Piperazine designer drugs induce toxicity in cardiomyoblast h9c2 cells through mitochondrial impairment

被引:41
作者
Arbo, Marcelo Dutra [1 ]
Silva, Renata [1 ]
Barbosa, Daniel Jose [1 ]
da Silva, Diana Dias [1 ]
Rossato, Luciana Grazziotin [1 ,2 ]
Bastos, Maria de Lourdes [1 ]
Carmo, Helena [1 ]
机构
[1] Univ Porto, Fac Farm, Dept Ciencias Biol, REQUIMTE,Lab Toxicol, P-4050313 Oporto, Portugal
[2] Univ Passo Fundo, Curso Farm, Inst Ciencias Biol, BR-99052900 Passo Fundo, RS, Brazil
关键词
Piperazine designer drugs; Mitochondrial impairment; Ca2+ overload; Mitochondrial membrane potential; Apoptosis; Mitochondrial permeability transition pore; GAS CHROMATOGRAPHY/MASS SPECTROMETRY; PERMEABILITY TRANSITION PORE; IN-VITRO; PHARMACODYNAMIC PROFILE; TOXICOLOGICAL DETECTION; CYTOTOXICITY ASSAYS; OXIDATIVE STRESS; RAT URINE; METABOLISM; DEATH;
D O I
10.1016/j.toxlet.2014.06.031
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Abuse of synthetic drugs is widespread among young people worldwide. In this context, piperazine derived drugs recently appeared in the recreational drug market. Clinical studies and case-reports describe sympathomimetic effects including hypertension, tachycardia, and increased heart rate. Our aim was to investigate the cytotoxicity of N-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl) piperazine (TFMPP), 1-(4-methoxyphenyl) piperazine (MeOPP), and 1-(3,4-methylenedioxybenzyl) piperazine (MDBP) in the H9c2 rat cardiac cell line. Complete cytotoxicity curves were obtained at a 0-20 mM concentration range after 24 h incubations with each drug. The EC50 values (mu M) were 343.9, 59.6, 570.1, and 702.5 for BZP, TFMPP, MeOPP, and MDBP, respectively. There was no change in oxidative stress markers. However, a decrease in total GSH content was noted for MDBP, probably due to metabolic conjugation reactions. All drugs caused significant decreases in intracellular ATP, accompanied by increased intracellular calcium levels and a decrease in mitochondrial membrane potential that seems to involve the mitochondrial permeability transition pore. The cell death mode revealed early apoptotic cells and high number of cells undergoing secondary necrosis. Among the tested drugs, TFMPP seems to be the most potent cytotoxic compound. Overall, piperazine designer drugs are potentially cardiotoxic and support concerns on risks associated with the intake of these drugs. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
引用
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页码:178 / 189
页数:12
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