Abstract
Drs Robert C. Smart and Ernest Hodgson have undertaken a major revision of the third edition of Introduction to Biochemical Toxicology (published in 2001 by John Wiley). The new fourth edition, Molecular and Biochemical Toxicology, is a remarkable improvement on the previous edition. The revision contains 35 chapters (compared to 26 in the previous edition), and many of the chapters that were carried over from the previous edition have undergone significant revision. Many of the chapter authors are affiliated with the editors’ institution, North Carolina State University, but experts with necessary expertise from other institutions have also contributed. Whereas I was hesitant to recommend that graduate students purchase the third edition, I believe that the very contemporary topics covered in excellent depth in the revised fourth edition would justify the purchase of this book as either a textbook for an upper-level biochemical/molecular toxicology class or as a reference book for anyone in this area of toxicology research.
Chapters 1 and 2 (“Molecular and Biochemical Toxicology: Definition and Scope” by Hodgson and Smart and “Overview of Molecular Techniques” by Smart) are not significantly different from the previous edition, with the exception of the omission of some of the introductory material in Chapter 1 and the addition of a new promoter deletion figure and a brief section on conditional knockout mice and Cre-lox recombination to Chapter 2. This chapter also contains a brief reference to microarray analysis, undoubtedly serving as a prelude to new chapters on toxicogenomics, proteomics, and metabolomics in the fourth edition.
Chapter 3 (“Toxicogenomics” by Marjorie F. Oleksiak) is new to the fourth edition. The major strengths of this chapter are the excellent glossary of genomic vocabulary and the comprehensive discussion of technical and biological replicates.
Chapter 4 (“Proteomics” by B. Alex Merrick) is similarly a new and timely topic in the fourth edition. After a brief introduction of the topic, Dr Merrick discusses properties of proteins in some detail, followed by a detailed discussion of mass spectrometry and various proteomic platforms. Figure 4.13 is a very useful summary of advantages and limitations of several proteomic platforms.
Chapter 5 (“Metabolomics” by Nigel Deighton) adds another new topic to the fourth edition. This chapter provides a literate and useful discussion of nonbiased versus pipelined approaches, followed by a brief description of mass spectrometry and nuclear magnetic resonance (NMR). The NMR section is particularly useful, thanks to very simple but effective figures. The chapter closes with brief discussions of very contemporary topics such as metabolomics in diagnostics and metabolomics and toxicology.
Chapter 6 (“Bioinformatics” by Eric Stone and Dahlia M. Nielsen) represents another new topic in the fourth edition. The chapter begins with a discussion of sequence comparisons and clarifies the definitions of orthologs, homologs, and paralogs, culminating with an extensive discussion of database searching with BLAST. This section concisely covers the BLAST algorithm, followed by a description of BLAST statistics. Section 6.6 presents a particularly comprehensive discussion of genetic mapping. Following a description of general principles (recombination, genetic markers, etc), the section continues with a discussion of linkage analysis, association mapping, and environmental factors in gene mapping. Figures 6.9 through 6.12 are particularly helpful and will likely see use by faculty teaching from this text.
Chapter 7 (“Immunochemical Techniques in Toxicology” by Gerald A. LeBlanc) is a slightly updated version of Chapter 3 in the previous edition. The chapter provides a very comprehensive and understandable discussion of protein analysis techniques. The chapter is filled with very helpful figures and will continue to be a very good teaching tool on this topic.
Chapter 8 (“Cellular Techniques” by Sharon A. Meyer) is also updated from the previous edition. A brief discussion of reconstructed/bioengineered tissues has been added, as has a very nice new figure (8.1) showing cell-extracellular matrix interactions in the context of tissue digestion and cell separation. Brief but useful discussions of stem cell culture and artifacts and confounders have also been added.
Chapter 9 (“Structure, Mechanism, and Regulation of Cytochromes P450” by Darryl C. Zeldin and John M. Seubert) is new to this edition and is a much-needed addition to a textbook of molecular and biochemical toxicology. The chapter is comprehensive, is readable, and contains a number of very useful figures and tables, many adapted from other sources. (A notable omission from Table 9.6 is CYP2F in the lung, given the importance of this enzyme in bioactivation of many pneumotoxins in rodent lungs.)
