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

Toxicol Lett. 2007 Sep 28;173(3):161-7. doi: 10.1016/j.toxlet.2007.07.010. Epub 2007 Aug 2.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / toxicity*
  • Biomarkers / blood
  • Biomarkers / metabolism*
  • Biomarkers / urine
  • Chemical and Drug Induced Liver Injury
  • Dose-Response Relationship, Drug
  • Fatty Acids / metabolism
  • Lipid Metabolism / drug effects
  • Liver / drug effects
  • Liver / metabolism*
  • Liver Diseases / blood
  • Liver Diseases / metabolism*
  • Liver Diseases / urine
  • Magnetic Resonance Spectroscopy*
  • Male
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism
  • Pattern Recognition, Automated
  • Principal Component Analysis
  • Pyridines / toxicity*
  • Pyrimidines / toxicity*
  • Rats
  • Rats, Wistar
  • Toxicity Tests / methods*

Substances

  • Antiviral Agents
  • BAY 41-4109
  • Biomarkers
  • Fatty Acids
  • Pyridines
  • Pyrimidines