (2) sulphate conjugation, (3) glutathione conjugation, and (4) epoxide hydrolase–mediated toxicity are understandably presented. The author emphasizes the significance of the confluence of phase I and phase II metabolism in protecting the body’s normal homeostasis.
Chapter Four expands the discussion on how the body responds to toxic stress. The author clearly describes topics such as (1) the generation of oxygen reactive species; (2) direct and indirect activation of gene expression including signal transduction pathways such as the mitogen-activated protein kinase (MAPK) cascades involved in response specific stress; (3) small reactive chemical species as signaling molecules; and (4) repair of cellular damage and regulation of apoptosis and necrosis.
Chapter Five examines examples of toxicity, showing how different chemicals can cause fundamentally different toxic effects by various modes of action. In the section on genotoxicity, the author clearly differentiates aneugens, clastogens, and mutagens. Moreover, hepatotoxicity, nephrotoxicity, neurotoxicity (including a discussion of the discovery of MPTP [1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine] as a model of Parkinson’s disease), and teratogenesis are concisely discussed. The author also covers receptor-dependent toxicity using aryl hydrocarbon receptor (AhR) and N-methyl-
In Chapter Six, the author apprises the reader to (1) the toxic effects of chemical mixtures, and (2) how true risk and toxicity can be predicted in real life situations where humans are exposed on a daily basis to a myriad of therapeutic drugs, environmental chemicals, food additives, and other substances. The chapter is basically divided up into an elucidation of simple and complex mixtures, including the different methods of assessing risk for each.
In Chapter Seven the author provides an excellent comprehensive discourse of the role genomics will play in understanding and predicting toxicity, and in the discovery of new therapeutic targets human and animals. The author discusses the mechanisms of genetic control, the methodologies used to study genetic responses to toxic insult, the variations in toxic response between the different animal models evaluated, and the occurrence of within species variations in toxic responses. The challenge will be to take all this information and extrapolate toxicity data obtained from animal models studied to humans.
The final chapter, Chapter Eight, can be used as a reference tool. The author establishes a concise synopsis of many of the state-of-the-science molecular technologies, for example, genomics, transcriptomics, proteomics, and metabonomics, available for the researcher to use in the quest to understand molecular mechanisms of cellular response to toxic stimuli.
Much needs to be continually cultivated and understood in this broad field of molecular toxicology. Numerous texts on the subject exist. The author’s text emerges as an advanced, explicit, and thorough introduction to the subject.