Modulation of the mutagenicity and metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by phenolic compounds.

NNK is a potent environmental carcinogen generated during tobacco processing and smoking. The carcinogenic response to tobacco smoking is modulated by nutritional factors. In this study, liver microsomes from phenobarbital and beta-naphthoflavone-treated or control hamsters were used to assay the mutagenicity (Salmonella typhimurium TA1535) of NNK. Western analysis of these microsomal preparations revealed an increased expression of protein recognized by polyclonal antibodies specific for P-450 1A2 in beta-naphthoflavone-induced microsomes and P-450 2B1/2B2 in phenobarbital-induced microsomes. Both inducers significantly increased the mutagenicity of NNK. Metabolism of NNK by the three microsomal preparations was compared. Metabolites formed by methyl-hydroxylation of NNK by microsomes from control animals were significantly greater than those formed by alpha-methylene hydroxylation. Phenobarbital treatment had the greatest effect on alpha-methylene hydroxylation while beta-naphthoflavone had the greatest effect on methyl hydroxylation. The antimutagenic action of the polyphenolic compounds ellagic acid, esculetin and propyl gallate correlated with an inhibition of the metabolism of NNK. There were, however, differences in the effects of these compounds on specific pathways of NNK metabolism depending upon the microsomal enzyme induction treatment. This suggests that phenolic compounds have selective affinity for specific P-450 isozymes activating NNK.