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 (N NK) is a potent lung carcinogen in mice, rats and Syrian golden hamste rs and a suspected human lung carcinogen. We have reported earlier tha t structural analogs of the naturally occurring pulmonary toxin 4-ipom eanol (IPO) were non toxic up to 50 mu mol/mouse. Because these analog s are in part structurally similar to NNK, they are expected to compet e for the same enzymes and/or reactive sites within DNA. Both NNK and LPO 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 a nd our investigation of four non-toxic IPO analogs as potential inhibi tors of NNK activation. The IPO analogs studied were 4-hydroxy-1-pheny l-1-octanone (4-HPO), 1,4-diphenyl-4-hydroxy-1-butanone (DPHB), 4-hydr oxy-1-phenylpentane (HPPentane) and amyl benzene (AB). When added to m icrosomal incubations of human liver cells at a concentration of 100 m u M, all of these compounds were strong inhibitors of NNK activation, decreasing the total alpha-hydroxylation of NNK, which is the main pat hway of activation, by 60-70% and preventing N-oxidation by 78-86%. (C ) 1998 Elsevier Science Ireland Ltd. All rights reserved.