GADD45a-GFP GreenScreen HC genotoxicity screening assay

Abstract

Background: Genetic toxicology is getting very interesting. The International Conference on Harmonisation has drafted new guidance that allows for the registration of pharmaceuticals without the submission of data from in vitro mammalian genotoxicity tests (in vitro micronucleus test, chromosomal aberrations, mouse lymphoma assay). These tests often produce falsely positive predictions of genotoxic carcinogenicity. Objectives: This article reviews the properties of the Gadd45a-GFP (green fluorescent protein) assay, for which positive results appear to provide more reliable predictions of genotoxic carcinogenicity. The criteria for assessment of genotoxicity assays are reviewed. Consideration is given to the value of genotoxicity hazard assessment early in pharmaceutical discovery. Methods: Peer-reviewed data have been reviewed, as well as information contributed to the public domain through conference presentations. Results/conclusion: The Gadd45a assay is increasingly used as a screening tool, and has utility in the prioritisation of Ames-negative compounds prior to in vivo genotoxicity assessment.

Keywords::

• aneugens
• carcinogenicity
• clastogens
• genotoxicity
• hazard
• mutagens
• safety
• screening

Acknowledgements

N Billinton and D Tweats are thanked for their critical reading of the manuscript, and D Kirkland is thanked for the quotations. The opinions are those of the author. BBSRC, NC3Rs and Gentronix Ltd are acknowledged for their support of research underpinning the development of the Gadd45a-GFP assay.