MDMA hepatotoxicity assessment in HepG2 cells using a 3D culture as an alternative to monolayer culture

Abstract

3,4-methylenedioxymethamphetamine is a synthetic drug that shows emphatogenic and hallucinogenic effects and whose use is often associated with raves and other party-related environments, especially in situations of simultaneous polidrug abuse. Although it has been already reported studies regarding its toxicity in vitro, the correlation between the effects observed in vivo is still the biggest hindrance to the use of these methodologies as a tool for a better understaning of its mechanism of action, therefore limiting the development of potential therapeutic approaches. Those studies, however, tend to use primary hepatocytes, which are expensive and of limited availability, or monolayer HepG2 cell cultures that are ilimited and quite more acessible, though its use is limited by the low expression of phase I drug metabolism enzymes and of the CYP450 complex enzymes, which makes the results obtained using this method questionable when compared to those in vivo. Nevertheless, there is a gap between the available in vitro models to preliminarly access the hepatotoxicity of drugs of abuse - and other xenobiotics -, and the animal models, that must be filled. In this context, 3D cell culture appears to be a potential candidate, showcasing the ability to mimic the in vivo environment by reaquiring hepatic properties lost in the imortalization process. The validation of this methodology as an alternative to evaluate the MDMA induced hepatotoxicity in HepG2 cells is the aim of this project and, if sucessful, can represent a new approach to the toxicity assessment of NPSs. (AU)