Gene expression profiles on acetaminophen-induced liver toxicity in rat using microarray technology

Abstract

microarray analysis of RNA from acetaminophen (APAP)-administered rat livers was performed at avarious time points to establish a global gene expression profile. A single dose of 1 g/kg of APAP was given by ip injection, and the liver smaples were obtained after 0 h, 24 h, 48 h, and 2wk. Histopathollogic studies of liver tissues enabled the classification of the APAP effect into early (24h and 48 h) and late (2wk) stages. The expression levels of 5,148 clones on a custom rat gene microarray were analyzed and the results were comfirmed by semi-quantitative RT-PCR. Teh greatest changes, hepatocellular degeneration and necrosis, were observed at 24 h and 48 h. by 2wk, severity of lesions had sgnificantly decreased. Significant alterations in gene expression, both positive and netgative, were noted within the livers of APAP-treated rat. GEne related to liver functions such as glycogen metabolism, chloesterol biosynthesis, fatty acid synthesis and gluconeogenesis were repressed by APAP in both early and late stages. Moreover, we observed a repression in mitochondrial-spcific genes such as acyl-CoA dehydrogenses and 2,4 dienoyl-CoA reductase at 24h. In contrast, a number of oxidative response genes and cytoplasmic ribosomal proteins were increased in APAP-treated livers at 24h and 48 h. These results suggest that mitochondirial damage and oxidative stress are identified as the principle mechanisms in APAP-mediated hepatotoxicity. In conclusion, these data provide new directions for mechanistic studies that may lead to a better understanding of the moleculat basis of APAP-induced liver injury. This work was supported by the grant from the National Institute of Toxicology Research, Korea (to Gu Kong).