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Toxicologic Pathology
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Articles

Metabolic Profiling as a Tool for Understanding Mechanisms of Toxicity

Christopher J. Clarke and John N. Haselden

Novartis Pharma AG, Basel, Switzerland

Correspondence: Address correspondence to: Dr. Christopher J. Clarke, Novartis Pharma AG, Preclinical Safety, WKL-105.4.21, CH-4002 Basel, Switzerland; email: christopher.clarke{at}novartis.com.

Metabolic profiling (metabolomics/metabonomics) is the measurement in biological systems of the complement of low-molecular-weight metabolites and their intermediates that reflects the dynamic response to genetic modification and physiological, pathophysiological, and/or developmental stimuli. The measurement and interpretation of the endogenous metabolite profile from a biological sample (typically urine, serum, or biological tissue extract) have provided many opportunities to investigate the changes induced by external stimuli (e.g., drug treatment) or enhance our knowledge of inherent biological variation within subpopulations. This article will focus on the basic principles of metabolic profiling and how the tools (nuclear magnetic resonance [NMR], liquid chromatography–mass spectrometry [LC-MS]) can be applied in toxicology and pathology. Metabolic profiling can complement conventional methodologies and other "omics" technologies in investigating preclinical drug development issues. Case studies will illustrate the value of metabolic profiling in improving our understanding of phospholipidosis and peroxisome proliferation. A key message will be that metabolic profiling offers huge potential to highlight biomarkers and mechanisms in support of toxicology and pathology investigations in preclinical drug development.

Key Words: Metabonomics • preclinical safety assessment/risk management • pathobiology • biochemistry • biomarkers

Abbreviations: ACMSD, amino-carboxy-muconate-semialdehydedecarboxylase • CAD, cationic amphiphilic drug • CCR5, chemokine receptor 5 • CSF, cerebrospinal fluid • GC, gas chromatography • HP, high performance • HPLC, high performance liquid chromatography • LBPA, lyso-bis phosphatidic acid • LC, liquid chromatography • MS, mass spectrometry • NMN, N-methyl-nicotinamide • NMR, nuclear magnetic resonance • PAG, phenyl acetyl glycine • PCA, principal component analysis • PP, peroxisome proliferation • PPAR, peroxisome proliferator activated receptor • QAPRT, quinolate phosphorlbosyl-transferase • RT, real time • RT-PCR, reverse transcriptase polymerase chain reaction • TSP, 1,1,2,2-d4 trimethylsilylproprionate • UP, ultra performance • 4PY, N-methyl-4-pyridone-3-carboxamide

Toxicologic Pathology, Vol. 36, No. 1, 140-147 (2008)
DOI: 10.1177/0192623307310947
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