Detection of in vivo biomarkers of phospholipidosis using NMR-based metabonomic approaches

The application of high-field H-1 NMR spectroscopy to the analysis of biological fluids has proved to be a valuable approach to toxicological screening. Coupled with data reduction and chemometric analyses, this technology has a high capacity for elucidating relevant metabolic information pertaining to the nature and mechanism of toxic processes in an organism. This approach is encapsulated in the concept of metabonomics, which is defined as 'the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification', and can be regarded as complementary to studies of the genome (genomics) and the proteins in an organism (proteomics). Here the metabonomics approach to drug toxicity evaluation is exemplified using H-1 NMR spectroscopy to investigate the biochemical perturbations in urine after dosing Fischer rats with the cationic, amphiphilic drugs chloroquine, amiodarone and DMP 777, a neutrophil elastase inhibitor. These drugs are known to induce phospholipidosis, characterized by lysosomal lamellar body and drug accumulation. Using a metabonomic approach, combinations of specific urinary biomarkers were identified for each compound, together with a putative general marker of phospholipidosis, phenylacetylglycine. Furthermore, in the case of chloroquine, clear evidence of hepatotoxicity was determined. Copyright (C) 2001 John Wiley & Sons, Ltd.