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Effect of ellagic acid on hepatic and pulmonary xenobiotic metabolism in mice: studies on the mechanism of its anticarcinogenic action.

Our recent studies have shown that ellagic acid, a naturally occurring dietary plant phenol, protects BALB/c mice against 3-methylcholanthrene-induced skin tumorigenesis. To further elucidate the mechanism of the antineoplastic action of ellagic acid its effect on hepatic and pulmonary benzo[a]pyrene (BP) metabolism, cytochrome P-450-dependent monooxygenases and glutathione S-transferase activities were studied in BALB/c mice. Chronic oral feeding of the compound in drinking water (0.3 mg/l for 16 weeks) or acute intraperitoneal administration (50 mg/kg for five consecutive days) of ellagic acid resulted in 20-25% decreases in hepatic and pulmonary cytochrome P-450 levels. Hepatic and pulmonary aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase activities in both groups of ellagic acid-treated animals were 33-52% and 28-43% lower than their respective non-ellagic acid-treated controls. Hepatic as well as pulmonary aminopyrine N-demethylase and epoxide hydrolase activities were unchanged in both groups of ellagic acid-treated mice. Hepatic glutathione S-transferase activity towards BP-4,5-oxide or 1-chloro-2,4-dinitrobenzene as substrates was found to be enhanced 51-79% and 38-58% in both groups of animals. H.p.l.c. analysis of organic solvent-soluble metabolites of BP by liver and lung microsomes indicated a substantial inhibition of diol formation (including BP-7,8-diol), as well as of phenols and quinones. In liver, these inhibitory effects were more pronounced after oral feeding than after intraperitoneal administration. Our results indicate that both acute and chronic administration of ellagic acid inhibits BP metabolism and/or enhances glutathione S-transferase activity. Thus the modulation of polycyclic aromatic hydrocarbon metabolism by ellagic acid may be related to the anticarcinogenic effects of this compound.