Urinary metabolic fingerprinting for alpha-naphthylisothiocyanate-induced intrahepatic cholestasis in rats using Fourier transform-ion cyclotron resonance mass spectrometry.
Urinary metabolic fingerprinting with Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) was performed to monitor metabolic changes in an alpha-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.
Hasegawa
Mina
M
Department of Veterinary Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan.
Ide
Mika
M
Fujita
Takuya
T
Takenaka
Shigeo
S
D015058:1-Naphthylisothiocyanate / Q000008:administration & dosage / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000737:chemistry / Q000652:urine*; D002780:Cholestasis, Intrahepatic / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D017357:Cyclotrons; D005583:Fourier Analysis; D008099:Liver / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D009676:Noxae / Q000008:administration & dosage / Q000633:toxicity; D025341:Principal Component Analysis; D051381:Rats
D015415:Biomarkers; D009676:Noxae; D015058:1-Naphthylisothiocyanate; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin