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Impact of interindividual differences in initial DNA repair capacity when evaluating DNA damage using extended-term cultures of human lymphocytes and the comet assay
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
In: Toxicology and applied pharmacologyArticle in journal (Refereed) Submitted
Identifiers
URN: urn:nbn:se:uu:diva-94940OAI: oai:DiVA.org:uu-94940DiVA: diva2:168970
Available from: 2006-10-06 Created: 2006-10-06Bibliographically approved
In thesis
1. Chemically Induced DNA Damage in Extended-term Cultures of Human Lymphocytes
Open this publication in new window or tab >>Chemically Induced DNA Damage in Extended-term Cultures of Human Lymphocytes
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Generation of DNA damage is regarded to be an important initial event in the development cancer. Consequently, a battery of tests have been developed to detect different types of genotoxic effects in order to be able to predict the potential genotoxicity and mutagenicity of chemicals, including both pharmaceutical drugs and various types of environmental and occupational agents, as well as dietary factors. The aim of this thesis was to evaluate whether the combination of the comet assay and the extended-term cultures of human lymphocytes (ETC) can be used as an alternative in vitro system to more commonly used transformed mammalian cell lines, and primary cell cultures from humans, when testing the potential genotoxicity of chemicals.

Using the comet assay, a panel of reference compounds showed that the ETC were found to detect the DNA-damaging effects with no remarkable difference to what has been reported in other cell types. Moreover, in comparison with a well-established rodent cell line, the mouse lymphoma L5178Y cells, the ETC showed similar sensitivity to the DNA damaging effects of the genotoxic agents hydrogen peroxide and catechol. Although there was an interindividual variation in induced DNA damage and the subsequent repair when using ETC from different blood donors, it did not seem to be of crucial importance for the identification of DNA-damaging agents. The demonstrated difference in sensitivity to catechol-induced DNA damage between freshly isolated peripheral lymphocytes and ETC may very well be due to their different proliferative status but despite this difference, both in vitro systems were able to identify catechol as a DNA-damaging agent at the same concentration.

Based on these results, it is proposed that the ETC and the comet assay are a useful combination when testing for the potential DNA damaging effects of chemicals. Representing easily cultivated cells possessing the normal human karyotype, where one blood sample can be used for numerous experiments performed over a long time, extended-term cultures appear to be a useful alternative, both to transformed mammalian cell lines, and primary cell cultures from humans. In fact, the extended-term lymphocytes, with or without S9 and/or lesion specific DNA repair enzymes, should be used more frequently when screening for the potential genotoxicity of chemicals.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 40 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 38
Keyword
Toxicology, Comet assay, DNA-damaging agents, DNA repair, Extended-term Cultures of Human Lymphocytes, Genotoxicity, Induced DNA damage, In vitro, Mouse Lymphoma Cells, Primary Cell Cultures, Reactive Oxygen Species, Toxikologi
Identifiers
urn:nbn:se:uu:diva-7179 (URN)91-554-6674-5 (ISBN)
Public defence
2006-10-27, B42, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-10-06 Created: 2006-10-06Bibliographically approved

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