Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in human hepatic microsomes by ipomeanol analogs - An exploratory study

The tobacco-specific 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen in mice, rats and Syrian golden hamsters and a suspected human lung carcinogen. We have reported earlier that structural analogs of the naturally occurring pulmonary toxin 4-ipomeanol (IPO) were non toxic up to 50 μmol/mouse. Because these analogs are in part structurally similar to NNK, they are expected to compete for the same enzymes and/or reactive sites within DNA. Both NNK and IPO are primarily metabolized by cytochrome P450 enzymes in the Clara cells of the lung but also in the liver. We describe here the optimal conditions for the study of NNK metabolism in human liver microsomes and our investigation of four non-toxic IPO analogs as potential inhibitors of NNK activation. The IPO analogs studied were 4-hydroxy-1-phenyl-1-octanone (4-HPO), 1,4-diphenyl-4-hydroxy-1-butanone (DPHB), 4-hydroxy-1-phenylpentane (HPPentane) and amyl benzene (AB). When added to microsomal incubations of human liver cells at a concentration of 100 μM, all of these compounds were strong inhibitors of NNK activation, decreasing the total α-hydroxylation of NNK, which is the main pathway of activation, by 60-70% and preventing N-oxidation by 78-86%.