Exploring the bioavailability and hepatotoxic effects of psychoactive chloro-cathinones.

Synthetic cathinones have emerged as the second-largest class of New Psychoactive Substances (NPS) reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Consumers have access to a wide array of cathinones with diverse structural features that attempt to replicate the effects of illicit psychostimulant drugs. However, this class of NPS poses considerable health risks due to the lack of information on the physiological consequences of their consumption. Based on reported cases of fatalities and liver damage associated with the intake of cathinones, our primary objective is to investigate the effect of their structural features on potential hepatic complications. Additionally, we aim to provide information on their bioavailability through oral ingestion, which is the predominant route of cathinones administration.

Therefore, 20 chloro-cathinones where synthetised, including several structural isomers, which differ in the amino group and/or the position of the chlorine atom in the aromatic ring (ortho, meta and para regioisomers). Their hepatotoxicity was evaluated in vitro using the hepatic cell line HepG2. The most hepatotoxic cathinones were then assessed for their cytotoxicity in the intestinal Caco-2 cell line to determine their gastrointestinal barrier permeability using an in vitro model of the intestinal lining with differentiated Caco 2 cells. All cytotoxic studies were performed with the MTT assay in the range of 0.1-10 mM. 

The LC50 values obtained for the cathinones tested in liver cells highlighted variations in their cytotoxic behaviour associated with their structural differences. Suggesting that the toxicity increases with the length of the N-alkyl chain of the amino group. Significant differences in the cytotoxicity were also observed between the majority of regioisomers. The most hepatotoxic cathinones showed moderate permeability across the intestinal barrier.

Our results represent the first evidence on the permeability of hepatotoxic chloro-cathinones, aiming to shed light on potential health risks that could result from their consumption. 

Authors acknowledge Fundação para a Ciência e Tecnologia (FCT) for funding the projects: UIDB/00100/2020 (DOI: 10.54499/UIDB/00100/2020) and UIDP/00100/2020 (DOI:10.54499/UIDP/00100/2020) to Centro de Química Estrutural, LA/P/0056/2020 (DOI 10.54499/LA/P/0056/2020) to the Associate Laboratory Institute of Molecular Sciences; UIDB/04046/2020 (DOI:10.54499/UIDB/04046/2020) and UIDP/04046/2020 (DOI: 10.54499/UIDP/04046/2020) to BioISI-Biosystems & Integrative Sciences Institute.