Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by hamster respiratory tissues cultured with ellagic acid

Add time:08/12/2019    Source:sciencedirect.com

Previous studies have shown that the nicotine-derived N-nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces tracheal papillomas and lung carcinomas in Syrian golden hamsters: In this study, we showed that hamster tracheal and lung explants metabolize NNK by α-carbon hydroxylation, pyridine N-oxidation and carbonyl reduction. α-Methylene hydroxylation and methyl hydroxylation yield methylating and pyridyloxobutylating intermediates, respectively. Levels of binding of the pyridyloxobutyl moiety to explant proteins was 200 times lower than the total amount of metabolites formed by α-carbon hydroxylation and released in the culture medium. Viable and heat-treated lung explants were cultured with [CH3-3H]NNK or [5-3H]NNK. In viable explants, the rate of binding of the methyl group was 2-fold higher than the rate of binding of the pyridyloxobutyl moiety of NNK. Heat treatment reduced 54-fold the binding of [CH3-3H] NNK but only 5-fold the binding [5-3H]NNK. Tracheal explants were cultured with [5-3H]NNK (5.6 μM) and ellagic acid (EA, 10 μM), a naturally-occurring plant phenol. EA did not inhibit any of the three metabolic pathways nor the binding of the pyridyloxobutyl moiety to explant proteins. Lung explants were cultured with NNK (3.7 μM) and with or without EA (100 μM). EA inhibits α-carbon hydroxylation by 19% and the overall metabolism of NNK by 6%. Formation of 7-methylguanine and O6-methylguanine was observed in lung explants and the levels of both adducts were reduced by EA (100 μM). These results suggest that high concentrations of EA modulate the metabolism of NNK and that NNK does not necessarily require enzymatic activation to bind to protein.

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