HepaRG

A significant limitation of the currently validated cell lines used in regulatory genetic toxicology is that these cells lines do not express key xenobiotic metabolizing Phase I and Phase II enzymes. Metabolically competent human HepaRG cells are emerging as human centric genetic toxicology New Approach Methodology cell-based test system for use as a follow up to positive response observed in the regulatory genetic toxicology test battery. Multiple endpoint genetic toxicology assessment in HepaRG cells quantifying the identical in vivo regulatory genotoxicity endpoints integrated with mechanistic transcriptomicshave the potential to reduce reliance on rodent testing to assess the impact of xenobiotics on genome integrity and human relevance. In this study, three direct acting genotoxic compounds that cause chromosomal damage by either DNA adducts ethyl methanesulfonate, cisplatin) or by effecting topoisomerases (etoposide) were positive.Two of three genotoxic compounds that require bioactivation by either CYP1A1 (benzo(a)pyrene) and the most common human CYP450 involved in drug metabolism CYP3A4 (cyclophosphamide, aflatoxin B1) were positive, howeveraflatoxin B1 was cytotoxic but did not induce MN. Two compounds (d-limonene and urea) were negative using the top dose criteria outlined in OECD 487 to assess if cytotoxicity would lead to non-specific genotoxic responses. These data and others indicate that the HepaRG cell MN assay cells meet OECD acceptance criteria and can serve as a genetic toxicology NAM aimed at reducing and replacing reliance on rodent based testing as the only follow up bioassays to positive results from the in vitro genetic toxicology bioassays.