Influence of bile acids on the cytotoxicity of chemicals in cultivated human hepatocytes

Bile acids (BA) are known to influence the susceptibility of hepatocytes to chemicals. We investigated the cytotoxicity of 18 compounds with known hepatotoxicity status and pharmacokinetics in cultivated primary human hepatocytes with and without the addition of a BA mix to the cell culture medium....

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Published in:Toxicology in vitro 2022-06, Vol.81, p.105344-105344, Article 105344
Main Authors: Brecklinghaus, Tim, Albrecht, Wiebke, Kappenberg, Franziska, Duda, Julia, Zhang, Mian, Gardner, Iain, Marchan, Rosemarie, Ghallab, Ahmed, Demirci Turgunbayer, Özlem, Rahnenführer, Jörg, Hengstler, Jan G.
Format: Article
Language:English
Subjects:
Atorvastatin
Bile acids
Bile Acids and Salts
Cell culture
Cell Culture Techniques
Cells, Cultured
Chemicals
Chenodeoxycholic acid (CDCA)
Cholestasis
Cyclosporin A
Cytotoxicity
Deoxycholic acid (DCA)
DILI
Glycochenodeoxycolic acid (GCDCA)
Glycocholic acid (GCA)
Glycodeoxycholic acid (GDCA)
Hepatocytes
Hepatotoxicity
Humans
In vitro methods and tests
Ketoconazole
Pharmacokinetics
Rifampin
Toxicity
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Summary:Bile acids (BA) are known to influence the susceptibility of hepatocytes to chemicals. We investigated the cytotoxicity of 18 compounds with known hepatotoxicity status and pharmacokinetics in cultivated primary human hepatocytes with and without the addition of a BA mix to the cell culture medium. This BA mix consisted of physiological ratios of the most abundant human BA at a cholestatic sum concentration of 0.5 mM, which corresponds to 50% of the EC10 (cytotoxicity) of the mix. The BA mix decreased the EC10 of 7 compounds by a factor greater than 1.5, but also increased the EC10 of 5 compounds. The compounds with increased susceptibility include the known hepatotoxicants and BSEP/MRP2 inhibitors rifampicin, ketoconazole, atorvastatin, and cyclosporin A. However, the cytotoxicity of some non-hepatotoxic compounds was also enhanced, among them glucose, which is not known to be an inhibitor of canalicular bile acid export. A recently established technique to quantify how well hepatotoxic and non-hepatotoxic compounds are separated by an in vitro test indicated that the addition of the BA mix did not improve separation. In conclusion, the addition of BA to cultivated hepatocytes leads to a complex situation with increased and decreased susceptibilities depending on the specific compound. •Addition of a bile acid mix to the culture medium influences the susceptibility of human hepatocytes to chemicals.•Increase in susceptibility were obtained for rifampicin, ketoconazole and glucose.•Increases in resistance occurred for ethanol, melatonin and acetaminophen.
ISSN:0887-2333
1879-3177
DOI:10.1016/j.tiv.2022.105344