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Molecular & Cellular Proteomics 5:1876-1886, 2006.
© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

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Other Diseases and Conditions

Biomarker Discovery by Imaging Mass Spectrometry

Transthyretin is a Biomarker for Gentamicin-induced Nephrotoxicity in Rat^*

Hélène Meistermann, Jeremy L. Norris, Hans-Rudolf Aerni, Dale S. Cornett, Arno Friedlein, Annette R. Erskine, Angélique Augustin, Maria Cristina De Vera Mudry, Stefan Ruepp, Laura Suter, Hanno Langen, Richard M. Caprioli and Axel Ducret^,¶

From the Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland and the Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee 37232

Adverse drug effects are often associated with pathological changes in tissue. An accurate depiction of the undesired affected area, possibly supported by mechanistic data, is important to classify the effects with regard to relevance for human patients. MALDI imaging MS represents a new analytical tool to directly provide the spatial distribution and the relative abundance of proteins in tissue. Here we evaluate this technique to investigate potential toxicity biomarkers in kidneys of rats that were administered gentamicin, a well known nephrotoxicant. Differential analysis of the mass spectrum profiles revealed a spectral feature at 12,959 Da that strongly correlates with histopathology alterations of the kidney. We unambiguously identified this spectral feature as transthyretin (Ser²⁸–Gln¹⁴⁶) using an innovative combination of tissue microextraction and fractionation by reverse-phase liquid chromatography followed by a top-down tandem mass spectrometric approach. Our findings clearly demonstrate the emerging role of imaging MS in the discovery of toxicity biomarkers and in obtaining mechanistic insights concerning toxicity mechanisms.

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