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Mutagenesis Advance Access originally published online on July 10, 2009
Mutagenesis 2009 24(5):455-463; doi:10.1093/mutage/gep029
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© The Author 2009. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Analysis of 75 marketed pharmaceuticals using the GADD45a-GFP ‘GreenScreen HC’ genotoxicity assay

Paul W. Hastwell*, Thomas W. Webster, Matthew Tate1,2, Nicholas Billinton2, Anthony M. Lynch, James S. Harvey, Robert W. Rees and Richard M. Walmsley1,2

Genetic Toxicology, GlaxoSmithKline plc, Park Road, Ware, Hertfordshire SG12 0DP, UK 1Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK 2Gentronix Ltd, CTF Building, 46 Grafton Street, Manchester M13 9NT, UK

The GADD45a-GFP (GreenScreen HC) reporter assay detects genotoxic damage in the human lymphoblastoid TK6 cell line and gives positive results for all classes of genotoxin, including mutagens, aneugens and clastogens. In this study, a collection of 75 marketed pharmaceuticals were tested in the assay. Compounds in the collection represent a broad range of chemical structures, pharmacologies and therapeutic indications, including neoplasia and viral infection where positive genotoxicity results are often associated with the pharmacological activity. Based on the results of this study, two main conclusions can be drawn: (i) the GreenScreen HC is more predictive of in vivo genotoxicity (88%) and genotoxic carcinogenicity (93%) data than the any of the other regulatory in vitro genotoxicity assay and (ii) no compounds were uniquely positive in the GADD45a-GFP assay. This analysis therefore provides additional evidence to support the use of the GADD45a-GFP assay as an effective tool either in early genotoxic liability identification or non-clinical safety assessment of candidate pharmaceuticals during development.

* To whom correspondence should be addressed. Tel: +44 1920 88 2750; Fax: +44 1920 88 2679; Email: paul.w.hastwell{at}gsk.com

Received on December 23, 2008; revised on March 12, 2009; accepted on June 15, 2009.


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