title: Biomarker discovery by imaging mass spectrometry: transthyretin is a biomarker for gentamicin-induced nephrotoxicity in rat.
abstract: 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 (Ser(28)-Gln(146)) 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.
authors.affiliation: Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Hélène
authors.initials: H
authors.lastname: Meistermann
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Norris
authors.forename: Hans-Rudolf
authors.initials: HR
authors.lastname: Aerni
authors.forename: Dale S
authors.initials: DS
authors.lastname: Cornett
authors.forename: Arno
authors.initials: A
authors.lastname: Friedlein
authors.forename: Annette R
authors.initials: AR
authors.lastname: Erskine
authors.forename: Angélique
authors.initials: A
authors.lastname: Augustin
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: De Vera Mudry
authors.forename: Stefan
authors.initials: S
authors.lastname: Ruepp
authors.forename: Laura
authors.initials: L
authors.lastname: Suter
authors.forename: Hanno
authors.initials: H
authors.lastname: Langen
authors.forename: Richard M
authors.initials: RM
authors.lastname: Caprioli
authors.forename: Axel
authors.initials: A
authors.lastname: Ducret
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000737:chemistry; D015153:Blotting, Western; D005839:Gentamicins / Q000633:toxicity*; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D011228:Prealbumin / Q000737:chemistry / Q000378:metabolism*; D040081:Protein Array Analysis; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*
chemical_list: D015415:Biomarkers; D005839:Gentamicins; D011228:Prealbumin