In situ mass spectrometry imaging and ex vivo characterization of renal crystalline deposits induced in multiple preclinical drug toxicology studies

PLoS One. 2012;7(10):e47353. doi: 10.1371/journal.pone.0047353. Epub 2012 Oct 23.

Abstract

Drug toxicity observed in animal studies during drug development accounts for the discontinuation of many drug candidates, with the kidney being a major site of tissue damage. Extensive investigations are often required to reveal the mechanisms underlying such toxicological events and in the case of crystalline deposits the chemical composition can be problematic to determine. In the present study, we have used mass spectrometry imaging combined with a set of advanced analytical techniques to characterize such crystalline deposits in situ. Two potential microsomal prostaglandin E synthase 1 inhibitors, with similar chemical structure, were administered to rats over a seven day period. This resulted in kidney damage with marked tubular degeneration/regeneration and crystal deposits within the tissue that was detected by histopathology. Results from direct tissue section analysis by matrix-assisted laser desorption ionization mass spectrometry imaging were combined with data obtained following manual crystal dissection analyzed by liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical composition of the crystal deposits was successfully identified as a common metabolite, bisulphonamide, of the two drug candidates. In addition, an un-targeted analysis revealed molecular changes in the kidney that were specifically associated with the area of the tissue defined as pathologically damaged. In the presented study, we show the usefulness of combining mass spectrometry imaging with an array of powerful analytical tools to solve complex toxicological problems occurring during drug development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatography, Liquid
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Female
  • Intramolecular Oxidoreductases / antagonists & inhibitors
  • Kidney / metabolism*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry / methods*
  • Prostaglandin-E Synthases
  • Rats
  • Toxicology

Substances

  • Enzyme Inhibitors
  • Intramolecular Oxidoreductases
  • Prostaglandin-E Synthases

Grant support

This study was sponsored by the Swedish Research Council (http://www.vr.se), grant no. 2008-5597, 2009-6050, 2010-5421, and the K&A Wallenberg Foundation (http://www.wallenberg.com/kaw/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscripts.