Inter-individual differences in the susceptibility of primary human hepatocytes towards the cholestatic drug hepatotoxicity are compound and time dependent.

Fiche publication

Date publication

juin 2018

Journal

Toxicology letters

Auteurs

Membres identifiés du Cancéropôle Est :
Pr BACHELLIER Philippe , Pr HEYD Bruno

Tous les auteurs :
Parmentier C, Hendriks DFG, Heyd B, Bachellier P, Ingelman-Sundberg M, Richert L

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/29913214

Résumé

Cholestasis represents a major subtype of drug-induced liver injury and novel preclinical models for its prediction are needed. Here we used primary human hepatocytes (PHH) from different donors in 2D-sandwich (2D-sw) and/or 3D-spheroid cultures to study inter-individual differences in response towards cholestatic hepatotoxins after short-term (48-72 h) and long-term repeated exposures (14 days). Cholestatic liabilities were determined by comparing cell viability upon exposure to the highest non-cytotoxic drug concentration in the presence and absence of a non-cytotoxic concentrated bile acid (BA) mixture. In 2D-sw culture, cyclosporine A and amiodarone presented clear cholestatic liabilities in all four PHH donors tested, whereas differences in the susceptibility of the various PHH donors towards the cholestatic toxicity of bosentan, chlorpromazine and troglitazone were observed. When PHH from one donor in which the cholestatic toxicity of chlorpromazine and troglitazone were not detected after a short-term exposure in 2D-sw culture, were maintained in 3D-spheroid culture, the cholestatic toxicity of chlorpromazine and troglitazone was only detected upon long-term repeated exposures, suggesting that cholestatic hepatotoxicity may require time to develop. In conclusion, inter-individual susceptibility exists towards drug-induced cholestasis, which depends on the choice of compounds as well as the exposure time.