title: Modulation of the activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by hamster liver microsomes to protein alkylating species.
abstract: During incubation with hamster liver microsomes, the tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was metabolized by alpha-carbon hydroxylation, pyridine N-oxidation and carbonyl reduction. The modulation of the activation of NNK to intermediates, alkylating microsomal proteins, by some compounds related to tobacco smoke, P-450 inhibitors, thiol and alcohol compounds, has been determined. Binding of both the pyridyloxobutyl and the methyl moieties of NNK was inhibited by more than 40% by N'-nitrosonornicotine or N-nitrosodimethylamine. In contrast, nicotine and 3-acetylpyridine inhibited only the binding of the pyridyloxobutyl moiety. Binding of both moieties of NNK was not inhibited by its deactivation metabolite, the NNK-N-oxide. Whereas the P-450 inhibitors metyrapone, [2-(diethylamino)ethyl 2,2-diphenyl pentenoate]hydrochloride and piperonyl butoxide inhibit the binding of the pyridyloxobutyl moiety selectively, carbon monoxide inhibits the binding of both moieties. Metyrapone reduced alpha-carbon hydroxylation but not pyridine N-oxidation, suggesting that in hamster livers pyridine N-oxidation is not mediated by P-450-dependent monooxygenases. The binding of the pyridyloxobutyl and methyl moieties was partially dependent on the presence of NADPH in the incubation mixture. Glutathione had no effect on the metabolism of NNK but inhibited the enzymatic and non-enzymatic binding of its pyridyloxobutyl moiety. It is concluded that the binding of NNK-derived intermediates to cellular proteins is inhibited by various substances present in tobacco smoke and by inhibitors of P-450 monooxygenases. Only part of this binding is enzymatically mediated.
authors: Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec City, Canada G1K 7P4.
authors: A
authors: A
authors: Castonguay
authors: G
authors: G
authors: Rossignol