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

Autor: Kvist AJ; IMED Operations Project Management, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. Electronic address: Alexander.Kvist@astrazeneca.com., Kanebratt KP; Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Walentinsson A; Translational Sciences, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Palmgren H; Bioscience Diabetes, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., O'Hara M; University Health Network, Toronto, Ontario, Canada., Björkbom A; Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Andersson LC; Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Ahlqvist M; Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden., Andersson TB; Drug Metabolism and Pharmacokinetics, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden; Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2018 Sep; Vol. 155, pp. 124-140. Date of Electronic Publication: 2018 Jun 25.
DOI: 10.1016/j.bcp.2018.06.026
Abstrakt: Primary human hepatocytes (PHH), HepaRG™, HepG2, and two sources of induced pluripotent stem cell (iPSC) derived hepatocytes were characterized regarding gene expression and function of key hepatic proteins, important for the metabolic fate of drugs. The gene expression PCA analysis showed a distance between the two iPSC derived hepatocytes as well as the HepG2 and HepaRG™ cells to the three PHH donors and PHH pool, which were clustered more closely together. Correlation-based hierarchical analysis clustered HepG2 close to the stem cell derived hepatocytes both when the expression of 91 genes related to liver function or only cytochrome P450 (P450) genes were analyzed indicating the non-liver feature and a similar low P450 profile in these cell models. The specific P450 activities and the metabolic pattern of well-characterized drug substances in the cell models demonstrated that iPSC derived hepatocytes had modest levels of CYP3A and CYP2C9, while CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 were barely detectable. High expression of several extrahepatic P450s such as CYP1A1 and 1B1 detected in the stem cell derived hepatocytes may have significant effects on metabolite profiles. However, one of the iPSC derived hepatocytes demonstrated significant combined P450 and conjugating enzyme activity of certain drugs. HepaRG™ cells showed many metabolic properties similar to PHHs and will in many respects be a good model in studies of metabolic pathways and induction of drug metabolism whereas there is still ground to cover before iPSC derived hepatocytes will be seen as a substitute to PHH in drug metabolism studies.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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