Metabolomics in Toxicology: Preclinical and Clinical Applications

Metabolomics first burst into the toxicology arena approximately 10–12 years ago, experiencing rapid growth as a science in the intervening period (Fig. 1). Though metabolomics still trails the publication rates of its sister technologies, genomics and proteomics, it is closing the gap in terms of both the numbers of publications and the quality of those publications. One continuing source of confusion is differentiating the terms metabolomics, metabonomics, and metabolic profiling. Although metabonomics was the first term formally defined (Nicholson et al., 1999), the term metabolomics came into usage shortly thereafter (Fiehn, 2002). Metabolic profiling is used by some as a generic term to avoid confusion of the two aforementioned ‘‘omic’’ terms, but that phrase itself can be confused with the comprehensive metabolite analysis of xenobiotics, so it is debatable whether its use adds any clarity to the situation. Whatever the case, it is now clear that metabolomics is the term preferred by most practitioners (Fig. 1). Therefore, metabolomics will be used in this review with the understanding that it represents all three terms. For most people, the names can be used interchangeably, but the reader is still advised to utilize all three terms when performing literature searches. Now that we have determined what to call it, we need to define what it is. The literature is replete with fine-tuned definitions, but the most succinct definition still appears to be most appropriate, and that is that metabolomics is ‘‘the comprehensive and quantitative analysis of all metabolites’’ (Fiehn, 2001). Every word in that phrase could be subject to debate as no analytical technique can measure ‘‘all’’ metabolites and what exactly qualifies as a metabolite? Do dietaryderived metabolites qualify, what about gut flora–derived metabolites? Rather than wade into this academic argument, we will leave it to the reader to define metabolomics as he or she chooses. For the toxicologist, the important point is that a metabolomics approach has the potential to reveal novel biochemical sequelae of toxicant administration that can lead to mechanistic insights and identification of biomarkers of cause and/or effect. Furthermore, the technology has the potential to characterize models or disease states to provide biochemical bases for observed interactions with xenobiotics. Given the explosion of recent literature, this review will not revisit the origins of metabolomics to any extent but will focus on recent advances in the field. Although botanical, environmental, and nutritional applications of the technology have expanded with the field, there is now such a wealth of literature this review will not be able to cover those burgeoning areas of metabolomic research. After providing some historical perspective, this review focuses on the biomedical applications of metabolomic technology with emphasis on new analytical approaches, preclinical, and clinical applications of the technology, particularly those areas relevant to practicing toxicologists.