Chapter 10 (“Phase 1 Metabolism of Toxicants and Metabolic Interactions” by Ernest Hodgson, Parikshit C. Das, Taehyeon M. Cho, and Randy L. Rose) is a streamlined and slightly rearranged version of Chapter 5 of the previous edition. The authors retained the previous edition’s exhaustive list of phase 1 reactions, together with many relevant examples. A several-page addition deals with interactions involving xenobiotic-metabolizing enzymes.
Chapter 11 (“Phase I—Toxicogenetics” by Ernest Hodgson and Edward L. Croom) is new in title to this edition but actually represents a modest update of material that was included in the phase 1 metabolism chapter in the previous edition. The RFLP figure for analysis of the CYP2C19*2 polymorphism continues to be an excellent teaching tool.
Chapter 12 (“Phase II—Conjugation of Toxicants” by Gerald A. LeBlanc) has been updated somewhat from the previous edition, most notably in the “SULT Superfamily” and “SULT Regulation” sections.
Chapter 13 (“Regulation and Polymorphisms in Phase II Genes” by Yoshiaki Tsuji) is a new and well-constructed chapter that continues a discussion of enzymes mentioned in the previous chapter. Unfortunately, the color panels for the entire book interrupt the flow of this chapter, and many of the figures are drawn with very small fonts and details and have dark shading, which may limit their use if photocopied.
Chapter 14 (“Developmental Effects on Xenobiotic Metabolism” by Martin J. J. Ronis and Helen C. Cunny) provides a much-needed update of the previous edition’s “Physiological Factors Affecting Xenobiotic Metabolism” by the same authors.
Chapter 15 (“Cellular Transport and Elimination” by David S. Miller) is a new chapter in this edition. After a brief introduction of transport processes, the chapter launches into a discussion of transporter families. This section seems a bit haphazard in its organization; for example, ABC transporters are mentioned on p. 279, but we do not learn that these are ATP-binding cassette proteins until the next page. A notable omission from the suggested reading list is the February 2004 issue of Pflügers Archiv, which contains a series of article on the SLC transporters. Despite these minor issues, this chapter contains new, interesting, and toxicologically relevant information.
Chapter 16 (“Mechanisms of Cell Death” by Mac Law and Susan Elmore) is a new chapter that includes a discussion of cells’ responses to stress, followed by a section on cell injury and cell death (necrosis). A section on apoptosis follows, which contains several very useful tables, as well as an excellent schematic representation of apoptotic events.
Chapter 17 (“Mitochondrial Dysfunction” by Jun Ninomiya-Tsuji) is a dramatic, yet brief, revision of the previous edition’s chapter on the effects of toxicants on electron transport and oxidative phosphorylation. The figures and tables included are excellent.
Chapter 18 (“Glutathione-Dependent Mechanisms in Chemically Induced Cell Injury and Cellular Protection Mechanisms” by Donald J. Reed) greatly expands on a subsection of the previous edition’s chapter on chemically induced cell injury and protection. Following a brief description of glutathione- dependent conjugation of chemicals and glutathione-dependent bioactivation of chemicals, the chapter focuses on oxidative stress and antioxidant defenses against oxidative stress. The next section deals with glutathione-dependent cellular defense systems and glutathione compartmentation, followed by the glutathione redox cycle and regulation of glutathione biosynthesis. The chapter concludes with a discussion of glutathione/glutathionylation-dependent signaling.
Chapter 19 (“Toxicant-Receptor Interactions: Fundamental Principles” by Richard B. Mailman) is largely unchanged from the previous edition. Nonetheless, it is an absolutely critical component of a biochemical toxicology textbook and is very well organized and clearly articulated. The stated objective of this chapter is to “provide the foundation necessary for understanding the interactions of small molecules . . . with receptors.” This is accomplished by initially discussing receptor subfamilies, followed by a discussion of receptor-toxicant interactions. This section includes a discussion of radioligand binding assays and calculation of equilibrium constants. Although many equations are presented and manipulated, the text is quite easy to follow.
Chapter 20 (“Reactive Oxygen/Reactive Metabolites and Toxicity” by Elizabeth L. MacKenzie) is an excellent new chapter added to the fourth edition. Following a discussion of contribution of phase I metabolism, phase II conjugations, and enterohepatic circulation in toxicant bioactivation, there is a brief discussion of stability of reactive metabolites, followed by an extensive discussion of factors affecting activation and toxicity. This chapter is quite upto- date and contains many excellent figures.
