Hepatotoxicity of piperazine designer drugs: Comparison of different in vitro models

• Type: Article in International Scientific Journal
• Date: 2015

Authors

Dias da Silva, D (Author) Other; Arbo, MD (Author) Other; Valente, MJ (Author) Other; Bastos, ML (Author) FFUP; Carmo, H (Author) FFUP

Journal

Title: Toxicology in Vitro

Vol. 29

Pages: 987-996

ISSN: 0887-2333

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 14 Citations

Scopus - 22 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-00A-D3P

DOI: 10.1016/j.tiv.2015.04.001

Abstract (EN): Piperazine derived drugs emerged on the drug market in the last decade. The aim of this study was to investigate in vitro the potential hepatotoxicity of the designer drugs N-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), 1-(4-methoxyphenyl)piperazine (MeOPP) and 1-(3,4-methylenedioxybenzyl)piperazine (MDBP) in two human hepatic cell lines (HepaRG and HepG2) and in primary rat hepatocytes. Cell death was evaluated by the MIT assay, after 24 h-incubations. Among the tested drugs, TFMPP was the most cytotoxic. HepaRG cells and primary hepatocytes revealed to be the most and the least resistant cellular models, respectively. To ascertain whether the CYP450 metabolism could explain their higher susceptibility, primary hepatocytes were co-incubated with the piperazines and the CYP450 inhibitors metyrapone and quinidine, showing that CYP450-mediated metabolism contributes to the detoxification of these drugs. Additionally, the intracellular contents of reactive species, ATP, reduced (GSH) and oxidized (GSSG) glutathione, changes in mitochondrial membrane potential (Delta psi m) and caspase-3 activation were further evaluated in primary cells. Overall, an increase in reactive species formation, followed by intracellular GSH and ATP depletion, loss of Delta psi m and caspase-3 activation was observed for all piperazines, in a concentration-dependent manner. In conclusion, piperazine designer drugs produce hepatic detrimental effects that can vary in magnitude among the different analogues.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10