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Mutagenesis vol. 19 no. 1 pp. 51-59, January 2004
© 2004 UK Environmental Mutagen Society/Oxford University Press

Use of the alkaline in vivo Comet assay for mechanistic genotoxicity investigations

Andreas Hartmann, Martin Schumacher1,{dagger}, Ulla Plappert-Helbig2,{dagger}, Phil Lowe1,{dagger}, Willi Suter2 and Lutz Mueller2,{dagger}

Preclinical Safety, 1Modeling and Simulation and 2Genetic Toxicology and Functional Validation, Novartis Pharma AG, CH-4002 Basel, Switzerland

The alkaline Comet assay was used to investigate the in vivo genotoxicity of 17 compounds. Altogether 21 studies were conducted with these compounds. The investigations were triggered for various reasons. The main reason for performing the studies was to evaluate the in vivo relevance of in vitro genotoxicity findings with 10 compounds. Eight of these compounds showed no effects in the in vivo Comet assay while two compounds induced altered DNA migration patterns in specific organs. The remaining seven compounds were tested to follow up on neoplastic/preneoplastic or chronic toxicity changes as detected in specific target organs identified in rodent studies, to investigate the possibility of site-of- contact genotoxicity and to test the liver as a target organ for a suspected reactive metabolite. For the studies, various organs of rodents were analyzed, depending on the suspected properties of the compounds, including liver, jejunum, leukocytes, stomach mucosa, duodenum, lung and kidney. All tissues were amenable to investigation by gel electrophoresis after simple disaggregation of organs by means of mincing or, in the case of epithelial cells from the gastrointestinal tract, scraping off cells from the epithelium. In conclusion, the Comet assay was found to be a reliable and robust test to investigate in vivo genotoxicity in a variety of rodent organs. Therefore, it is concluded that in vivo Comet assay data are useful for elucidating positive in vitro genotoxicity findings and to evaluate genotoxicity in target organs of toxicity.

3To whom correspondence should be addressed. Tel: +41 61 32 45619; Fax: +41 61 32 49843; Email: andreas.hartmann{at}pharma.novartis.com
{dagger}Declaration of interest. A.Hartmann holds stock in Novartis Pharma AG and is an employee of the company; M.Schumacher and P.Lowe hold stock in Novartis Pharma AG and are currently conducting research sponsored by this company; U.Plappert-Helbig and L.Mueller are employees of Novartis Pharma AG whose compounds and their effects are described in this article

Received on July 25, 2003; revised on September 24, 2003; accepted on September 29, 2003


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