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Urinary Metabolic Fingerprinting for -naphthylisothiocyanate-induced Intrahepatic Cholestasis in Rats Using Fourier Transform-ion Cyclotron Resonance Mass Spectrometry

¹ Department of Veterinary Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
² Exploratory Toxicology and DMPK Research Laboratories, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan

Correspondence: Shigeo Takenaka, Ph.D., Department of Veterinary Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan; e-mail;takenaka{at}vet.osakafu-u.ac.jp.

Urinary metabolic fingerprinting with Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) was performed to monitor metabolic changes in an -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.

Key Words: intrahepatic cholestasis • hepatotoxicity • metabolomics • FT-ICR MS • ANIT • rat • urine

Abbreviations: ALT, alanine aminotransferase • ALP, alkaline phosphatase • AST, aspartate aminotransferase • FT-ICR MS, Fourier transform-ion cyclotron resonance mass spectrometry • GC, gas chromatography • HE, hematoxylin-eosin • HA, hippurate • LC, liquid chromatography • MS, mass spectrometry • NMR, nuclear magnetic resonance • PAG, phenylacetylglycine • PC, principal component • PCA, principal component analysis • SORI-CID, sustained off-resonance irradiation collision-induced dissociation • TA, taurocholic acid • TBIL, total bilirubin

This version was published on October 1, 2008

Toxicologic Pathology, Vol. 36, No. 6, 818-826 (2008)
DOI: 10.1177/0192623308323622


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