Evaluation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) mutagenicity using in vitro and in vivo Pig-a assays

Publication date: Available online 29 October 2018Source: Mutation Research/Genetic Toxicology and Environmental MutagenesisAuthor(s): Roberta A. Mittelstaedt, Vasily N. Dobrovolsky, Javier R. Revollo, Mason G. Pearce, Yiying Wang, Azra Dad, Page B. McKinzie, Hans Rosenfeldt, Berran Yucesoy, Raymond Yeager, Shu-Chieh Hu, Yunan Tang, Seonggi Min, Hyun-Ki Kang, Dong-Jin Yang, Mallikarjuna Basavarajappa, Robert H. HeflichAbstract4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a genotoxic carcinogen found in tobacco and tobacco smoke. Several in vitro and in vivo assays have been used for evaluating the genotoxicity of tobacco smoke and tobacco smoke constituents like NNK, yet it is not clear which in vitro assays are most appropriate for extrapolating the in vitro responses of these test agents to animal models and humans. The Pig-a gene mutation assay can be performed in vitro, in laboratory animals, and in humans, a potential benefit in estimating in vivo responses from in vitro data. In the current study we used Pig-a as a reporter of gene mutation both in vitro, in L5178Y/Tk+/- cells, and in vivo, in Sprague-Dawley rats. NNK significantly increased Pig-a mutant frequency in L5178Y/Tk+/- cells, but only at concentrations of 100 µg/ml and greater, and only in the presence of S9 activation. Pig-a mutations in L5178Y/Tk+/- cells were detected in 80% of the NNK-induced mutants, with the predominate mutation being G→A transition; vehicle control mutants contained dele...
Source: Mutation Research Genetic Toxicology and Environmental Mutagenesis - Category: Genetics & Stem Cells Source Type: research