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Relevance of the incubation period in cytotoxicity testing with primary human hepatocytes

Relevance of the incubation period in cytotoxicity testing with primary human hepatocytes

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GU, Xiaolong, Wiebke ALBRECHT, Karolina EDLUND, Franziska KAPPENBERG, Jörg RAHNENFÜHRER, Marcel LEIST, Wolfgang MORITZ, Patricio GODOY, Cristina CADENAS, Jan G. HENGSTLER, 2018. Relevance of the incubation period in cytotoxicity testing with primary human hepatocytes. In: Archives of Toxicology. 92(12), pp. 3505-3515. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-018-2302-0

@article{Gu2018-12Relev-43583, title={Relevance of the incubation period in cytotoxicity testing with primary human hepatocytes}, year={2018}, doi={10.1007/s00204-018-2302-0}, number={12}, volume={92}, issn={0340-5761}, journal={Archives of Toxicology}, pages={3505--3515}, author={Gu, Xiaolong and Albrecht, Wiebke and Edlund, Karolina and Kappenberg, Franziska and Rahnenführer, Jörg and Leist, Marcel and Moritz, Wolfgang and Godoy, Patricio and Cadenas, Cristina and Hengstler, Jan G.} }

Moritz, Wolfgang 2018-10-19T09:11:32Z Rahnenführer, Jörg Hengstler, Jan G. Gu, Xiaolong Hengstler, Jan G. Albrecht, Wiebke Leist, Marcel Cadenas, Cristina Cadenas, Cristina 2018-10-19T09:11:32Z Godoy, Patricio Edlund, Karolina Albrecht, Wiebke Leist, Marcel Edlund, Karolina Relevance of the incubation period in cytotoxicity testing with primary human hepatocytes terms-of-use Moritz, Wolfgang Rahnenführer, Jörg Godoy, Patricio 2018-12 Gu, Xiaolong Kappenberg, Franziska Kappenberg, Franziska eng Primary human hepatocytes (PHHs) remain the gold standard for in vitro testing in the field of pharmacology and toxicology. One crucial parameter influencing the results of in vitro tests is the incubation period with test compounds. It has been suggested that longer incubation periods may be critical for the prediction of repeated dose toxicity. However, a study that systematically analyzes the relationship between incubation period and cytotoxicity in PHHs is not available. To close this gap, 30 compounds were tested in a concentration-dependent manner for cytotoxicity in cultivated cryopreserved PHHs (three donors per compound) for 1, 2 and 7 days. The median of the EC<sub>50</sub> values of all compounds decreased 1.78-fold on day 2 compared to day 1, and 1.89-fold on day 7 compared to day 1. Median values of EC<sub>50</sub> ratios of all compounds at day 2 and day 7 were close to one but for individual compounds the ratio increased up to almost six. Strong correlations were obtained for EC<sub>50</sub> on day 1 and day 7 (R = 0.985; 95% CI 0.960-0.994), day 1 and day 2 (R = 0.964; 95% CI 0.910-0.986), as well as day 2 and day 7 (R = 0.981; 95% CI 0.955-0.992). However, compound specific differences also occurred. Whereas, for example, busulfan showed a relatively strong increase on day 7 compared to day 1, cytotoxicity of acetaminophen did not increase during longer incubation periods. To validate the observed correlations, a publicly available data set, containing data on the cytotoxicity of human hepatocytes cultivated as spheroids for incubation periods of 5 and 14 days, was analyzed. A high correlation coefficient of EC<sub>50</sub> values at day 5 and day 14 was obtained (R = 0.894; 95% CI 0.798-0.945). In conclusion, the median cytotoxicity of the test compounds increased between 1 and 2 days of incubation, with no or only a minimal further increase until day 7. It remains to be studied whether the different results obtained for some individual compounds after longer exposure periods would correspond better to human-repeated dose toxicity.

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