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  • Title: Modulation of 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone demethylation and denitrosation by rat liver microsomes.
    Author: Castonguay A, Pepin P, Briere N.
    Journal: Cancer Lett; 1991 Jul 26; 59(1):67-74. PubMed ID: 1878861.
    Abstract:
    The nicotine-derived N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK) is abundant in tobacco smoke and is a potent carcinogen in laboratory animals. We have characterized and compared methyl hydroxylation leading to formaldehyde formation (activation pathway) and denitrosation (putative deactivation pathway) of NNK using rat liver microsomes. Methyl hydroxylation was linear between 10 and 50 min and denitrosation was linear between 20 and 65 min. The ratio of nitrite/formaldehyde formation was smaller with 4 mM NNK (0.016) than with N-nitrosodimethylamine (NDMA) (0.037). Liver microsomes exhibited at least two apparent Km values (0.005 and 0.534 mM) for NNK methyl hydroxylation. In vitro methyl hydroxylation of NDMA and NNK were induced by pretreatment of the rat with isopropanol. Butylated hydroxytoluene pretreatment doubled the rate of microsomal denitrosation but did not affect the rate of methyl hydroxylation (+)-Catechin is a flavonoid present in tea, wine and apple skin. We observed that 0.10 mM (+)-catechin inhibited methyl hydroxylation and denitrosation of 4 mM NNK by 40% and 62%, respectively. These results indicated that NNK could be deactivated by denitrosation. Hydroxylation of the NNK methyl group by rat liver microsomes was 34 times more extensive than denitrosation.
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