Mechanism of ketone-induced protection from acetaminophen hepatotoxicity in the rat.

The effects of ketones on acetaminophen metabolism and hepatotoxicity were investigated in male rats. Ketosis was produced by oral administration of either acetone or 1,3-butanediol. Histologic studies revealed that both ketogenic agents conferred protection from acetaminophen-induced liver necrosis. Pharmacokinetic studies indicated that both acetone and 1,3-butanediol: a) increased the blood half-life of acetaminophen, b) markedly decreased the apparent rate constant for formation of acetaminophen mercapturate, and c) modestly decreased the capacities for acetaminophen sulfate formation and renal elimination of the drug. Neither acetone nor 1,3-butanediol had any effect on either the apparent rate constant for formation of acetaminophen glucuronide or on the predrug levels of hepatic glutathione. However, after a large dose of acetaminophen, the rate and percentage of glutathione depletion were markedly less in 1,3-butanediol-treated rats and modestly less in acetone-treated rats as compared with controls. These data indicate that acetone- or 1,3-butanediol-induced ketosis confers protection from hepatic necrosis due largely to decreased formation of the reactive metabolite. The effects of ketosis and of diabetes on acetaminophen metabolism and hepatotoxicity are compared.