ToxSci Advance Access published July 3, 2016 TOXICOLOGICAL SCIENCES, 2016, 1–14 doi: 10.1093/toxsci/kfw105 Advance Access Publication Date: June 2, 2016 Research article Characterization of Hepatotoxicity Mechanisms Triggered by Designer Cathinone Drugs (b-Keto Amphetamines) Maria Joao~ Valente,* Ana Margarida Araujo,* Maria de Lourdes Bastos,* † Eduarda Fernandes, Fe´lix Carvalho,* Paula Guedes de Pinho,* Downloaded from Marcia Carvalho*,‡,1 *UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Porto, Portugal; †UCIBIO, REQUIMTE, Laboratory of Applied Chemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal; and ‡FP-ENAS, CEBIMED, Fundac¸ao~ Ensino e Cultura Fernando Pessoa, Porto, Portugal http://toxsci.oxfordjournals.org/ 1To whom correspondence should be addressed at FP-ENAS, CEBIMED, Fundac¸ao~ Ensino e Cultura Fernando Pessoa, PrauˆI¨a 9 de Abril, 349, 4249-004 Porto, Portugal. Fax: +351 225074630. E-mail address:
[email protected]. 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- by guest on July 4, 2016 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.