An NMR-spectroscopy-based Metabonomic approach to the analysis of Bay41-4109,a novel anti-HBV compound, induced hepatotoxicity hi rats

摘要

An integrated metabonomics study using highresolution 1H NMR spectroscopy has been applied to investigate the biochemical composition of urine,serum,liver tissue aqueous extracts (acetonitrile/water) and liver tissue lipidic extracts (chloroform/methanol) obtained from Bay414109 treated rats (10,50,400mg ? kg-1 ? d-1 for 5 days,i. g.). Principal components analysis was used to visualize similarities and differences in biochemical profiles. The elevation of 3HB,lactate,2-hydroxy-acetol,hydroxymaleic acid and dglucose was found in the urine, and the levels of VLDL/LDL(CH2) n, VLDL/LDL-CH3 ,2-oxo-3-methyl-nvalerate,3-HB,lactate, pyruvate,taurine,3-aminoisovalerate,2-hydroxy-isovalerate in serum were increased significantly in 400mg ? -1 ? d-1 group. The predominant changes identified in liver tissue aqueous extracts included an increase in the signal intensities of lactate,3-amino-isovalerate, pyruvate,taurine,choline,TMAO and a reduction in the intensities of trytophan and d-glucose. In liver tissue chloroform/methanol extracts, there was a remarkably increase in many of the lipid signals including the triglyceride terminal methyl,methylene groups,and CH2CO,N+(CH3)3,CH2OPO2,CH2OCOR. The results showed that fatty acid metabolism disorder and mitochondrial inability might contribute to the hepatotoxicity of Bay41-4109. The application of 1H NMR spectroscopy to an array of biological samples comprising u-rine,serum and liver tissue extracts yields new insight into the hepatotoxicity of xenobiotics.