Detection of the toxicity of a candidate compound at an early stage of drug
development is an emerging area of interest. It is difficult to determine all of
the effects of metabolism of a compound using traditional approaches such as
histopathology and serum biochemistry. The goal of a metabolomics approach is to
determine all metabolites in a living system, with the potential to detect and
identify biomarkers involved in toxicity onset. Here, we summarize the metabolic
fingerprints for detection and identification of metabolic changes and
biomarkers related to drug-induced toxicity using Fourier transform ion
cyclotron resonance mass spectrometry (FT-ICR MS).
Urinary metabolic fingerprinting with Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) was performed to monitor metabolic changes in an α-naphthylisothiocyanate (ANIT)-induced rat model of intrahepatic cholestasis and to investigate the relationships among metabolic changes, histopathology, and blood chemistry. ANIT was administered orally as a single dose of 100 mg/kg. Urine samples were collected predose (-31 to -24 hours) and postdose at 0-7, 7-24, 24-31, 31-48, 48-55, 55-72, and 72-96 hours, and serum samples were collected on days 1, 2, and 4 postdose. Increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin were seen on day 2. The negative ion profiles for urine samples collected after 7-24, 24-31, 31-48, and 48-55 hours differed from the predose profile based on principal component analysis. Onset of recovery was observed after 24-31 hours, when the urinary composition reverted toward the predose position. In conclusion, it is possible to monitor the progression of and recovery from drug-induced hepatotoxicity by urinary metabolic fingerprinting with FT-ICR MS and to search for potential biomarkers involved in intrahepatic cholestasis.
Metabolic fingerprinting of amniotic fluid from streptozotocin-induced diabetic pregnant rats was performed using Fourier transform-ion cyclotron resonance mass spectrometry. Some of the fetuses from the diabetic pregnant rats exhibited ventricular septal defect. The positive ion profiles of amniotic fluids from diabetes were different to those of the control rats. The alteration of biochemical composition in the diabetic amniotic fluid suggests the presence of potential biomarkers to indicate progression of malformation under the diabetic pregnancy.
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