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Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE or “compound A”), a haloalkene degradant of the volatile anesthetic sevoflurane, is nephrotoxic in rats. FDVE bioactivation mediates the toxicity, but the molecular and cellular mechanisms of toxification are unknown. FDVE caused rapid and brisk changes in kidney gene expression, providing potential insights into mechanisms of toxicity, and potential biomarkers for nephrotoxicity.1 Nevertheless, it is unknown whether gene-expression changes are reflected in protein expression, or whether such tissue changes would be reflected in excreted urine proteins. This investigation was to evaluate FDVE effects on urine protein excretion using mass spectrometry.
After Animal Use Committee approval, male Fisher 344 rats (250–300 g) housed in individual metabolic cages received a single intraperitoneal injection of 0.25 mmol/kg FDVE, and all urine was collected daily for 1 wk, as described previously.2
The samples were labeled with iTRAQ reagents, and both the 4800 MALDI TOF/TOF Analyzer and the 4000 Q TRAP system (AB/MDS SCIEX) were used to acquire data in MS and MS/MS modes. Data were processed with MarkerView software and ProteinPilot Software (AB/MDS SCIEX).
The results demonstrate that FDVE causes certain alterations in urine protein/peptide excretion. Multiple components were differentially expressed in a time-dependent manner. Excretion of several endogenously excreted proteins was rapidly decreased by FDVE. Other native peptides showed increased excretion following FDVE, and then gradually decreased to pre-dose levels. Excretion of a third set of proteins/peptides, minimally or not detectable in controls, was upregulated following FDVE. Further experiments will be conducted to identify the protein/peptide markers using LC MALDI MS/MS and other technologies to further investigate the usefulness of MS for identifying biomarkers for FDVE nephrotoxicity.
Key to Abstract Numbering
Prefixes: P, Poster; RG, Research Group; SP, Scientific Session Presenter; EP, Educational Session Presenter.
Following the hyphen is the designated presentation day: S, Sunday; M, Monday; T, Tuesday.
Supported by NIH DK53765