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

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• 作者：Chang Shi ; Chun-qi Wu ; An-min Cao ; He-Zhang Sheng ; Xian-zhong Yan ; Ming-yang Liao
• 关键词：Bay41-4109 ; Hepatotoxicity ; Metabonomics ; ¹H NMR spectroscopy ; Pattern recognition
• 刊名：Toxicology Letters
• 出版年：2007
• 出版时间：28 September 2007
• 年：2007
• 卷：173
• 期：3
• 页码：161-167
• 全文大小：444 K

文摘

An integrated metabonomics study using high-resolution ¹H 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, 400 mg·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 400 mg·kg⁻¹·d⁻¹ are different from those induced at 10, 50 mg·kg⁻¹·d⁻¹. The biochemical profiles of 400 mg·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(CH₂)_n, VLDL/LDL-CH₃, 2-oxo-3-methyl-n-valerate, 3-HB, lactate, acetate, taurine, 2-hydroxy-isovalerate in serum were increased significantly in 400 mg·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 CH₂CO, N⁺(CH₃)₃, CH₂OPO₂, CH₂OCOR. These observations all provide evidence 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 urine, serum and liver tissue extracts yields new insight into the hepatotoxicity of xenobiotics.