In this issue dium of expertise on critical developments in mechanistic toxicology that have occurred since CRT’s inception. We trust that you will find these perspectives interesting, informative, and inspiring. Here, we provide a brief summary of what this issue has to offer.
Global Toxicology Readers of our recent series of perspectives, The Future ofToxicology,arewellaware of how the field has changed over the past 20 years. The 21st century offers new challenges and opportunities in all aspects of toxicology, not only in terms of research problems but also in terms of funding sources, student interest, and broader community support. As it begins its third decade, Chemical Research in Toxicology is looking outward to gain a perspective on how the field is developing globally. We have invited preeminent researchers from around the world to share their views of the most important issues in toxicology within their own countries. Editor-in-Chief, Larry Marnett, introduces this new series, and our first Guest Editorial is written by Dr. Hiroshi Yamazaki of Showa Pharmaceutical University, Tokyo, Japan. Dr. Yamazaki informs us of the major research initiatives that are engaging Japanese toxicologists. He also reveals an interesting problem related to the presence of a genetic variant of glutathioneS-transferase in the Japanese populationsa variant that leads to unique challenges in the field of drug discovery and toxicity in his country.
No review of progress in toxicology can overlook the extensive research on the cytochromes P450, key enzymes in the metabolism, detoxification, and excretion of xenobiotics, including most pharmaceuticals. It is well-known that P450catalyzed transformations of some otherwise benign molecules leads to the generation of reactive and toxic species. Considerable progress has been made over the past 20 years in understanding the chemistry and enzymology of the P450s. Guengerich (p 70) summarizes these advances from the aspect of structure, function, and diversity of the class, providing specific examples of the roles of P450s in pharmacology and toxicology. Hollenberg et al. (p 189) describe the susceptibility of the P450s to mechanism-based inactivation and explains how this phenomenon can be used to probe the enzymes’ active sites and to selectively inactivate specific isoforms to alter drug metabolism or toxicity. Gillam (p
20 Years of Toxicology As part of its 20th anniversary celebration, Chemical Research in Toxicology invited experts in some of the hottest fields to share their perspectives on the most important developments over the past 20 years. The result is this issue, a compenPublished online Published on Web 01/21/2008 © 2008 American Chemical Society
220) goes a step further, describing how P450s can be engineered to alter their substrate specificity, cofac•
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tor requirements, and tolerance to changing environmental conditions. She posits the fascinating possibility that enzymes may be produced that will serve specific functions such as selective organic synthesis or bioremediation. The induction of gene expression of selected P450 isoforms is a consequence of activation of the aryl hydrocarbon receptor (AHR). Yet, as Nguyen and Bradfield (p 102) explain, data from Ahr null mice suggest that this receptor is also im-
portant for vascular developmentandmayserveother physiologic functions. They go on to summarize efforts to search for endogenous AHR ligands, an intriguing ongoing puzzle. The consequences of cytochrome P450 metabolism are legion, as illustrated by
Bolton and Thatcher (p 93), who propose that P450dependent activation of endogenous or exogenous estrogens leads to the generation of reactive quinones that mediate DNA damage targeted by the estrogen receptor. This mechanism may explain the association between hormone replacement therapy for menopause and gynecologic cancers. Similarly, a significant role for P450-mediated activation of tobacco carcinogens is described by Hecht (p 160), who goes on to relate how the identification of key components of tobacco smoke has led to the development of biomarkers, allowing an assessment of the risk of secondhand smoke and a major alteration in societal attitudes to smoking exposure. Of course, not all bioactivation is due to cytochromes P450, as illustrated by Anders (p 145) in his comprehensive description of glutathione-dependent bioactivation of halogencontaining compounds. Regardless of the mechanism,
Celebrating the PastsMoving into the Future! In 2008, Chemical Research in Toxicology embarks on its third decade of service to the toxicology community. The January issue celebrates the past 20 years with a compendium of perspectives on important areas of toxicology as they have evolved since CRT’s inception. We also introduce our expanded format with new features, In this issue, which highlights selected articles each month, and Spotlight, aimed at keeping you informed of interesting developments in the field. Plus, we have expanded our scope and our outlook. Do not miss our series of guest editorials from toxicologists around the world.
