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Ellagic acid (EA), derived from fruit ellagitannins, is known to be antimutagenic and anticarcinogenic in various animal tumor models. In this study, EA at a dose of 4 g/kg diet inhibited multiplicity of tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice by 54%. This inhibition was dose related between 0.06 and 4.0 g/kg diet. In contrast, two related compounds, esculin and esculetin, had no effect on lung tumorigenesis. The biodistribution of EA was studied as a function of dose and time after gavage of EA. The levels of EA in the lung were directly proportional to the dose of EA between 0.2 and 2.0 mmol. The maximum level of EA, corresponding to 21.3 nmol/g, was observed 30 minutes after gavage with 2.0 mmol of EA/kg body wt, which corresponds to only 70 ppm of the administered dose. The levels in liver tissues were 10-fold lower and reached a maximum 30 minutes after gavage. At this interval, the blood level of EA was 1 nmol/ml. The inclusion of EA in cyclodextrin doubles the level of EA in lung tissues. These results demonstrate that EA localizes preferentially in lung tissues and confirm that EA administered orally can inhibit lung tumorigenesis.

Ellagic acid (EA) is generated by hydrolysis of ellagitannins present in fruit berries and edible nuts and grapes. Large doses of EA prevent lung tumorigenesis induced by the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice. In this study, we document the efficacies of the EA structural analogue (3,4,7,8-tetrahydroxy-6H-benzo[b,d]pyran-6-one) (analogue 1) to inhibit specific P450 activities, pulmonary metabolism of NNK in A/J mice, and NNK-induced mutations in Salmonella typhimurium. Mouse lung microsomes metabolized benzyloxyresorufin, a marker of cytochrome P450 2B1 activity, more extensively than methoxyresorufin or ethoxyresorufin. The EA analogue was more effective than EA in inhibiting dealkylation of the three alkoxyresorufins, suggesting that it is a nonspecific inhibitor of P450s. Mouse lung microsomes hydroxylate testosterone in the 7alpha and 6beta positions, suggesting contributions of P450 2A1 and P450 3A2 isozymes, respectively. Inhibition of both pathways was more effective with the EA analogue than with EA. Mouse lung explants metabolized NNK by alpha-carbon hydroxylation (activation) and pyridine N-oxidation (deactivation). Both pathways were inhibited when 100 microM EA was added to the culture medium. The EA analogue was a better inhibitor of the activation of NNK to electrophilic species than EA. Mouse lung microsomes activate NNK to intermediates mutagenic to S. typhimurium. Inhibition of NNK mutagenicity by EA or the EA analogue was 20 or 65%, respectively. The distribution of the EA analogue in lung and liver was determined following gavage with 1.7 mmol of the EA analogue. In the lung, a maximal level of EA analogue corresponding to 105 nmol was observed 30 min after administration of the analogue. The level in liver tissues was 4-fold lower than in the lung. Results of this study demonstrate that the EA analogue is more effective than EA in inhibiting the pulmonary activation of NNK and suggest that the EA analogue could be effective in preventing lung tumorigenesis.

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