Critical differences in drug metabolic properties of human hepatic cellular models, including primary human hepatocytes, stem cell derived hepatocytes, and hepatoma cell lines

Kvist, Alexander J.; Kanebratt, Kajsa P.; Walentinsson, Anna; Palmgren, Henrik; O'Hara, Matthew; Björkbom, Anders; Andersson, Linda C.; Ahlqvist, Marie; Andersson, Tommy

doi:10.1016/j.bcp.2018.06.026

Cited by 43 publications

(31 citation statements)

References 39 publications

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“…However, the CYP 3A4 activity was still about 1.5-fold higher in human hepatocytes in 2 out of 3 individuals compared to DMSO treated HepaRG cells as determined by measuring the clearance of the CYP 3A4 probe substrate midazolam (Kanebratt and Andersson 2008). Other studies also showed that P450 activities such as CYP 1A2, CYP 2B6, CYP 2C8, CYP 2C9, CYP 2C19 and CYP 2D6 were generally lower in HepaRG cells than in human hepatocytes, except for CYP 3A4 showing a generally 1.5-fold higher activity in HepaRG cells (Kvist et al 2018;Lubberstedt et al 2011). However, Gerets et al (2012) reported that CYP 3A4 activity was about 17.0-fold lower in the HepaRG cells than in freshly isolated human hepatocytes from three different donors.…”

Section: Discussionmentioning

confidence: 96%

Use of an in vitro–in silico testing strategy to predict inter-species and inter-ethnic human differences in liver toxicity of the pyrrolizidine alkaloids lasiocarpine and riddelliine

et al. 2019

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Lasiocarpine and riddelliine are pyrrolizidine alkaloids (PAs) known to cause liver toxicity. The aim of this study was to predict the inter-species and inter-ethnic human differences in acute liver toxicity of lasiocarpine and riddelliine using physiologically based kinetic (PBK) modelling based reverse dosimetry of in vitro toxicity data. The concentration-response curves of in vitro cytotoxicity of lasiocarpine and riddelliine defined in pooled human hepatocytes were translated to in vivo dose-response curves by PBK models developed using kinetic data obtained from incubations with pooled tissue fractions from Chinese and Caucasian individuals, providing PBK models for the average Chinese and average Caucasian, respectively. From the predicted in vivo dose-response curves, the benchmark dose lower and upper confidence limits for 5% effect (BMDL 5 and BMDU 5) were derived and subsequently compared to those previously obtained in rat to evaluate inter-species differences. The inter-species differences amounted to 2.0-fold for lasiocarpine and 8.2-fold for riddelliine with humans being more sensitive than rats. The inter-ethnic human differences varied 2.0-fold for lasiocarpine and 5.0-fold for riddelliine with the average Caucasian being more sensitive than the average Chinese. In conclusion, the present study provides the proof-of-principle to predict inter-species and inter-ethnic differences in in vivo liver toxicity for PAs by an alternative testing strategy integrating in vitro cytotoxicity data with PBK modelling-based reverse dosimetry.

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Section: Discussionmentioning

confidence: 96%

Use of an in vitro–in silico testing strategy to predict inter-species and inter-ethnic human differences in liver toxicity of the pyrrolizidine alkaloids lasiocarpine and riddelliine

et al. 2019

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“…Gerets et al (2012) reported that CYP 3A4 activity was about 17.0-fold lower in the HepaRG cells than in primary human hepatocytes from three different donors (Gerets et al 2012). However, Kvist et al (2018), and Lübberstedt et al (2011) who investigated the CYP 1A2, CYP 2B6, CYP 2C8, CYP 2C9, CYP 2C19, and CYP 2D6 activities in HepaRG cells and primary human hepatocytes, showed that these enzyme activities were generally lower in HepaRG cells than those in human hepatocytes, except for CYP 3A4 which showed a generally 1.5-fold higher activity in HepaRG cells (Kvist et al 2018;Lübberstedt et al 2011). We previously investigated the cytotoxicity of lasiocarpine and riddelliine in primary rat hepatocytes, primary human hepatocytes and HepaRG cells, providing an indirect measurement of the CYP-mediated bioactivation of these PAs in the different cell models.…”