Chapter 21 (“Metals” by David B. Buchwalter) is a new chapter that fills an obvious gap in the previous edition of this text. Following discussions of metal deficiencies and essential metals, the topic of metal ion reactions in biological systems is addressed. Sections on modes of metal toxicity and metals and oxidative stress are, appropriately, followed by a very useful section on metallothioneins. The chapter continues with a discussion of some toxic metals and concludes with a very brief discussion of metals and cancer.
Chapter 22 (“DNA Damage and Mutagenesis” by Zhigang Wang) is another new chapter in this edition. This chapter is long (50 pages) and detailed and includes many very useful figures. Following detailed discussions of endogenous and environmentally induced DNA damage, the chapter moves into mutagenesis. This section begins with 3 pages of vocabulary, followed by a very extensive discussion of DNA damage–induced mutagenesis.
Chapter 23 (“DNA Repair” by Isabel Mellon) was the topic of a very short section in a chapter that was not carried over intact from the third edition to the fourth edition of this text. This new chapter is a significant addition to the text and begins with an overview that contains a summary table of DNA repair pathways, which acts as the framework on which the chapter is constructed. The chapter contains many very useful diagrams, and the sections on human diseases associated with genetic defects in DNA repair and mismatch repair and human cancer are fascinating.
Chapter 24 (“Carcinogenesis” by Robert C. Smart, Sarah J. Ewing, and Kari D. Loomis), a comprehensive 50-page chapter, contains updated cancer statistics and several new and informative figures (particularly 24.22, depicting PI3K signaling; 24.24, showing cell cycle regulation by retinoblastoma; and 24.25, showing p53 regulation of apoptosis and cell cycle progression). The epigenetics and tumor promotion sections have been updated, as has Table 24.7, listing human oncogenes.
Chapter 25 (“Genetic Toxicology” by R. Julian Preston) is very modestly updated from the previous edition of this text. Unfortunately, the previous edition contained phrases that dated it (“in the past 15 years”) that were not updated in this edition, so references to dates are not terribly accurate. The section on transgenic rodent models for assessment of tissue-specific genotoxicity is disappointingly brief. The major addition to this edition is a section on the use of mechanistic data in cancer and genetic risk assessments.
Chapter 26 (“Molecular Epidemiology and Genetic Susceptibility” by Ruth M. Lunn and Mariana C. Stern) is dramatically updated from the previous edition, with new authors. The chapter begins with a discussion of basic concepts of epidemiology, including some excellent examples. The chapter then continues with an in-depth discussion of biomarkers, beginning with a working definition of a biomarker, followed by an insightful discussion of the distinctions between biomarkers of exposure, biomarkers of internal dose, biomarkers of effective dose, and finally biomarkers of response or outcome susceptibility.
Chapter 27 (“Respiratory Toxicity” by James C. Bonner) is dramatically revised from the previous edition by a new author. The chapter begins with a discussion of the anatomy and function of the respiratory tract, including several pages of vocabulary. The next section focuses on toxicant-induced lung injury, remodeling, and repair. The figures in this section are particularly effective. A discussion of oxidative stress and lung injury reiterates some points made in previous chapters, which serves to reinforce these important concepts. The final section of this chapter provides a discussion of occupational and environmental lung diseases. Again, the figures included here are excellent. One technique that could have been covered, given its diagnostic value both in laboratory animals and humans, is bronchiolar alveolar lavage (BAL).
Chapter 28 (“Hepatotoxicity” by Andrew D. Wallace and Sharon Meyer) is largely unchanged from the previous edition. Nonetheless, the concepts important for a chapter on this topic are covered (although Figure 28.1, depicting the “zonal” organization of the liver, is suboptimal). Important but brief additions to this chapter include a discussion of fibrosis and a section on enterohepatic circulation in the context of such toxins as phalloidin and α-amanitin.
Chapter 29 (“Biochemical Mechanisms of Renal Toxicity” by Joan B. Tarloff and Andrew D. Wallace) is not significantly revised from the previous edition, but given the exhaustive depth and detail, it is an excellent resource on this topic. Major strengths of the chapter are the discussions of site-specific renal toxicants and diagnostic methods. The addition of a discussion of “omics” in the context of known renal toxicants is effective, and the addition of a section on mercury nephrotoxicity is useful. Figure 28 is not at all effective, given the lack of labeling and context, and notable omissions from the chapter are N-acetylβ- D-glucosaminidase (NAG) and kidney injury molecule- 1 (Kim-1) as urinary markers of nephrotoxicity.