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In this issue however, Karlberg et al. (p 53) argue that bioactivation of allergens plays an important role in the pathogenesis of allergic contact dermatitis, and Uetrecht (p 84) asserts, with equal force, that bioactivation is a critical step in the development of most idiosyncratic drug reactions. Of course, not all molecules that are subject to bioactivation are drugs, but the role of bioactivation in drug toxicity is receiving increased interest in the pharmaceutical industry. Baillie (p 129) describes how new technologies and better understanding of pharmacokinetics, drug transporters, pharmacogenomics, and gene regulation have changed the approach to drug development. His article is complemented by that of Coen et al. (p 9), who describe the use of NMR-based metabonomics to evaluate mechanisms of xenobiotic toxicity, predict toxic responses, diagnose disease, and define the role of genetic and environmental effects on individual responses to exogenous and endogenous insults. Although much of what we know about the consequences of reactive electrophile formation comes from the study of xenobiotic metabolism, it is becoming increasingly evident that highly reactive and toxic species may also be generated by endogenous metabolic processes. This principle is beautifully illustrated by Uchida and Shibata (p 138) in their description of the biochemistry and toxicology of 15-deoxy∆12,14-prostaglandin J2. This nonenzymatic dehydration product of prostaglandin 6
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D2, a cyclooxygenase metabolite of arachidonic acid, has multiple biologic effects, largely attributed to its electrophilicity and consequent reaction with multiple cellular nucleophiles. Perhaps the most thoroughly studied target of reactiveelectrophiles,whether endogenous or exogenous, is DNA. As Delaney and Essigmann (p 232) relate, the study of the consequences of DNA modification by electrophiles has reached maturity,producingawealth of information, including methods for synthesizing modified DNA bases and producing specifically modified oligonucleotides, as well as double- and singlestranded vectors containing those oligonucleotides. Consequently, the mutagenicity, replication, and repair of specifically modified bases have now been explored, both in vitro and in vivo. A recent development in the field is outlined by Broyde et al. (p 45), who describe studies of the structure of native and adducted DNA both in solution and at the polymerase active site. Such studies hold great promise for explaining the effects of adducts on replication and mutagenicity.
Although the studies of DNA damage have largely focused on the purine and pyrimidine bases, Dedon (p 206) details the consequences of oxidative dam-
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age to the 2′-deoxyribose moiety. These studies show that sugar oxidations may lead to a wide range of outcomes, from strand breaks, to abasic sites, to actual adduct formation with the bases, and clearly demonstrate that these reactions must not be ignored when considering potential causes of DNA damage leading to mutagenesis. It is clear that direct damage to DNA by reactive electrophiles can be a major source of mutagenicity and carcinogenicity. However, as related by Salnikow and Zhitkovich (p 28), not all carcinogens act by inducing mutations. Specifi-
cally, metals such as nickel, arsenic, and chromium are known to cause specific forms of cancer in exposed workers; yet of the three, only chromium has been shown convincingly to produce mutagenic DNA adducts. The others appear to work by epigenetic mechanisms, such as alterations in DNA methylation and/or histone acetylation and by promoting disturbances in metabolism and redox balance within the cell. As the study of DNA damage has moved toward maturity, new interest has developed in the consequences of protein damage by reactive electrophiles. Liebler (p 117) describes how the use of modern proteomics techniques, including
adduct-specific antibodies, novel affinity probes, and shot gun mass spectrometry, is providing a way to explore the outcome of protein adduction and its relationship to cell toxicity. As the study of toxicology has increasingly moved its focus from xenobiotic agents to the products of endogenous metabolism, oxidative stress has taken center stage. It is now evident that derangements in oxidative metabolism produce an array of reactive species that can damage cellular constituents. Oxidative stress is believed to play a role in the pathophysiology of multiple human diseases, including the neurodegenerative diseases. Sayre et al. (p 172) summarize the data tying oxidative stress to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis. Factors, including reactive oxygen and nitrogen radicals produced in response to inflammation, a dyshomeostasis between redox-active and -inactive metals, and mitochondrial dysfunction vary in importance among the different diseases. It is clear that considerable progress has been made in the study of chemical toxicology over the past 20 years, and CRT is proud to have played a role in conveying many of these advances to the toxicology community. We thank all of the authors who participated in our 20th anniversary celebration by continuing to share their knowledge, insights, and experience with our readers. TX7003954
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