Section: Discussionmentioning

confidence: 99%

Prediction of in vivo genotoxicity of lasiocarpine and riddelliine in rat liver using a combined in vitro-physiologically based kinetic modelling-facilitated reverse dosimetry approach

et al. 2019

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Pyrrolizidine alkaloids (PAs) are naturally occurring genotoxic compounds, and PA-containing plants can pose a risk to humans through contaminated food sources and herbal products. Upon metabolic activation, PAs can form DNA adducts, DNA and protein cross links, chromosomal aberrations, micronuclei, and DNA double-strand breaks. These genotoxic effects may induce gene mutations and play a role in the carcinogenesis of PAs. This study aims to predict in vivo genotoxicity for two well-studied PAs, lasiocarpine and riddelliine, in rat using in vitro genotoxicity data and physiologically based kinetic (PBK) modelling-based reverse dosimetry. The phosphorylation of histone protein H2AX was used as a quantitative surrogate endpoint for in vitro genotoxicity of lasiocarpine and riddelliine in primary rat hepatocytes and human HepaRG cells. The in vitro concentration-response curves obtained from primary rat hepatocytes were subsequently converted to in vivo doseresponse curves from which points of departure (PoDs) were derived that were compared to available in vivo genotoxicity data. The results showed that the predicted PoDs for lasiocarpine and riddelliine were comparable to in vivo genotoxicity data. It is concluded that this quantitative in vitro-in silico approach provides a method to predict in vivo genotoxicity for the large number of PAs for which in vivo genotoxicity data are lacking by integrating in vitro genotoxicity assays with PBK modelling-facilitated reverse dosimetry.

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“…To date, the most functional human liver cell line is the HepaRG cell line [25], which further differentiates by culturing in the AMC-BAL system [26]. Comparison of the transcriptomes of different proliferative sources of human liver cells showed that HepaRG cells most closely resembled primary human hepatocytes [24,27]. Further improvement of existing cell systems may be achieved by (conditional) ectopic expression of limiting regulatory or structural genes and by application of cell culture systems promoting maturation, e.g.…”

Section: Concluding Remarks Clinically Applied Cell-based Alssmentioning

confidence: 99%

End-stage liver failure: filling the treatment gap at the intensive care unit

Chamuleau

Hoekstra

2019

J Artif Organs

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End-stage liver failure is a condition of collapsing liver function with mortality rates up to 80. Liver transplantation is the only lifesaving therapy. There is an unmet need for therapy to extend the waiting time for liver transplantation or regeneration of the native liver. Here we review the state-of-the-art of non-cell based and cell-based artificial liver support systems, cell transplantation and plasma exchange, with the first therapy relying on detoxification, while the others aim to correct also other failing liver functions and/or modulate the immune response. Meta-analyses on the effect of non-cell based systems show contradictory outcomes for different types of albumin purification devices. For bioartificial livers proof of concept has been shown in animals with liver failure. However, large clinical trials with two different systems did not show a survival benefit. Two clinical trials with plasma exchange and one with transplantation of mesenchymal stem cells showed positive outcomes on survival. Detoxification therapies lack adequacy for most patients. Correction of additional liver functions, and also modulation of the immune system hold promise for future therapy of liver failure.

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Critical differences in drug metabolic properties of human hepatic cellular models, including primary human hepatocytes, stem cell derived hepatocytes, and hepatoma cell lines

Cited by 43 publications

References 39 publications

Use of an in vitro–in silico testing strategy to predict inter-species and inter-ethnic human differences in liver toxicity of the pyrrolizidine alkaloids lasiocarpine and riddelliine

Use of an in vitro–in silico testing strategy to predict inter-species and inter-ethnic human differences in liver toxicity of the pyrrolizidine alkaloids lasiocarpine and riddelliine

Prediction of in vivo genotoxicity of lasiocarpine and riddelliine in rat liver using a combined in vitro-physiologically based kinetic modelling-facilitated reverse dosimetry approach

End-stage liver failure: filling the treatment gap at the intensive care unit

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