Effect of methylxanthines on acetaminophen hepatotoxicity in various induction states

The effect of caffeine, theophylline and theobromine on acetaminophen-induced hepatotoxicity was evaluated in uninduced, 3-methylcholanthrene- and phenobarbital-induced adult male Sprague-Dawley rats. The methylxanthines themselves did not cause hepatotoxicity in any induction state. In 3-methylcholanthrene-induced rats, each methylxanthine afforded protection (in varying degrees) against acetaminophen-induced hepatotoxicity as reflected by serum alanine aminotransferase and liver histopathology determined 24 hr after acetaminophen administration. However, in phenobarbital-induced rats, caffeine and theophylline substantially potentiated the hepatotoxicity of acetaminophen whereas theobromine had no effect. Hepatic glutathione (GSH) was determined in rats that received caffeine 4 hr after acetaminophen or vehicle. Acetaminophen alone substantially depleted hepatic GSH in each induction state, whereas caffeine depleted hepatic GSH in uninduced and phenobarbital-induced, but not in 3-methylcholanthrene-induced rats. In rats that received both caffeine and acetaminophen together, hepatic GSH depletion was greater than in rats that received acetaminophen only. The effect of caffeine on hepatic GSH is most likely due to a decrease in core body temperature. The most likely mechanisms for the effects observed are 1) inhibition of acetaminophen reactive metabolite formation in 3-methylcholanthrene-induced animals by each of the methylxanthines, and 2) activation of the phenobarbital-inducible forms of cytochrome(s) P-450 toward formation of acetaminophen reactive metabolites by caffeine and theophylline, but not theobromine.