A genotoxin is a substance that either permanently alters DNA (mutagenicity) or alters a cell’s ability to regulate DNA structure and content. Mutation or damage to DNA may or not result in a permanent change in its content or structure, depending on several factors including DNA repair, metabolism, apoptosis, and oxidative stress defence mechanisms.
While generally regulated as a toxicity endpoint in its own right, genotoxicity is actually a set of modes of action that can lead to adverse outcomes such as cancer, inherited mutations and diseases, developmental toxicity and ageing. As such, testing for potential genotoxic properties is often one of the first things a toxicologist will do to rule out safety hazards or to shape a risk assessment for a new chemical or product.
The inclusion of genetic toxicology into the early drug discovery phase is a key step in both improving the safety profile of the chemical series under development and increasing the chances of project success by avoiding late-stage toxicology failures. Incorporating mode-of-action assessments at these early stages helps inform where an adverse genotoxicity result is observed, enabling toxicologists to determine the risks associated and whether the chance of program success is impacted.
Our BlueScreen HCTM assay utilises the human-derived, p53 competent, TK6 cell line that has been stably transfected to express a GADD45a-Gaussia luciferase reporter construct. When these cells are exposed to genotoxic substances, the resulting upregulation of the GADD45a gene leads to an accumulation of Gaussia luciferase and a detectable luciferase signal that is proportional to levels of DNA damage. Operated in a 96-well microplate this assay delivers prediction of all mechanisms of genotoxicity in a 48 hr assay format, using as little as 5 mg of compound and providing high sensitivity and specificity.
Our MultiFlow®️ genotoxicity screening assay uses flow cytometry techniques to deliver powerful biomarker prediction of genotoxicity and determination of whether the mode-of-action is indicative of a Clastogen or Aneugen. Using biomarkers of p53, H2AX, H3 and polyploidy, this assay is capable of screening multiple compounds and delivering statistical prediction of mechanism using machine learning strategies.
Our combination of the 24-well Ames and 96-well in vitro micronucleus tests enables all mechanisms of genotoxicity to be assessed in methods consistent with the regulatory battery, across responsive timelines and using minimal test item amounts. Incorporating FISH techniques into the MNT screen enables centromeres to be labelled and positive results to be assigned a clastogenic or aneugenic mechanism.
These screening services deliver a comprehensive prediction of genetic toxicology, optimised for use in the early stages of drug discovery to deliver quick and highly accurate results, boosting the chances of success.