| ABSTRACT: |
|
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. |