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Metabolism, Sister Chromatid Exchanges, and DNA Single-Strand Breaks Induced by 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and Their Modulation by Vitamin A in Vitro¹

School of Pharmacy, Laval University, Quebec, Canada G1K 7P4

The nicotine-derived N-nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is abundant in smokeless tobacco and tobacco smoke and is hepatocarcinogenic in F344 rats. We have investigated how vitamin A modulates sister chromatid exchanges and DNA single-strand breaks induced by NNK. In V79 cells, vitamin A at concentrations ranging from 34.9 to 139.6 µM inhibited sister chromatid exchange frequencies induced by 20 mM NNK activated by primary rat hepatocytes. Sister chromatid exchanges were inhibited by 24, 44, and 55% when cells were cotreated with 34.9, 69.8, and 139.6 µM vitamin A, respectively. DNA single-strand breaks induced by NNK in rat hepatocytes were also inhibited by vitamin A. After 9 h of elution, DNA single-strand breaks induced by 1, 5, and 10 mM NNK were inhibited by 13, 5, and 3.5% in the presence of 69.8 µM vitamin A, respectively. This protective effect by vitamin A was associated with a reduction of -carbon hydroxylation, an activation pathway of NNK. This pathway was inhibited by 50% when cells were cotreated with 3.49 µM vitamin A. The reduction in the hepatic microsomal aminopyrine N-demethylase, aniline hydroxylase, and N,N-dimethyl aniline N-demethylase in the presence of vitamin A (0.035 to 0.35 µM) suggests that vitamin A could reduce NNK genotoxicity by inhibiting the enzymes involved in the activation process.

¹ This study was supported by grants from the Cancer Research Society, Inc. (Canada), and the Medical Research Council of Canada (MA-8691). M. A. A-J. is a postdoctoral fellow of the Canadian Lung Association. Animals were treated according to the guidelines adopted by the Canadian Council on Animal Care.

² Present address: Department of Oncology, Montreal General Hospital Research Institute, McGill University, 1650 Cedar Ave., Montreal, Quebec, Canada H3G 1A4.

³ To whom requests for reprints should be addressed.

Received 4/26/91. Accepted 5/15/91.

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