Abstract: BACKGROUND AND AIM:To study the hepatotoxicity and its probable mechanism(s) of a novel anti-HBV compound, Bay41-4109, using microarray technology. MATERIALS AND METHODS: Male Wistar rats were fed Bay41-4109 orally for 5 days. And Phenobarbital (PB), one of the typical inducers of CYP450, was used as a positive control in the study. The liver/body weight ratios and histological examination were conducted. In in vitro studies, the cytotoxicity of Bay41-4109 on HepG2 cells was detected using MTT chromometry. Then the effects of Bay41-4109 on liver gene expression profile in male Wistar rats and cultured HepG2 cells were both investigated with rat whole genome chip and human whole genome chip, respectively. Cluster analysis and the functions of differential expression genes were then analyzed. Some of the differential expression genes were authenticated by RT-PCR. RESULTS: The liver/body weight ratios were increased significantly, and focal necrosis was found in the liver in both Bay41-4109 and PB treated animals. The differential expression genes induced by Bay41-4109 were mainly related to drug metabolism, fat and energy metabolism, and 26 of them were similar to those induced by PB. In in vitro studies, the differential expression genes in HepG2 cells induced by Bay41-4109 at IC20 and IC50 concentrations were mainly relevant to fat, amino acids, energy metabolism, which coincided with the in vivo study. The differential expression genes could be authenticated by RT-PCR. CONCLUSION:The abnormal metabolism of fat and energy, and abnormal expression of CYP450 contributed to the hepatotoxicity of Bay41-4109.

Key words: Bay41-4109, HepG2, gene chip, hepatotoxicity