NMR-spectroscopy-based metabonomic approach to the analysis of Bay41-4109, a novel anti-HBV compound, induced hepatotoxicity in rats.

An integrated metabonomics study using high-resolution (1)H nuclear magnetic resonance (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 control and Bay41-4109 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 results showed the effects induced by Bay41-4109 at 400mg.kg(-1).d(-1) are different from those induced at 10, 50mg.kg(-1).d(-1). The biochemical profiles of 400mg.kg(-1).d(-1) group might reflect the hepatotoxicity of Bay41-4109 more exactly. The elevation in the level of 3-HB, lactate, 2-hydroxy-acetol and d-glucose was found in the urine, and the levels of VLDL/LDL(CH(2))(n), VLDL/LDL-CH(3), 2-oxo-3-methyl-n-valerate, 3-HB, lactate, acetate, taurine, 2-hydroxy-isovalerate in serum were increased significantly in 400mg.kg(-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, choline, trimethylamine-N-oxide (TMAO) and a reduction in the intensities of taurine, hippurate 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 CH(2)CO, N(+)(CH(3))(3), CH(2)OPO(2), CH(2)OCOR. These observations all provide evidence that fatty acid metabolism disorder and mitochondrial inability might contribute to the hepatotoxicity of Bay41-4109. The application of (1)H NMR spectroscopy to an array of biological samples comprising urine, serum and liver tissue extracts yields new insight into the hepatotoxicity of xenobiotics.

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Chang Shi, Chun-Qi Wu, An-Min Cao, He-Zhang Sheng, Xian-Zhong Yan, Ming-Yang Liao. NMR-spectroscopy-based metabonomic approach to the analysis of Bay41-4109, a novel anti-HBV compound, induced hepatotoxicity in rats. Toxicology letters. 2007 Sep 28;173(3):161-7

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PMID: 17826925

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