Research in NOVEMBER/DECEMBER 1993 VOLUME 6, NUMBER 6 0 Copyright 1993 by the American Chemical Society
Commentary Frontiers in Molecular Toxicology For the past several years, Chemical Research in Toxicology has published a Forum in the last issue of each volume. The Forums contained contributions from authors with different perspectives on a controversial research area. They have provided some very interesting and important discussions. This year we decided to take a somewhat different tack and use these perspectives to highlight research advances at the frontiers of molecular toxicology. Contributions were solicited in the areas of analytical chemistry, gene regulation, molecular epidemiology, and mechanisms of mutagenesis and toxicity. The first two perspectives highlight frontiers of mass spectrometry and computer technology applied to toxicology. Mass spectrometry now provides more and more information on smaller and smaller amounts of material; the limit of detection is in the attomole range. Furthermore, as Ian Blair points out in his perspective, the application of mass spectrometric methods is no longer limited to small molecules but is increasingly yielding important information on nucleic acids and proteins. Spectacular advances in computerization have contributed to quantum leaps in analytical capabilities, but it should also be recognized that computers themselves are being increasingly applied to toxicological problems. The perspective by Bill Milne and Shaomeng Wang demonstrates how computers can organize and analyze reams of toxicological data and relate them to chemical structure. Although this field is in its infancy, it is obvious that the sheer power of computers to perform calculations clearly exceeds the capabilities of the human mind and may provide new understandings of complex toxicological data sets. Structure-activity studies linking toxicological effects to particular chemical structures are an important area of research with clear human health implications. 0893-228~19312706-0739$04.00/0
Another exciting research area in toxicology is the identification of mechanisms by which chemicals induce mutations or kill cells. Here again our technological capabilities are awesome even when compared to those of ten years ago. Methods are now available to identify functionally important moleculeswhich can then be cloned and overexpressed to provide large amounts of protein for structural and functional studies. Site-direded mutagenesis of proteins or incorporation of unnatural amino acids can facilitate these mechanistic investigations. Molecular biological approaches can also be used to study the regulation of expression of critical genes. For example, molecular biological studies have revealed that there are many cytochromes P450 which play a role in metabolism of foreign chemicals. Cytochrome P4501A1 has been the focus of much activity because it is induced by a wide range of chemicals, among which dioxin is the most potent, and because it plays an important role in the metabolic activation of PAH carcinogens. The perspective by Jim Whitlock highlights recent advances in the understanding of the regulation and function of this important protein. A central dogma of toxicology is that biological effects result from modification of macromolecules. We can now identify these molecular targets and-determine how chemical modification affects their function at a precise molecular level. For example, once a compound is known to be mutagenic, one can combine chemical and molecular biological approaches to determine the structure of the adducts it forms to DNA, incorporate these adducts into viral genomes, and determine their mutation profile. One can also study the structure of the adducts in duplex oligonucleotides and their interaction with replication and repair proteins. Thus, one can precisely tie the structure of a chemical adduct to its biological consequences. Furthermore, by applying a variety of analytical methods, 0 1993 American Chemical Society
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one can quantitate the levels of biologically significant adducts in target tissues. The relation of structure to function is fundamental to the evolving discipline of molecular epidemiology which attempts to quantitate the level of toxin-macromolecular conjugates in target tissues. Tom Kensler and John Groopman review the recent advances in molecular dosimetry that underlie this quantitative approach to human risk assessment. Much of human disease is self-inflicted toxicology. We are often done in by what we eat, drink, breathe, or smoke. It is generally assumed that all the damage is a result of exposure to exogenous chemicals, and current risk assessment efforts are based on this assumption. It has recently been discovered that chemical adducts exist in DNA from normal animals and human beings which appear to be derived from chemicals produced endogenously. Developments in this field are forcing a re-evaluation of strategies for risk assessment to consider this base line of DNA damage. They are reviewed in the article by Phil Burcham and myself. Understanding the chemistry and biology of macromolecular adducts with DNA is much further ahead than for protein adducts. However, the window is beginning to open on the chemistry and biology of protein adducts.
Marnett Several investigators have utilized what is known about the structuresof reactive derivatives of chemical toxins in combination with immunological methods to identify the in vivo protein targets of these reactive intermediates. It will not be long before we have a catalog of the proteins modified in target tissues by particular toxins and the consequences of their alteration. These advances are reviewed by Lance Pohl. The topics in this year’s Forum were chosen from a list provided by our Editorial Advisory Board. Space precluded inclusion of many equally interesting topics that were suggested. The difficulty the Editors had in choosing these six articles is a tribute to the vigor and excitement of contemporary toxicology. The application of chemistry and molecular biology is solving old research problems and opening new ones at a phenomenal rate. Sometimes, the speed with which data are acquired exceeds our ability to interpret them. This, however, is only a temporary problem that is healthy for the development of toxicology and its application to the prevention of human disease.
Lawrence J. Marnett Editor
