Intraperitoneal injection of ethionine to male rats for up to 12 days caused a pronounced fall in S-adenosylmethionine (AdoMet) in liver, but did not or only slightly affect AdoMet in kidney and spleen. Liver and to a lesser degree kidney showed a dose-dependent, massive accumulation of the metabolic product, S-adenosylethionine (AdoEth), and this metabolic response was most pronounced within the first days of exposure. Trace amounts of AdoEth was demonstrated in the spleen. Both S-adenosylhomocysteine (AdoHcy) and homocysteine (Hcy) in the liver were markedly increased in a dose- and time-dependent manner. There was a moderate increase in Hcy content in spleen and kidney, whereas the AdoHcy levels in these tissues were not affected. The amount of reduced glutathione (GSH) was significantly increased in liver and kidney. This response in liver was evident within 2 days of ethionine exposure and then leveled off whereas there was a gradual increase in GSH in kidney. The GSH content in spleen was unaltered. In addition to a massive build-up of AdoEth, the unique features of the metabolic response of the liver are a pronounced decrease in the AdoMet/AdoHcy ratio (from 15 to 2) associated with an elevated Hcy content and a rapid increase in the amount of GSH. The possibility that the metabolic response of the liver could be assigned to the existence of isozymes or metabolic pathways unique to hepatic cells is discussed.