Five key events* characterize constitutive androstane receptor (CAR) mediated liver carcinogenesis in rats, a process which is not human-relevant. Using SpheroMatrices technology, we have tested whether these events can be detected in 3D rat liver microtissues vs human liver microtissues.

We treated rat and human liver microtissues with the prototypical CAR activator phenobarbital (PB)  over a range of doses and times in a dose response/time course analysis.  We observed  dose- and time-dependent hepatocyte proliferation in the rat but not the human liver microtissues, and the response was maintained over a time span similar to the in vivo situation, unlike 2D hepatocyte cultures which rapidly lose this response.

Transcriptomic and proteomic analyses demonstrated  dose and time dependent PB-mediated induction of CAR regulated genes in both rat and human microtissues indicating CAR was functional and activated in both species microtissues.

This breakthrough study showed expected responses for 3/5 of the key events, indicating the 3D LiMT models are fit for the purpose of assessing several key events necessary for establishing a CAR-mediated MOA for rat liver tumours and for assessing the human relevance of this response. Using  an in vitro model that is more relevant to in vivo will reduce the need to use of animals for this purpose.

This work will be published later this year and presented at  Eurotox Helsinki September 2019.

*Key events: (1) activation of the CAR receptor; (2) altered gene expression; (3) hepatocellular proliferation; (4) clonal expansion; (5) increased hepatocellular adenomas/carcinomas.

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