title: Piperazine designer drugs induce toxicity in cardiomyoblast h9c2 cells through mitochondrial impairment.
abstract: 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 (μM) 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.
authors: REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal. Electronic address: m.arbo@terra.com.br.
authors: Marcelo Dutra
authors: MD
authors: Arbo
authors: REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal.
authors: Renata
authors: R
authors: Silva
authors: REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal.
authors: Daniel José
authors: DJ
authors: Barbosa
authors: REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal.
authors: Diana Dias
authors: DD
authors: da Silva
authors: REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal; Instituto de Ciências Biológicas, Curso de Farmácia, Universidade de Passo Fundo (UPF) Campus I, km 292, BR 285, Passo Fundo, Rio Grande do Sul 99052-900, Brazil.
authors: Luciana Grazziotin
authors: LG
authors: Rossato
authors: REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal.
authors: Maria de Lourdes
authors: Mde L
authors: Bastos
authors: REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal.
authors: Helena
authors: H
authors: Carmo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D015198:Designer Drugs / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000473:pathology*; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000473:pathology*; D009336:Necrosis / Q000473:pathology; D009499:Neutral Red; D010879:Piperazines / Q000633:toxicity*; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D004396:Coloring Agents; D015198:Designer Drugs; D010879:Piperazines; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D009499:Neutral Red; D000255:Adenosine Triphosphate; D005980:Glutathione Reductase; D053148:Caspase 3; C022616:thiazolyl blue; D005978:Glutathione; D002118:Calcium
keywords: Apoptosis; Ca(2+) overload; Mitochondrial impairment; Mitochondrial membrane potential; Mitochondrial permeability transition pore; Piperazine designer drugs