Chapter 30 (“Biochemical Toxicology of the Peripheral Nervous System” by Jeffry F. Goodrum, Arrel D. Toews, and Thomas W. Bouldin) is very brief and not significantly updated from the previous edition, except for a couple of paragraphs on “omics” and the need for their validation. A welcome addition to this chapter would be a section on testing for peripheral nervous system damage.
Chapter 31 (“Biochemical Toxicology of the Central Nervous System” by Bonita L. Blake) is extensively revised from the previous edition. The current chapter omits the introductory material (basic description of synapses, neurotransmitters, etc) and immediately delves into central nervous system (CNS) sites of toxic action. The following section on factors affecting neurotoxicant susceptibility discusses endogenous factors, genetic determinants, epigenetic determinants, susceptibility windows (age), and interactions between endogenous and environmental factors. The next section discusses mechanisms of neurotoxicity and neuroprotection, and the chapter concludes with a discussion of nervous system adaptability, plasticity, and repair. The chapter contains only a few figures, and as with the previous chapter, a section on methods for testing for CNS damage would enhance the chapter. A reference regarding PON1 polymorphisms would be a nice addition to the Suggested Reading list.
Chapter 32 (“Immunotoxicity” by MaryJane K. Selgrade, Dori R. Germolec, Robert W. Luebke, Ralph J. Smialowicz, Marsha D. Ward, and Christal C. Bowman) has been updated to discuss several contemporary topics, including the mechanism of immune suppression by glucocorticoids, food allergies, adjuvants, and autoimmune diseases; the latter is extensive and accompanied by a very useful summary table. Table 32.2, listing Toll-like receptors and known ligands, is a nice addition. In terms of organization of the text, it would make sense to present this chapter prior to the respiratory toxicity chapter, as the concepts of Th1 and Th2 responses is described in detail in this chapter but is briefly mentioned (with little explanation) in the respiratory toxicity chapter. The organic solvents section would be strengthened by mention of studies of benzene toxicity in Cyp2e1(–/–) mice, and it is unclear why PAHs and halogenated aromatic compounds are handled separately with regard to mechanism of immunotoxicity, as both classes of compounds work at least in part through the aryl hydrocarbon receptor (which is mentioned in the context of HAHs but not PAHs).
Chapter 33 (“Reproductive Toxicology” by John F. Couse) is greatly expanded from the previous edition’s chapter on reproductive and developmental toxicity by a new author. The chapter begins with a neuroendocrine focus, and Table 33.1, which lists examples of known and potential endocrine disruptors, is an excellent resource. The chapter is then organized to discuss the male and female reproductive systems, as well as targets for toxicant damage by compartment in each system. The chapter concludes with a brief discussion of general categories of reproductive toxicants. Table 33.2 provides a very nice summary.
Chapter 34 (“Developmental Toxicology” by John F. Couse) is a new and interesting chapter for the fourth edition. After a historical perspective and an overview of development, the embryonic period is discussed, complete with subsections on sonic hedgehog signaling and homeobox genes, followed by a very brief description of the fetal period. The chapter then switches to a discussion of teratology, including Wilson’s general principles, with examples of each. The chapter concludes with an in-depth discussion of several selected developmental toxicants. The chapter contains several excellent figures and tables.
Chapter 35 (“Dermatotoxicology” by Nancy A. Monteiro-Riviere) covers the basics of structure and function of the skin as well as percutaneous absorption. Mechanisms of keratinocyte mediation of skin irritation, cell death, irritancy testing protocols, phototoxicity, and vesication are subsequently addressed. The only notable addition to the chapter in the fourth edition is a brief discussion of the dermal toxicity of nanoparticles. Standard techniques, such as use of diffusion cells to study permeation, as well as contemporary techniques involving organotypic (living skin equivalent) and ex vivo approaches (skin explant) cultures, would further update this chapter.
In summary, this is an excellent toxicology resource. Chapter lengths are in general quite appropriate, and overall, the figures are excellent. The book does a very good job of covering contemporary topics. It is by no means a text for an introductory course, but in that sense, it fills a unique niche. It is hoped that the publisher will consider making this book available online through institutional purchases, as students and researchers are increasingly more inclined to obtain information online rather than by purchasing textbooks.