PerspectiVe Potentialities and Pitfalls Accompanying Chemico-Pharmacological Strategies against Endogenous Electrophiles and Carbonyl Stress Philip C. Burcham Pharmacology and Anaesthesiology Unit, School of Medicine and Pharmacology, the UniVersity of Western Australia, Nedlands, WA 6009, Australia ReceiVed NoVember 8, 2007 The use of powerful analytical technologies to detect endogenous carbonyls formed as byproducts of oxidative cell injury has revealed that these species contribute to many human diseases. As electrophiles, they are attacked by reactive centers in cell macromolecules to form adducts, the levels of which serve as useful biomarkers of oxidative cell injury. Because the pathobiological significance of such damage is often unclear, the possibility of using low molecular weight drugs as exploratory sacrificial nucleophiles to intercept reactive carbonyls within cells and tissues is appealing. This perspective highlights the potential benefits of using carbonyl scavengers to evaluate the significance of endogenous carbonyls in particular diseases but also canvasses a number of challenges confronting this therapeutic strategy. Chief among the latter is the task of confirming that carbonyl sequestration underlies any suppression of disease symptoms elicited by these multipotent reagents, an issue needing clarification if these compounds are to command consideration as drug interventions in humans. Other problems include adverse consequences of reactions between carbonyl scavengers and important endogenous carbonyls (e.g., neurotoxicity due to pyridoxal depletion), as well as the potential for drugs to form ternary complexes with carbonylated cell proteins, raising the prospect of immunotoxicological outcomes. Strategies for moving carbonyl sequestering reagents from the laboratory bench to a clinical testing environment are discussed within the context of the search for new treatments for spinal cord injury, one of the most debilitating medical conditions sustainable by humans. This condition seems an appropriate test case for assessing carbonyl sequestering drugs given growing evidence for noxious carbonyls in the wave of neuronal cell death that follows traumatic injury to the spinal cord. Contents 1. Introduction 779 2. Electrophilic Carbonyls and Human Disease 780 3. Potential of Carbonyl Scavengers as Biological Probes 780 4. Pitfalls Accompanying Use of Carbonyl Scavengers 781 4.1. Biological Relevance of Data from Cell-Free Systems 781 4.2. Need for Druglike Physicochemical Properties 781 4.3. Robust Criteria for In Vivo Carbonyl Scavenging Activity 782 4.4. Side Effects Due to Nonspecific Carbonyl Depletion 782 4.5. Drug Reactions with Carbonyl-Adducted Proteins 782 4.6. Metabolic Fate of Scavengers 782 4.7. Cytoprotective Actions Unrelated to Carbonyl Sequestration 783 5. Moving Carbonyl Scavengers from the Test Tube to the Clinical Testing Laboratory 783 6. Disease Focus: Spinal Cord Injury and Carbonyl Stress 783 7. Conclusion 784 1. Introduction The opening essay in the recent Future of Toxicology series published by CRT articulated a key challenge facing modern toxicology in terms of its standing within the broader biomedical research community (1). This concern centers on a perceived feeling among nontoxicologists that knowledge gained from longstanding efforts to characterize risks accompanying exposure to xenobiotics is of questionable etiological relevance to the diseases that take the greatest toll on 21st century public health. On this view, toxicologists are guilty of preoccupying them- selves with chemicals that are of dubious significance to obesity, diabetes, neurodegeneration, and other conditions that afflict aging populations. Countering this perception, Liebler argued for expanding the horizons of the toxicological enterprise to include noxious chemicals of endogenous origin, contending that the conceptual tools and methodologies of molecular toxicology are well-suited to investigating the role of endog- enous electrophiles in common diseases (1). While this approach deservedly finds growing support among toxicologists, it may nonetheless be subject to its own conceptual challenges and epistemic uncertainties. Chem. Res. Toxicol. 2008, 21, 779–786 779 10.1021/tx700399q CCC: $40.75  2008 American Chemical Society Published on Web 02/15/2008