Editorial pubs.acs.org/crt
Enzymology in Chemical Toxicology: Beyond P450s
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involved in the metabolic activation and detoxication of that compound, as well as the identity of the reactive intermediate that acts as the ultimate toxic form and the molecular target(s). Preliminary studies aimed at elucidating the mechanism of action of a toxin generally involve the identification of any reactive intermediate(s) and the enzymes involved in their formation as well as in their detoxication. These studies are initially performed in vitro using animal and human homogenates, and subsequent studies are performed in appropriate animal models to validate the conclusions derived from the in vitro studies. This virtual issue features a collection of papers that are concerned with the roles of non-P450 enzymes and other proteins in toxicology that were published within the past two years. In order to prepare this virtual issue, we surveyed all of the papers concerned with the enzymology related to the metabolism of toxic compounds. There were 62 papers describing the role of various P450s, and there were 58 papers about non-P450 enzymes and proteins. From these 58 papers on non-P450 proteins, we selected 16 papers to highlight in this virtual issue. Among the 16 papers highlighted here, you will find significant interest in oxidations (dehydrogenases, oxidases, peroxidases, and oxidoreductases), reductions (aldo-keto and thioredoxin), and conjugations (UDP-glucuronosyltransferases, sulfotransferases, and glutathione transferases). These papers also use a variety of different experimental approaches to investigate the enzymes involved in altering the efficacy of toxicants by catalyzing the bioactivation or detoxication. Many of the papers are aimed at elucidating mechanistic details at the molecular level. Readers of this virtual issue will certainly recognize the fact that there are numerous places where we need much more knowledge at the molecular level in order to truly understand the action of various toxicants. We hope that this very exciting collection of papers will inspire researchers in toxicology to apply the approaches described in these studies to their own enzymes of interest and identify other individuals with whom they may collaborate, leading to cutting edge studies in the field of chemical toxicology that will ultimately lead to manuscripts that may be submitted to CRT. We also hope this collection proves to be a useful reference for researchers interested in mechanisms of chemical toxicology and in applying the principles described here to their own studies on various potential toxicants. The collection can be viewed here: http://pubs.acs.org/page/vi/ beyondP450s.html.
oxicology is defined as the study of the adverse effects of compounds on living systems. These can be naturally occurring compounds in the environment, or they can be manmade chemicals (xenobiotics). Toxicology is concerned with two different aspects of toxicants: the first is the effect of the toxic compound on the body, and the second is the effect of the body on the toxic compound. Both of these play critical roles in determining the overall outcome of the exposure of living organisms to toxicants. This series of articles is concerned with the effects of the body on toxicants, and thus, it is primarily concerned with those enzymes that catalyze the biotransformation of toxicants and are often referred to as the drugmetabolizing enzymes. The drug-metabolizing enzymes are found in essentially all tissues in the human body and catalyze a wide variety of different reactions that can be categorized primarily as involving hydrolysis, oxidation, reduction, and conjugation. In general, the biotransformation of toxicants is accomplished by a limited number of enzymes having relatively broad specificities, although this is not always the case. It is now recognized that not all biotransformation reactions in the human body are catalyzed by mammalian enzymes. Some biotransformation reactions are catalyzed by the gut microflora, which are part of the microbiome. Metabolism of toxicants by the drug metabolizing enzymes can lead to significant alterations in the biological properties of that toxin. Metabolism can make a toxic compound less toxic (detoxification), or it can make it more toxic (bioactivation). Metabolism also has a significant effect on the rate of clearance of the toxin from the organism, thereby altering the overall exposure and the effective dose. In many cases, the toxicity is not due to the parent compound but due to a reactive metabolite that is formed by activation of the compound by one of the drug metabolizing enzymes. When a reactive intermediate is formed, it may then react with a target molecule resulting in toxicity, or it can then undergo detoxification catalyzed by a second enzyme, oftentimes a member of the family of conjugating enzymes. The biotransformation of some toxicants can result in the production of reactive oxygen species (ROS), which can cause cell toxicity through oxidative stress and lipid peroxidation. The toxic effects of ROS can be limited by a variety of different cellular enzymes. The balance between activation and detoxification by the biotransforming enzymes is oftentimes a key determinate of the response of an organism to a chemical toxicant. Although the cytochrome P450 family of enzymes has gained tremendous notoriety for its important role in the metabolic activation, as well as in the detoxication, of many naturally occurring and man-made toxicants, modern toxicology has identified the roles for many other types of enzymes and proteins in modulating the deleterious effects of many toxicants. Over the years, Chemical Research in Toxicology (CRT) has published numerous papers on the metabolic activation and detoxication of many toxicants and their mechanisms of action. A complete understanding of the mechanism by which any compound causes toxicity requires a knowledge of the enzymes © 2016 American Chemical Society
Paul F. Hollenberg
Department of Pharmacology, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, Michigan 48109-5632, United States Published: September 19, 2016 1365
DOI: 10.1021/acs.chemrestox.6b00263 Chem. Res. Toxicol. 2016, 29, 1365−1366
Chemical Research in Toxicology
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Editorial
AUTHOR INFORMATION
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Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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DOI: 10.1021/acs.chemrestox.6b00263 Chem. Res. Toxicol. 2016, 29, 1365−1366
