
Predictive genotoxicity and mutagenicity of drugs using liver-on-a-chip
Predictive genotoxicity and mutagenicity of drugs using liver-on-a-chip
Liver-on-a-chip (LOC) models are increasingly recognized as a powerful tool in drug development. These models replicate the complex environment of the human liver, offering a more accurate representation of how drugs and their metabolites interact with human tissues. As the pharmaceutical industry moves towards reducing reliance on animal testing, LOC models are key to preclinical testing, especially in evaluating possible genetic hazards.
A recent paper published by Kopp et al. exemplifies the enormous potential of liver-on-a-chip in this context. The study details developing and applying a specific LOC model designed to assess the drug’s genotoxicity.
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Assessing several genotoxic endpoints in one model
The liver-on-a-chip enormous promise lies in its ability to mimic the liver’s metabolic processes. Many drugs require metabolic activation to exert their therapeutic effects or, conversely, to reveal their toxic potential. Traditional in vitro assays, mainly based on 2D primary human hepatocyte (PHH) cultures, lack metabolic complexity, missing these effects and leading to incomplete safety profiles.
LOC addresses this gap by incorporating PHHs within a microfluidic system that simulates the dynamic environment of the liver, including blood flow and nutrient exchange, and conserving hepatocyte functionality and differentiation. In this specific case, PHHs were co-cultured with human lymphoblastoid (TK6), a cell type widely used for in vitro genetic toxicology evaluation.
Regulatory guidelines for drug safety require the assessment of three main genotoxic endpoints: gene mutations, chromosomal aberrations caused by chromosome breakage, and chromosome loss. The traditional approach to genotoxicity testing involves a combination of in vitro and in vivo assays to cover all these endpoints, which is time-consuming and may involve using animal models.
By co-culturing hepatocytes with other cell types, such as TK6 lymphoblastoid cells, the authors assessed multiple genotoxic endpoints simultaneously. In this model, hepatocytes retain their metabolic capabilities, allowing to test either direct-acting genotoxicants such as methyl methanesulfonate (MMS) or genotoxicants requiring metabolic activation, such as benzo[a]pyrene (B[a]P) or cyclophosphamide (CP).
The LOC model was useful for evaluating DNA strand breaks in hepatocytes using the comet assay. It could also assess chromosome damage and mutations in TK6 cells using assays like the micronucleus test and advanced sequencing techniques like Duplex Sequencing (DS).
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Advantages of liver-on-a-chip models to assess drug genotoxicity
LOC offers a significant advantage by potentially consolidating diverse assessments into a single, more human-relevant test system.
The predictive power of the LOC model is further enhanced by its ability to maintain long-term cultures, allowing for the assessment of chronic drug exposure. This is particularly important for identifying genotoxic effects that might only emerge after prolonged exposure, which is often the case in clinical stages of drug development. The model’s capacity to simulate repeated dosing and its ability to maintain the functional state of primary hepatocytes over extended periods make it a robust tool for evaluating the long-term safety of pharmaceutical compounds.
Organ-on-a-chip aligns with the growing regulatory acceptance of alternative methods to animal testing. The recent FDA Modernization Act 2.0 encourages using non-animal models, like LOC, for drug testing. This shift reduces the ethical concerns associated with animal testing and promises to improve the translatability of preclinical findings to human outcomes.
Providing a more accurate and human-relevant drug safety assessment streamlines the drug development process, reduces reliance on animal testing, and ultimately leads to safer pharmaceuticals.
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BeCytes is your partner to line your organ-on-a-chip model
In a joint effort to make organ-on-a-chip an integral part of the drug safety assessment toolkit, BeCytes has joined the UNLOOC project to provide lung and liver primary cells for organ-on-a-chip development. This international project, which accounts for more than 50 partners, aims to develop, optimize, and validate organ-on-a-chip systems to replace the need for animal and in-human testing in drug discovery, clinical testing, and validation.
If you also need primary liver cells for your liver-on-a-chip, check out our extensive portfolio. If you do not find the cell type you are looking for, BeCytes has also specialized in procuring fresh human tissue for cell isolation.
We are currently working on isolating lung cells to offer them completely characterized and ready to use in our portfolio. They will be available very soon.
We can also isolate a wide variety of cell types under request for specific models.
Contact us and speed up your research!
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References
European Medicines Agency. ICH S2 (R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use: Scientific Guideline [Internet]. 2012 [cited 2024 Sep 16]. Available from: https://www.ema.europa.eu/en/ich-s2-r1-genotoxicity-testing-data-interpretation-pharmaceuticals-intended-human-use-scientific-guideline
Kopp B, Khawam A, Di Perna K, Lenart D, Vinette M, Silva R, Zanoni TB, Rore C, Guenigault G, Richardson E, Kostrzewski T, Boswell A, Van P, Valentine Iii C, Salk J, Hamel A. Liver-on-chip model and application in predictive genotoxicity and mutagenicity of drugs. Mutat Res Genet Toxicol Environ Mutagen. 2024 May-Jun;896:503762. doi: 10.1016/j.mrgentox.2024.503762.
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