title: Editor's Highlight: Characterization of Hepatotoxicity Mechanisms Triggered by Designer Cathinone Drugs (β-Keto Amphetamines).
abstract: The use of cathinone designer drugs in recreational settings has been associated with severe toxic effects, including liver damage. The precise mechanisms by which cathinones induce hepatotoxicity and whether they act by common pathways remain to be elucidated. Herein, we assessed the toxicity of the cathinones methylone, pentedrone, 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylethcathinone (4-MEC) in primary rat hepatocytes (PRH) and HepaRG cells, and compared with that of 3,4-methylenedioxymethamphetamine (MDMA). MDPV and pentedrone were significantly more toxic than MDMA, while methylone was the least cytotoxic compound. Importantly, PRH revealed to be the most sensitive experimental model and was thus used to explore the mechanisms underlying the observed toxicity. All drugs elicited the formation of reactive oxygen and nitrogen species (ROS and RNS), but more markedly for methylone, pentedrone and 4-MEC. GSH depletion was also a common effect at the highest concentration tested, whereas only MDPV and pentedrone caused a significant decrease in ATP levels. The antioxidants ascorbic acid or N-acetyl-L-cysteine partially attenuated the observed cell death. All cathinones triggered significant caspase activation and apoptosis, which was partially reversed by the caspase inhibitor Ac-LETD-CHO. In conclusion, the present data shows that (1) cathinones induce in vitro hepatotoxic effects that vary in magnitude among the different analogues, (2) oxidative stress and mitochondrial dysfunction play a role in cathinones-induced hepatic injury, and (3) apoptosis appears to be an important pathway of cell death elicited by these novel drugs.
authors.affiliation: *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Porto, Portugal; mcarv@ufp.edu.pt.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Valente
authors.affiliation: *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Porto, Portugal;
authors.forename: Ana Margarida
authors.initials: AM
authors.lastname: Araújo
authors.affiliation: *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Porto, Portugal;
authors.forename: Maria de Lourdes
authors.initials: Mde L
authors.lastname: Bastos
authors.affiliation: UCIBIO, REQUIMTE, Laboratory of Applied Chemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal;
authors.forename: Eduarda
authors.initials: E
authors.lastname: Fernandes
authors.affiliation: *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Porto, Portugal;
authors.forename: Félix
authors.initials: F
authors.lastname: Carvalho
authors.affiliation: *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Porto, Portugal;
authors.forename: Paula
authors.initials: P
authors.lastname: Guedes de Pinho
authors.affiliation: *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Porto, Portugal; FP-ENAS, CEBIMED, Fundação Ensino e Cultura Fernando Pessoa, Porto, Portugal mcarv@ufp.edu.pt.
authors.forename: Márcia
authors.initials: M
authors.lastname: Carvalho
mesh_terms: D000470:Alkaloids / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D015198:Designer Drugs / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D008297:Male; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000470:Alkaloids; D000975:Antioxidants; D015198:Designer Drugs; C023665:cathinone
keywords: apoptosis; hepatotoxicity; oxidative stress; synthetic cathinones; β-keto amphetamines