抄録
The primary objective of this study was to discover surrogate biomarkers which are correlated with hepatotoxicity induced by acetaminophen (APAP) using urinary and plasma proton nuclear magnetic resonance (1H NMR) spectral data. A procedure of 1H NMR urinalysis using pattern recognition was proposed for early screening of the hepatotoxicity of APAP in humans. The hepatotoxicity was tested through clinical chemistry. APAP (3 g/day, two 500-mg tablets every 8 h) was administered to 20 healthy males (20-29 yr) for 7 days and urine was collected daily before and during dosing and 6 days after final dosing. All the subjects didn’t show significant changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GTP), and lactate dehydrogenase (LDH) by APAP compared to before treatment. However, urinary metabolite profiles were obtained from subjects showing mild liver injury, as indicated by increase in ALT or AST to a level more than 1.7-fold the before treatment. 1H NMR spectroscopy revealed evidently different clustering between pre-dosing and APAP treatment in global metabolomic profiling through principal component analysis (PCA) and partial least aquare (PLS)-discrimination analysis (DA). In targeted profiling, urinary endogenous metabolites of trimethylamine-oxide, citrate, 3-chlorotyrosine, phenylalanine, glycine, alanine, taurine, betaine, glutarate, glutamine, and dimethylamine were significantly changed by APAP, while plasma metabolites of lactate, ethanol, isoleucine, choline, N-acetylglycine, and creatine were significantly changed. These results might be applied to predict or screen potential hepatotoxicity caused by drugs using urinary and plasma 1H NMR analysis.
