The evaluation of drug safety and toxicology has benefited in recent years from biomarker applications, particularly in the area of biomarker discovery. As the number of drugs and drug targets grows, there is a commensurate need for readily measurable markers that can provide an early indicator of undesirable side effects. Indeed, the battery of established markers that can currently be measured in preclinical toxicology studies and in the clinic can all be considered broadly as biomarkers of toxicity71; however, there remains a need for additional biomarkers that can serve as indicators of potential toxicity at the earliest possible time, and in a manner that is specific to a given target, pathway, or drug chemotype. The emphasis on toxicity biomarker identification has led to a convergence of a number of disciplines focused on this area; key among these are genomics,72'73 proteomics,74 metabonomics,49'50 and bioinformatics.75 The ability of these approaches to efficiently evaluate vast numbers of endpoints simultaneously and to sort and correlate large amounts of information can impact toxicology studies in the same manner as in applications in target characterization or pharmacology studies. An emerging paradigm has been the investigation of well-characterized agents with known toxicant profiles in specific, well-established systems; molecular profiles generated by such agents in the appropriate organ or other biological compartment can then be used as comparators for the evaluation of previously uncharacterized agents, to query whether profiles match or to what extent. This is a challenging field given the daunting number of existing agents and of mechanisms of toxicity; however, as databases expand and profiling technologies are refined there is reason to expect considerable progress to be made in coming years.
Some examples of toxicity biomarker discovery efforts are worth noting as cases in point. An early gene expression profiling effort in toxicology applied oligonucleotide microarrays in a rat study of a panel of well-studied compounds and led to identification of response profiles of drug metabolism, metabolic effect, and stress response genes; some of these were previously characterized or otherwise verified by qRT-PCR.76 In an interesting twist of profiling for toxicant or drug metabolic response transcripts, a variant approach has been described as a means to select for potential targets that are specific to drug effect in a target tissue and not coincidentally up- or downregulated as part of a drug absorption, distribution, metabolism, and excretion (ADME) pharmacokinetic response pathway; by restricting screening of transcripts to those that are not expressed in cells derived from ADME-related tissues (liver, colon, and kidney), this may provide a means to more selective potential targets or target-specific biomarkers.77 At the same time, the catalog of transcripts that are expressed in ADME-related tissues may be of utility in potential toxicity marker discovery. Meanwhile, increasing emphasis is being placed on the use of surrogate tissues to allow monitoring of toxic effects in accessible compartments such as the peripheral blood or hair follicle rather than in internal organs.78 Metabonomic analysis of an accessible biological fluid has been applied effectively in an investigation of urine markers of vasculitis; here the effect of a phosphodiesterase known to induce vasculitis in rats was assessed in urine samples, followed by principal components analysis which led to a pattern that could separate cases with vasculitis from those without.79 Imaging technologies can also be used to assess biomarkers of toxicity; rather than detecting endogenous biomarkers, noninvasive assays utilizing transgenic reporter molecules can be applied in vivo. An example is an approach wherein a transfected luciferase reporter gene under control of the heme oxygenase-1 promoter serves as a bioluminescent reporter probe for toxicant effects in the liver and other tissues.80 Reiterative testing in preclinical model systems as well as validation studies in both preclinical species and ultimately in the clinic will be critical in establishing the true utility and applicability of biomarkers of drug toxicity as well as in the refinement of large numbers of putative biomarkers into the simplest panels that are sufficiently informative and robust.
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