Abstract
Metabolomic data in rat plasma samples administered with hepatotoxicants in Toxicogenomics Informatics Project (TGP2), an industry-government-academia joint research in Japan were analyzed. The results shown that localization specific changes in necrotic hepatocyte were observed in some metabolites. 5 hepatotoxicants (N-nitrosodiethylamine [DEN], ethionamide [ETH], thioacetamide [TAA], metapyrylene [MP], acetaminophen [APAP]) were orally administered to rats for 7 or 14 consecutive days. Plasma samples collected 24 hours after last dosing were comprehensively analyzed for metabolites using CE-TOFMS, and 223 metabolites were identified and quantified. An increase in glutamine (Gln) concentrations and a decrease in glutamate (Glu) concentrations in plasma were simultaneously observed only in MP-treated rats. A Gln/Glu ratio in plasma increased also in the same group. On the other hand, an increase in urea concentrations in plasma was observed in all hepatotoxicants-treated rats except for low of dose DEN- and TAA-treated rats. In TGP2-archived histopathology data, hepatocyte necrosis is observed in periportal zone in MP-treated rats and the change is observed in perivenous zone in the other hepatotoxicant-treated rats. In detoxication process of ammonia in the liver, ammonia convert to urea in periportal hepatocytes, and glutamate is converted to glutamine as detoxication of ammonia in perivenous hepatocytes. Taken together, a change of ammonia detoxication pattern show from urea synthesis to glutamine synthesis in MP-treated rats and inverse change was observed in the other groups. Interestingly, both changes were simultaneously observed in MP-treated rats. Accordingly, an increase in a Gln/Glu ratio in plasma will be a useful biomarker as prediction of hepatotoxicity localization (hepatocyte necrosis in periportal zone).
